The human immune system has been evolving for millions of years in a race against pathogens that it now seems doomed to lose. Due to their drastically shorter life cycle and the sheer number we are constantly exposed to, it would be virtually impossible for humans to evolve a defence against every pathogen. Whilst we have developed a complicated and well functioning immune system that can defend against many pathogens and build memory in case of future exposure, this memory is often not heritable and there are still some pathogens that have outsmarted us. For this reason, scientists have spent centuries attempting to invent new ways to kill pathogens that would otherwise kill large numbers of humans due to their ability to evade or alter immune cells. This research has culminated in the invention of vaccines, which are highly effective at protecting us against individual pathogens. Whilst vaccines are something upon which we heavily depend, they are not perfect. It is critical for researchers to study their impacts for us to ensure that their benefits outweigh their costs.
I. Introduction: The Basic Tenets of Evolution
In biology, the theory of evolution is based upon the idea that organisms change over time due to the heritable traits encoded in their genes. Organisms with advantageous traits tend to pass down more genes due to their increased fitness. The key mechanisms that drive evolution are mutation, random mating, gene flow, genetic drift, and natural selection. Over time, the ratio of the various genetic types changes because of these mechanisms, and the population as a whole evolves. Evolution creates the diversity and complexity of our world today.
The theory of natural selection plays a key role as a guiding force for evolution. Natural selection forces a species to adapt due to selective pressures, whereby advantageous traits are selected for by competition over resources, predation, or the spread of pathogens. More fit organisms have a higher chance of surviving and reproducing. Variations in fitness come from variation in genotype, and this variation arises from random mutation and genetic diversity. The overall outcome of natural selection drives evolution, which is the accumulation of diversity over time .
An interesting byproduct of evolution is analogous features, which are features shared by multiple species but that arose independently through convergent evolution. The presence of analogous features indicates that they provide a large fitness advantage to diverse species that face the same selective pressures. Through scientific observation, we can obtain evidence to support evolution as it takes place in front of us. For example, individuals can inherit alleles that provide resistance to certain pathogens or otherwise aid in survival. Their offspring will benefit from this increased fitness and over time so will the population as a whole. However, certain biological entities such as viruses and bacteria evolve much more quickly than species such as humans due to their shorter life cycles. This creates a situation in which it is almost impossible for a species to evolve resistance to the pathogens that attack it .
II. The War on Pathogens
Many different types of pathogens attack living creatures ranging from bacteria to humans. These pathogens include viruses, bacteria, multicellular parasites, and more. Bacteria are single-celled organisms that carry circular molecules of DNA and reproduce by the process of binary fission, the transfer of genetic material, or by creating spores. Whilst helpful bacteria contribute to the regulation of our immune system, certain species of bacteria can evade the immune system’s proper response and begin growing uncontrollably, which results in disease. Infections through bacteria are generally due to exposure to the pathogen in one’s environment. Once inside the body, the rapid rate in which bacteria multiply may cause severe damage and perturb the normal function of the body and its cells. For example, an overproduction of toxins that certain bacteria produce may destroy tissue and cell machinery .
Viruses are another infectious agent which are responsible for a vast array of diseases. Unlike bacteria, a virus must use its machinery as well as a host cell to replicate. Viruses have evolved to efficiently create as many copies of themselves as possible to continuously infect new host cells and hosts. The life cycle of a virus begins with attachment, where it binds to the surface of a host cell and certain receptors via a capsid protein. This interaction between the virus and the specific receptors on the host cell determines the range of infectiousness for the virus. Once attached, the process of viral entry occurs and the viral genomic nucleic acid enters the host cell. The virus is then able to hijack the cell’s machinery and create copies of itself. Eventually, the new copies of the virus can leave the cell, either by killing the cell or exiting through the membrane and continuing to infect other cells . Viruses are also able to spread through exposure as well and avoid eradication by overriding the checkpoints of the immune system. Over time, as these pathogens adapt to survive under different circumstances they improve their ability to persist against an immune response. The most contagious viruses, such as HIV, measles, and plague, have adapted to disarm the immune system which is the host’s main line of defence. By circumventing the immune response, whether through killing memory cells to cause immune amnesia, infiltrating immune cells, or causing it to malfunction, pathogens with these types of attack mechanisms have been able to establish themselves as highly contagious . This is an excellent example of analogous features that arose in multiple pathogens through convergent evolution .
