Terry M. Bella
Despite the highly efficient and capable immune system of the human, we still get sick. What will be discussed in this section is how and why disease is prevalent. Disease is the result of the immune system malfunctioning or being overwhelmed or subverted.
Bacterial Diseases
It is common practice now to sanitize our hands and common surfaces frequently. This is done so to target the "less than 1 percent of the different types (of bacteria that) make people sick. Many are helpful. Some bacteria help to digest food, destroy disease-causing cells, and give the body needed vitamins."
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How do we deal with an opponent that his hiding amongst friends?
The human body, at any given time, is host to 10 times more bacterial cells than human cells. This is referred to as the microbiota. There is a deep seated commensal relationship between bacteria and humans. The process of vaginal birth exposes the newborn to their first bacteria. As the baby is exposed to the world more and more bacteria are acquired and they take residence on the different epithelial tissues of the body. This is the key, the bacteria are confined to the external body surfaces. There is, as discussed earlier, ample innate immune defenses to keep microbes out of the body. Even when some do breach, it is likely they are not virulent. Issues arise when the virulent microbes enter the body and get a foot hold.
If a virulent microbe is able to circumvent or overwhelm the immune system the body will become diseased. This is achieved with virulence factors that give the bacteria an advantage against the immune system. Pathogenic bacteria may quickly populate normally sterile tissue, release toxins, and damage cells. The medical marvel of the 20
th
century was the discovery of antibiotics. These are chemicals that kill bacteria but do not harm our cells. This is due to structural differences between the prokaryotic bacteria and eukaryotic cell of humans. Antibiotics are very effective if you infected but are not a prophylactic and have not residual effect on bacteria.
Lately the use of antibiotics is concerning the public and professionals for two reasons. They encourage the proliferation of antibiotic-resistant strains of bacteria by selecting for them. Through random mutation progeny of a bacterium may, by chance, be resistant to an antibiotic. If this is a virulent bacteria and the disease is being treated with antibiotics, the individuals that are resistant will have an advantage and go on to proliferate. The second concern is that antibiotics are commonly broad spectrum. This means that they kill any number of different species of bacteria and not just the single virulent species that is inflicting the person. The ramifications of this are not understood, but considering our relationship with a microbiota it is not hard to believe that killing off our good bacteria with an antibiotic is a good sound practice.
Bacterial Diseases: Virulence Factors
Bacterial disease results from a failure of the immune system to respond appropriately to virulent bacteria. Often bacteria are able to infect the body because the immune system is compromised already or suppressed. Pathogenic bacteria often have unique traits that give them an advantage. These traits are called virulence factors and they help bacteria to infect a host, cause disease, and get by host defenses.
Virulence Factors:
- Adherence Factors: Many pathogenic bacteria colonize mucosal sites by using
pili
(fimbriae) to adhere to cells.
- Invasion Factors: Surface components that allow the bacterium to invade host cells can be encoded on plasmids, but more often are on the chromosome.
- Capsules: Many bacteria are surrounded by capsules that protect them from opsonization and phagocytosis.
- Endotoxins: The lipopolysaccharide endotoxins on Gram-negative bacteria cause fever, changes in blood pressure, inflammation, lethal shock, and many other toxic events.
- Exotoxins: Exotoxins include several types of protein toxins and enzymes produced and/or secreted from pathogenic bacteria. Major categories include cytotoxins, neurotoxins, and enterotoxins.
- Siderophores: Siderophores are iron-binding factors that allow some bacteria to compete with the host for iron, which is bound to hemoglobin, transferrin, and lactoferrin.
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Viral Diseases
A virus is non-living pathogen. Viruses are protein packages of RNA or DNA that require a host to reproduce and manufacture its proteins. A virus that can infect a human has receptors for proteins expressed on human cells. This also helps explain why viruses do not commonly jump from one species to another, because cells of one species are inherently different from another. Furthermore it makes sense that viruses transmit more frequently among more closely related species. For example, it is more likely that a virus will transmit from a monkey to a human than from an oak tree to a human. The method of a viral infection makes them a difficult adversary for the immune system because they are hiding within cells. By the time a lymphocyte or leukocyte detects one it has already infected a cell and began manufacturing proteins. As mentioned early, byproducts of the viral molecules will be presented on the host cell, available for detection by phagocytes and helper T-cells.
Viruses make us sick because they destroy cells. Once the body realizes that it is infected with a virus the immune system is set to action. The immune response is the sickness that is associated with the virus. As the viral infection destroys cells making copies of itself the immune system responds. The symptoms of a virus are the actions of the immune system. Unfortunately there are not many antiviral medications and the body is left to fight the virus on its own. In general we can treat the symptoms but not the cause. The antibiotic that works against a bacterial infection is useless without a bacterial target. Taking antibiotics to treat viral infection may make matters worse as they destroy many commensal bacteria and select for antibiotic resistant virulent strains.