The presence of pathogens has led to a biological arms race in which species must evolve resistance to pathogens, whilst those pathogens simultaneously try to evolve to overcome that resistance. This biological arms race is essentially a coevolutionary competition between species for survival. This results in a situation where species are constantly changing, but relative to their rivals, they don’t get any more fit . Mechanisms of resistance to pathogens range from simple to quite complex. One exceedingly complex yet effective resistance mechanism that evolved approximately 500 million years ago was the development of an immune system that can respond to individual pathogens and protect the host from being killed .
The earliest immune system precursors evolved in the Proterozoic eon. As evolution continued, the immune system grew increasingly complex and split into the adaptive and innate immune systems found in present-day mammals approximately 500 million years ago. The human immune system is a diverse set of cells capable of responding to a variety of pathogens in a highly specialized manner. It includes cells such as B cells, T cells, macrophages, signaling cells, neutrophils, dendritic cells, natural killer cells, and granulocytes. Once the immune system recognizes an unknown antigen or a foreign body, it first triggers the innate immune system as its first line of defence. The adaptive immune system then arrives as a secondary response to enhance the immune response and generate memory against future exposure to the same pathogen. However, this process is delayed and the adaptive immune response tends to take several days to identify the antigen and produce antibodies. Both components of the immune system work together to combat these invaders, but each has specialized skills to take on particular tasks.
The innate immune system works as a primary response towards invaders. It is the first part of the body to recognize the invader and all animals rely on it to help control disease during the stages of early exposure. Innate immunity is composed of various components such as physical barriers, chemical barriers, phagocytes, and leukocytes. Once the pathogen enters the body, the innate immune system employs several of its mechanisms to combat it and reduce harm. In the early stages of infection when the pathogens are first present in the bloodstream, leukocytes can detect its presence and its pathogen-associated molecular pattern (PAMP). Pathogens possess a range of structurally diverse PAMPs and once they are recognized, the immune system can designate it as a target, allowing it to differentiate to avoid attacking host cells. Cells such as dendritic cells and macrophages are then able to detect these PAMPs using pattern recognition receptors (PRR) to help recognize these pathogens. Once these PRRs bind to the PAMPs, cytokines are released into circulation and act as messengers and send signals to target immune cells to initiate a specific response attack. They trigger defence mechanisms such as natural killer cells, macrophages, neutrophils, and inflammatory response to the site of infection. By fighting the infection at an early stage, the innate immune system can actively slow the spread of the foreign bodies .
The adaptive immune system is the secondary response to the exposure of a foreign pathogen if the innate immune system is unable to fully combat it. Unlike the innate immune system, the adaptive immune system can use immunological memory to learn to recognize the threat and enhance its response if it happens to encounter the same pathogen in the future. This memory allows adaptive immunity to be highly specific, allowing it to identify the differences in various pathogen structures.
The major cells involved in the adaptive immune system are B and T lymphocytes. B cells originate in bone marrow, where they begin to mature until they move into the lymphatic system to circulate throughout the body and encounter antigens. B cells express receptors that assist in antigen-binding as well as internalization and processing of the antigen. Once the antigen is processed, several cell signaling pathways are initiated. These pathways depend on whether the cell is a plasma or memory cell. Plasma B cells are activated by T cells and can secrete antibodies specific to antigens after binding to their target. Various B cells are then transformed into memory cells where they maintain the same antibody structure from the first response to the pathogen to form a faster immune response the next time it is encountered. Regulatory B cells also ensure that an autoimmune disorder does not arise during an immune response .
T cells mature in the thymus and come in the form of helper, cytotoxic cells, or regulatory cells in the immune response along with B cells. They originate in the bone marrow as well and move to the thymus to mature and develop receptors such as CD4, CD8, and the highly specialized T cell receptor (TCR). TCRs are only able to identify an antigen when it is attached to a membrane-bound receptor molecule, the Major Histocompatibility Complex class 1 (MHCI) or 2 (MHC II). Each T cell expresses a TCR to target an antigen, and either the CD4 or CD8 co-receptor attaches to MHCI or MHC II to activate the T cell response. The CD4 co-receptor is associated with helper and regulatory T cells. Regulatory T cells help in the process of identifying between foreign and host cells to avoid autoimmune disease. Their function also regulates helper T cells to suppress any dysfunctional activity. Helper T cells support the immune system by controlling the adaptive immune response. They activate various immune cells such as cytotoxic T cells and B cells to initiate a specific response. Lastly, cytotoxic T cells are associated with the CD8 receptor and release cytotoxic material to eliminate the infectious cells. Cytotoxic cells help in the administration of cell-mediated immunity .
When in the early stages of development in the thymus, diversity in the B cell antibodies and T cell receptors is generated through genetic recombination, allowing for a broad range of binding diversity. The process of DNA rearrangement is similar for both B and T cells. They undergo V(D)J recombination in which their gene segments are randomly assembled (figure 1). With each rearrangement, a unique antigen receptor is formed that should mount an appropriate immune response when activated. A successful rearrangement results in advanced antigen recognition, diverse antibodies, as well as benefiting the development of the immune cells. However, it carries a risk of forming an autoimmune disorder if the rearrangement configuration causes the cell to be unable to differentiate between a self cell and a foreign pathogen . Checkpoints are placed in the immune system to eliminate abnormal cells but are not always guaranteed in protection against autoimmune diseases. The process of V(D)J recombination is an essential contributor to the diversity of our immune system and enables individual cells to evolve to target a broad, but not limitless, set of antigens.
Figure 1: V(D)J Recombination Takes Place within the BCR and TCR loci
The most important and unique function of the adaptive immune system is its ability to hold immunological memory and provide protection if exposed to the same pathogen. Its memory is activated by exposure to pathogens and the immune system uses this memory to learn about the threat and enhance its response for the future. When first exposed to a disease, these memory cells, a type of T or B cell, hold information about the pathogen, which allows them to produce antibodies or kill virally infected cells at a faster rate after re-exposure. They can recognize specific antigens and reduce the time in which the adaptive immune system initiates its response. B lymphocytes create antibodies to attack the antigens, and if the germ is detected in the body again, these memory B cells can quickly produce antibodies for the attack. After fighting a disease, some T lymphocytes are left behind as memory cells. Therefore, if the body encounters the pathogen again, the T cells are able to recognize it at a faster rate . Immunological memory can also be gained through modern practices such as the use of vaccines and serum antibodies, where a part of the pathogen is exposed to the body in a controlled manner to gain memory from the disease and improve the immune response in case the host encounters the pathogen.
An unfortunate disadvantage of the memories one gains when exposed to diseases is that they are unique to oneself and are not able to be passed down to children as inherited immunity. This is because V(D)J recombination occurs in individual B or T cells, but not the genes contained within eggs or sperm. However, for newborns who lack any immune memory whatsoever, there is an exception to this rule. When a child is born, they gain a form of passive immunity through nursing in which the mother passes on her antibodies to her child in breastmilk. Passive immunity is only a temporary shield against diseases. After several weeks, this immunity begins to decline and they begin to rely on vaccinations and growing immunity from exposure to microbes for protection. No matter how broad of a range the mother has evolved of immune memory cells, their child is left with a blank slate of immune memory and is forced to build its immunity . Therefore, the evolution of the immune system in one human does not lead to the evolution or change in others and the fitness that one gains in their lifetime is not heritable. Over time, the subtle changes in the basic functionality of the immune system are what have evolved to cause increased susceptibility or resistance to certain pathogens, but the highly effective adaptive immune responses that evolve in one individual cause no net improvement to the resistance of a species as a whole. The functionality of the immune system as a whole is heritable, but the adaptive memory that you gain with exposure to pathogens is not. This means that pathogens can evolve quicker than us because we begin the process anew with each new generation, while they are continually evolving to outsmart our immune system and they have a much shorter life cycle.
An example of the way immune functionality can be inherited is increased susceptibility to pathogens in the case of genetic immune defects. These immune disorders are generally linked to genes that encode proteins critical for the proper function of immune cells. Examples of heritable immune disorders are autoimmune diseases, trouble fighting infections, and frequent infection. People with immune system disorders tend to rely on modern technology to alleviate symptoms that may arise, making them extremely vulnerable if the amount of drug-resistant pathogens increases or if there is a novel global pandemic for which we have no treatment .
Our immune cells can fend off almost all pathogens that humans come into contact with. Additionally, we use tools such as antibiotics and cleaning products to defend from bacteria that are present in our day to day environment. However, our increased reliance on these may be leading to decreased overall fitness or increased fitness of the pathogens we encounter. As today’s modern-day society places a great emphasis on cleanliness and sanitation, this affects our immune system and its capability to learn how to defend against certain pathogens from a young age. This phenomenon can be explained by the hygiene hypothesis, which observes that children who are not exposed to sufficient microbes at a young age are more susceptible to pathogens they may encounter in the future. When a child is unable to develop an early immune memory, the immune system may overreact when exposed to new pathogens as it is not prepared to combat them. The hygiene hypothesis directs its attention towards an emphasis on building the immune system at a young age. Since immunity is built and not inherited, the microbes in a young child\’s environment play a key role during development. Fortunately, this theorized decreased fitness in a cleaner world is not heritable as it is not related to the inherent immune system function .