Though there are not many options once a viral infection has occurred, we can limit the spread of the virus to other people. Limiting the transmission of any given virus requires that we understand the mode of transmission for the virus. For example, if the virus requires blood to blood contact from an infected individual to a healthy individual we can limit transmission by avoiding blood contact. The most contagious viruses are the ones that transmit through the air wherein you can be in the same room as an infected person and catch the disease. The best way to protect ourselves against viral infections is with vaccines, a prophylactic.
Vaccinations were discovered in the 19
th
century through work with cowpox virus. A virus that inflicts cows and is similar to the human virus smallpox led to the discovery that people can become immune to a virus. Though scientists of the time did not know all of the details about how vaccinations were working they did know that if a person was exposed to cowpox they were protected against smallpox. This is the human immune system working, the secret to vaccinations are the lymphocytes, particularly the memory B-cells. The cowpox virus is not dangerous to humans, but the immune system still identifies it as foreign and responds to the antigen. In this case, the antigen is the same as the smallpox antigen, thus giving the immune system a chance to learn how to recognize the antigen without the threat of getting infected. Subsequent encounters with the smallpox virus are neutralized by the immune system because it is prepared for the attack and can move swiftly enough to neutralize the infection. Many more vaccinations have been developed using the same principals and natural action humoral immunity.
Autoimmune Diseases
Autoimmune diseases are remarkably different from an infectious disease concerning the cause and treatment but share commonality as a problem with the immune system. There are some 80 known autoimmune diseases, and as the name implies, these are diseases wherein the immune system is attacking the body. The reason is that the immune system is incorrectly recognizing body cells as antigens. As the white blood cells try to neutralize the perceived threat other immune responses are elicited. The person feels sick because of the symptoms.
Scientists do not know yet why autoimmune diseases develop and for the most part treatments are limited to treating symptoms. It is, however, understood now that autoimmunity begins when the immune system turns on the body and that can happen for many reasons including error, self cells looking like bacteria or viruses "mimicry" or simply an over exaggerated immune response. One complication is that many of diseases present similarly as general immune responses. For example, fever, inflammation, swelling, and redness. Though the cause can be very specific it is difficult to determine what pseudo antigen is causing the immune response. Autoimmune diseases are similar to allergies in that the immune system is responding inappropriately to a non-threatening antigen. At some time the immune system incorrectly learned that an innocuous antigen was pathogenic and it is just carrying out its normal processes to neutralize the threat.
Engineering Immune System Solutions and the System Itself
Understanding how the immune system works is the key to finding solutions for diseases. Rather than treating symptoms the goal of medicine is to treat the problem. If the complexity of the immune system is understood by the students they can think appropriately about how medicines work and what future medicines need to do. With knowledge of the inner workings of the immune system students are able to understand antibiotics, hygiene, vaccinations, and future solutions for diseases. Through understanding of the immune system students can study it from the appropriate perspective, one in which the diseases that inflict humans are the result of immune system failures. This allows them to think about novel solutions to the problem, using the innate intricacies of the system to remedy disease. Ultimately, the goal, is that students understand that engineering is at the core of the solution, engineering that is guided by actions of the existing immune system that has served human kind so well for hundreds of thousands of years.
Immune system failures are not a modern day problem in so much as they are just be exacerbated by modern technology. Diseases have been around for as long as humans have been in existence, but aspects of the modern life may be amplifying the impact of any single disease. Today we have global travel; we live in large cities; we eat exotic foods; stress our bodies with pollution; and use antibiotics. Our exposure to and ability to deal with microbes are both affected by these actions. Consider living in a city with air pollution wherein your immune system is constantly expending energy and resources to maintain a healthy body. This increases the possibility for infection because the immune system is compromised. Consider the impact of cities, millions of people living in close proximity to each other, the perfect environment of a contagious disease.
Viruses to Fight Cancer
There is current research and preliminary successes using viruses to fight cancer. The ability of a virus to enter a cell and wreak havoc can be used against cancerous cells. Imagine a medicine that is a virus. Imagine infecting oneself with a virus with a cancer cell host in order to cure a cancer.
Viruses to Fight Cancer: Measles
The insidious measles virus, nearly eradicated in this country the with effective use of vaccines, may hold be solution to tumors. "Measles virus offers an ideal platform from which to build a new generation of safe, effective oncolytic viruses."