Several pathogens can be considered to have won the evolutionary arms race against us, as evidenced by their lethality and infectiousness. One reason that we live in such a clean world is the existence of pathogens that have evolved more successfully than our immune system. We rely on harsh chemicals and antibiotics to reduce exposure to these potentially deadly pathogens. However, the overuse and misuse of antibiotics have influenced our susceptibility as it has led to an increase in the prevalence of drug-resistant pathogens. When antibiotics are prescribed, the survivors of the pathogen that don’t respond to the drug can continue multiplying and spreading. This increases the amount of drug-resistant germs and inefficient medication. Resistance has been observed in almost all antibiotics that have been produced, and as pathogens continue to evolve to evade medication, scientists and the pharmaceutical industry must combat this by racing to create more effective antibiotics. Because antibiotics now tend to have a shorter lifespan of effectiveness, the investment of developing new antibiotics is not seen as wise by pharmaceutical companies, which creates a problem when it is necessary to race against the rapidly evolving pathogens, and human lives are at stake. To slow drug resistance, doctors are now being pressured to use antibiotics as a last resort to prevent the catastrophic consequences of a large range of drug-resistant pathogens . Because today’s immune systems heavily rely on antibiotics, there could be devastating consequences if the amount of drug-resistant pathogens continues to grow. Antibiotic resistance, as well as the resistance of fungi and parasites to common pesticides, is expected to become a huge problem by 2050 if it is not addressed properly in the near future (figure 2).
Figure 2: Deaths attributable to antibiotic resistance every year by 2050
In addition to bacteria evolving resistance to antibiotics, viruses have also evolved resistance to our immune system. Some examples of these are HIV, Smallpox, Zika virus, and Measles. These superbugs have convergently evolved under similar pressures to be able to take advantage of and manipulate the immune system to survive. They tend to target immune cells that help fight infection in the body, such as B and T cells. By targeting these immune cells, the immune system becomes weakened to a point where it is unable to combat disease as it is essentially fighting against itself. This makes it onerous to eliminate the pathogen from the body as it evades the normal immune system mechanisms. Some viruses, like measles, are also capable of immunosuppression, a hazardous side effect. The measles virus infects memory T and B cells, leading to immune-mediated destruction of these memory cells. This immune abnormality causes one to lose their immune memory, a unique but deadly ability of the virus. Due to this immune amnesia, many patients have a high risk of mortality after the disease as they no longer have the antibodies and protective memory they once formed .
III. A New Weapon: Vaccines
Due to the invention of antibiotics, the immune system is not outmatched when fighting certain bacterial pathogens. They have been a major contribution and advancement in the field of medicine and technology. However, the fact that they often lead to resistance is an extremely impactful consequence that should be avoided whenever possible. As an alternative to antibiotics, another option to fend off pathogens is to generate immunity before exposure, rather than attempting to reverse an infection that has already begun. Thankfully, humans evolved a tool that enables us to keep up with the increased evolutionary rate of our pathogens even when our immune system or antibiotics are incapable of it. That tool is our brain, which has allowed us to invent a wide range of biotechnology, including vaccines.
The first recorded vaccination was performed in 1796 using cowpox inoculation, and vaccination has since developed into a modern-day necessity . Vaccines train the immune system to recognize and combat pathogens by taking advantage of the immune memory cells to build memory and immunity from the antigen. When administering a vaccine, typically an antigen from the pathogen is introduced into the body to provoke an immune response. The adaptive immune system is then able to produce specific antibodies for the antigen so it can initiate a stronger and faster response if exposed to the pathogen, preventing the development of severe symptoms. Unfortunately, some rapidly evolving viruses are capable of adapting and growing into several strains, which means new vaccines are constantly being created to keep up in this race . Over time, if a virus can quickly adapt, the vaccines produced provide only limited protection. An example of a rapidly evolving virus is influenza, transforming into several types of strains each year (figure 3). Due to its rapid evolution, influenza requires a new vaccine frequently to combat the spread. Influenza-associated deaths have been estimated to be from 12,000 to 79,000 people in the United States when the vaccine is administered, stressing the importance for people to receive the vaccine to prevent a greater amount of deaths .
Figure 3: Phylogeographic reconstruction and spatial history of the trunk lineage representing the evolutionary lineage of influenza strains from 2000 to 2007
Early vaccines had mainly been based upon trial and error, but now scientists are able to build upon and use knowledge of microbiology, cell biology, and mechanisms of immunity and infection to create vaccines. There are several types of vaccines that have saved many lives, and as biotechnology progresses, the efficacy of vaccines has increased as well. Some examples of today’s vaccines include live attenuated vaccines, inactivated vaccines, subunit vaccines, conjugate vaccines, and toxoid vaccines. The most common classification of vaccines administered today are live attenuated and inactivated vaccines. Live attenuated vaccines introduce a weakened form of the virus into the body to create antibodies. This form of vaccine is not issued to patients with weakened immune systems as this type of vaccine still holds the risk of mutating into a pathogenic form of the virus. However, many live vaccines only require 1 to 2 doses for lifelong immunity. Examples of diseases which have been combated with live attenuated vaccines are measles, chickenpox, influenza, and mumps.