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The virus needs to gain access to the cell, it does so by happening to have a receptor for a surface level protein on the targeted cell. Cancer cells do not express the common access protein that measles uses, but by chance mutation attenuated measles strains have a receptor for a different protein that is more prevalent on tumor cells than non-tumor cells. This is a non-harmful form of measles that targets tumor cells. The original virulent form of measles infects cells through a different receptor. A problem with this solution is that most people are vaccinated for measles and the immune system still recognizes the attenuated form of measles and defends against it. The ultimate solution may involve suppressing the immune, which as discussed may result in other diseases, or by circumventing the immune system by sneaking the virus past the lymphocytes in a cell carrier.
It is important to expose students to these new methods of disease control. Initially it sounds ridiculous that a person suffering from cancer will find sanctity in measles because of our general knowledge about this highly virulent disease. Exposing our students to such methods of cancer relief through a deep understanding of the immune system results in a more informed student that can think more appropriately about how diseases will be remedied in the future. One need only imagine the reaction of the general public to news about measles being given to cancer patients and how this can manifest into deeper misunderstandings of the immune system and how diseases operate.
Nanotechnology
Some of the latest developments in medicine are occurring within the realm of nanotechnology. Scientists are engineering drug delivery tools that are beyond microscopic. The particles made at the nano scale are so small that they must be viewed using scanning equipment that construct images of objects as small as 1/1,000,000,000 of a meter. The invention of such technology is pivotal to the development of nanotechnology. Furthermore nano probe development is fostering advances in diagnostics: "the ability to monitor antibody binding and sense the cellular immune response in real time with readily available technology should facilitate widespread diagnostic applications."
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This brings immunology to whole new realm wherein immunologists can see the immune system in action at a molecular level.
Nanotechnology: Effective and Localized Delivery of Medicines
Nano scale is that of molecules. This allows us to engineer medicines at a molecular level, small enough to pass directly into cells. These molecules are small enough to allow us to communicate with the immune system via antigens. Scientists are experimenting with packaging molecules inside nano scale vessels. These vessels can be made to mimic bacteria in shape and with antigen presentation. This gives them the ability to send a package to T-lymphocytes in order to program them. If for example, you want to teach the immune system about an antigen you have to present the antigen to the immune system first. If you package the desired virulent antigen into a vessel that is readily perceived by the immune system as pathogenic the leukocytes and lymphocytes will act accordingly and neutralize the perceived threat. This delivers the virulent antigen directly to the immune system in a safe package. The result is that the humoral immune system will develop a memory for the antigen, protecting the body from possible future attack. A superior approach to vaccination that by nature has the potential to be more effective, less expensive, and easier. A major downfall of vaccinations is shelf-life, nanotechnology solutions can overcome that barrier because of their relative stability and ease of transport and storage.
Nano particles made of ploy lactic-co-glycolic acid (PLGA) are being produced to encapsulate medicines for delivery in the body. These are important because the biodegradable polymer of the capsule can be manipulated to have varying breakdown rates. "a wide variety of agents—from extremely hydrophobic to highly hydrophilic—can be encapsulated in PLGA nanoparticles, drug release rates can be tailored to particular applications, and size and loading are easily manipulated to provide further control over drug delivery."
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Imagine that you have some leftovers in your refrigerator. That rotting food is stinking up the kitchen. Now imagine that you soaked your kitchen in Clorox to remedy the situation. Sure, it may work, but what is the collateral damage? Instead you are able to target the offender, delivering the necessary cleaning protocol directly to the food and container. The drugs of today are not dissimilar to the analogy. Though they may work to remedy a situation, they must delivered in such a fashion that they affect many non-target areas and must be taken on a time schedule maintain a concentration in the body. Solutions with PLGA encapsulated drugs may be coming soon. This is a probable solution that can solve multiple problems with one eloquent answer, nanotechnology.
Nanotechnology: Engineering the System
Engineering a better immune system will likely be the outcome of nanotechnology as it applies to vaccinations. The teaching and re-teaching of the immune system is in essence a form of engineering wherein the immune system is improved through science and technology.
The teaching of the immune system is paramount to our defense against current and future viral attacks. There may be answers to treating those infected with a virus as well. The re-teaching of the immune system is critical at this time wherein modern day plagues are those of autoimmune nature. Immune system malfunctions wherein lymphocytes have incorrectly associated cells of the self as pathogenic. The answer to fixing autoimmune disease may be in the reprogramming of lymphocytes. Now that we are in a new era wherein we can communicate directly with the immune system we can operate under a different paradigm that treats the immune system as bank of information that can be modified. Abandoning previous methods wherein the solution was to augment or suppress the system and instead strengthen it with information.