The risk of the live vaccine mutating into a pathogenic form has led to the development of inactivated or non-live vaccines. Non-live vaccines are a chemically killed form of the pathogen or some of its antigens, which diminishes the chance of an adverse reaction because the vaccine is incapable of mutating or proliferating. The dead cells are introduced into the body and prompt an immune response, similar to but weaker than live vaccines, to create memory cells. Since inactivated vaccines are unable to mimic the actual disease and its potency, many of them require several doses to build immunity. Currently, inactivated vaccines are the preferred type of vaccines amongst doctors as it appears to hold the least health risks .
Vaccines are an essential part of humanity’s healthcare regimen since childhood. Immunization reduces future burden on our immune system by obtaining immunity without major risk. Whilst vaccination appears to be helpful only on an individual level, it contributes to society as a whole in an extremely helpful way. Vaccines don’t work simply on an individual. They are able to protect entire groups, including people whose immune systems do not function properly, by building herd immunity. To achieve herd immunity, a large percent of the population must have immunity to a specific disease. This allows the population to be able to control the spread of the virus as well as protect those who are unable to receive the vaccine. The use of vaccines and herd immunity has been effective in eradicating both smallpox and rinderpest in the recent past. As the population continues to receive vaccines, society can push towards targeting eradicable diseases, which would have significant economic and societal benefits as well. Vaccines are of high importance in today\’s world, especially during a pandemic. In 2020 the world has seen the outcome and consequence of not having a vaccine or defence mechanism against a novel virus, which emphasizes the remarkable significance modern medicine holds .
Unfortunately, the use of vaccines can sometimes be a complicated issue. Recently, inactivated vaccines have been observed to have unfavorable nonspecific effects on one’s health in developing countries. A recent study in Guinea-Bissau by Dr. Christine Stabell Benn has led to shocking conclusions about the side effects of these inactivated vaccines. Non-live vaccines have become favored by doctors and are administered around the world as they have no risk of recreating the original disease. However, these non-live vaccines have non-specific effects that may cause the immune system to be underprepared when fighting other diseases. In Dr. Benn\’s investigation, a consistent pattern appeared where inactivated vaccines were associated with a higher percentage of negative health effects, sometimes leading to death. These findings were similarly replicated in more affluent countries, but they only affected hospitalization rates, not mortality. Previous research has proved that the immune system is receptive to the order in which we obtain vaccinations. Whilst inactivated vaccines may be slightly detrimental to overall health, they are still able to be used without the detrimental effects as long as a live vaccine is administered at the end of each immunization set. These non-specific effects prove that the perception of vaccines must be broadened. Whilst vaccines are extremely important today, the overall effect of vaccines on society and their specific as well as non-specific effects must be researched through various perspectives. Today, this research creates a battle between outweighing the positive and negative effects of non-live vaccines. Vaccines are not a perfect protective force, but they have undoubtedly saved more people than they have killed. We can potentially solve the complex issue of non-specific vaccine effects by studying the long-term cumulative effects of vaccines .
Over time, evolution has succeeded in making certain pathogens highly effective at infecting humans. The gene pool of humanity today continues to compete in a race in which it is outpaced by constantly evolving pathogens, but fortunately, our survival is aided by the use of vaccines. When combined with practices such as improved hygiene, communities have been able to build individual and herd immunity to protect against diseases. As the medical and biotechnology fields continue to grow, and the defence mechanisms we invent against deadly pathogens become increasingly efficient and specific, humanity has achieved something extremely unusual. These modern advances enable us to evolve as a species longer than one would otherwise expect as we are no longer more fit than some of the organisms we are competing against. In the conventional sense, there is no longer a selective pressure that tends to guide our path of evolution. However, we do not need this selective pressure to maintain our fitness so long as we continue to invent, carefully study, and distribute new vaccines as quickly as new pathogens arise.
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VI. Figure References
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About the author
Jenovia Mistry is a STEM-focused 17-year-old student. Her interests are centered around researching modern biotechnology techniques as well as human evolution. She is also interested in studying the future advancements and applications of computer science in the biology field. Jenovia has always had a passion for learning and is eager to further explore the life sciences field.