Evolution and Disease: Exploring the effects of Pathogenesis as a factor driving Natural Selection

Evolution and Disease:
Exploring the effects of Pathogenesis as a factor driving Natural Selection Published by L.F. 2010. Similar Research Conducted in 2014, See image link.


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One of the most interesting topics that I have encountered thus far in my study of evolution, is the evolution of pathogenic populations. One cannot help but be fascinated by the possibilities to be explored therein, that can illuminate disease processes and how we may successfully or more efficiently treat and(or) prevent diseases, chronic illness and autoimmune disorders.

From science to popular culture, we often hear about how pathogens are evolving more rapidly and becoming more virulent, even resistant to conventional pharmaceutical remedies but there is a tangent to that story about pathogens and their role in evolution, less told. That emerging story is about how pathogens actually infect and integrate within the human genome, and it is being written everyday by scientists and researchers alike. This topic is a newer one and it centers on evolutionary development. Dr. Scott F. Gilbert, practically the founder of the field of Evolutionary Development, wrote in his book, “Developmental Biology” (1985) that he intended to blur the lines that separate biology, genetics and evolution. Gilbert focused on how genetic mutations affect evolution through development and the elucidation of the mechanisms by which it is accomplished which he proposed would introduce one of the most exciting chapters of modern biology. I would like to take you on an exploration of the current research that may reveal more about how mutations may arise by result of pathogenesis and how those mutations may play an integral role in natural selection, both in the past and presently.

We must start out with a basic understanding of natural selection. Charles Darwin proposed in his work On the Origin of the Species (1859) that there are three requirements for natural selection that must exist in order for a population to evolve. First, a distribution of variation for some characteristic(s) must exist in a population, whereby spontaneous mutations that occur in the reassortment of genetic material during fertilization and reproduction may be the cause of variation. Second, the variation is at least partially heritable and third, some variants survive to reproduce at higher rates then others. It is necessary that we account for all three criteria when we consider how pathogens may drive what I question to be real-time adaptions, through inheritable and de novo mutations leading to new genomic and epigenetic effects that may be driving evolutionary change at a more rapid rate then even Darwin might have expected. In fact, I suspect that pathogenic processes may underlay evolutionary change in all living populations, creating pressure at the molecular level.

Some basic reference toward pertinent topics in genetics will be helpful here. The discoveries of what Gregor Mendel called “discrete units of inheritance” and the groundbreaking work of Avery, MacLeod and McCarty in determining the synonymous “transformation principle” to be Deoxyribonucleic Acid (DNA) ignited the field of Genetics which epitomized studies originating in the further determination of the structure and the latter of which, the function of DNA, often concomitant to evolution. Evolution is the study of populations and how the heritable traits of select species and groups have reciprocal value in successive generations. In line with the above,
infectious pathogens called Viruses are of particular interest. Viruses, that exist in great variety and number are not considerably a living population however they are comprised of DNA or it’s substructural Ribonucleic Acid (RNA). In order for these infectious agents to inevitably survive they must infect host cells, that are confined to the systems of living organisms. This has profoundly effected the evolution of genotypes and possibly, phenotypes, across populations.

An idea that can be conceptualized is that every biological taxonomical domain encompasses populations that have undergone evolutionary change due to selection pressures. This also applies in several ways to viral families. Despite conflicts over taxonomical classifications for the multitude of viral agents, viral genomic elements have proved to integrate within the genome of living organisms and are also a driving force in selection, which makes them important to the process of evolution in several if not all domains. More obviously, viral pathogens are also responsible for devastating health effects and mortalities, so we want to understand them from an evolutionary perspective, to solve pervasive health-related problems and increase quality of life in populations. In order to begin to piece together the evidence of how viruses and other pathogens may shape biological organisms and drive evolutionary change, it is necessary to identify the genomic composition of infective agents. While several viruses have been identified and studied in this contexts, many more viruses may have not even been discovered thus far. In that, pathogenic populations evolve in and of themselves which can account for the idea that pathogens seem to emerge in different timeframes and in some cases, specific environments. Additionally, some pathogens may not be directly linked as a causative factor in some disease processes. For example, Multiple Sclerosis, an autoimmune disease may be linked to previous viral infection or to a regional cause, but the evidence remains inconclusive. Regional spread of certain disease is also an important clue because it might indicate the sort of environment that the causative agent thrives in. The study of these relationships is multidisciplinary. Geneticists, virologists, biologists, chemists and other scientific disciplines have collaborated to weigh-in on the overlap between pathogenesis, evolution and the developmental disease process.

For each and every domain, under the three domain hypothesis (Woese, 1990), that has come to be identified and differentially defined by biotechnological applications, there are entire genomes to be looked at, that have been shaped through selection. If we can assume that some evidence points to populations in all taxonomical categories within each domain as possibly sharing in symbiotic or synergistic relationships, and if pathogenesis takes a strong hold in mechanizing selection, think of the probabilities for the crossing-over of genetic information that are possible. It is well known that our bodies synthesize new DNA throughout the lifespan. This DNA is encoded by transcription and translation of nucleic acid sequences from mRNA, tRNA and rRNA. Some of these nucleic acids as well as amino acids are also found in viruses, and so there is a certain compatibility factor that allows for a sort of communication between our genetic material and viral genetic material. While one might be able to think of this idea conceptually, we would have to rely on computer technology and perhaps advanced algorithms to look at these possibilities as inputs and outputs of each domain in and of itself and across multiple-domains, to further advance our knowledge of the form and function of genes and proteins. A computer assisted approach may
allow for genomic sequencing or mapping of multiple populations that can be analytically compared and contrasted. Other techniques such as the construction of phylogenic trees can reveal genetic distance and relationships in ancestral species as well. It seems that various methods have been utilized to consider derived traits across populations thus far, so how has pathogenesis driven derived traits in populations, both in the past and presently, and where does this fit into the big picture? Continuing to utilize the technology available for such investigation could probably lead to estimated risk projections for pathogenic evolution and how that projection might infect living organisms based on their unique genetic profile. In essence, this would incorporate the identification of biological niches that are just as important to evolution theory as ecological niches where the nature to nurture paradigm can become more clear in terms of nature. If such a feat were able to be accomplished then perhaps we can learn more about how derived characteristics pose advantages and disadvantages, which could suggest why specific traits may be conserved, especially traits involved in disease processes. Right now, what we are looking at are pieces of genetic puzzles and sometimes seeing a correlation to disease, but I am proposing that once we have even more pieces of the puzzle sorted out, it will reveal a more conclusive foundation to understanding the relevance of evolution to the medical sciences. In theory, all the above can be addressed in a central consideration to the projective process of pathogenesis acting on living populations as a doorway to the synthesis of new disease prevention strategies.

Pathogenesis may drive mutagenesis, the process by where mutations develop. Mutation or variation that is at least partially heritable is a criteria for evolution by natural selection. Mutations are an important factor in inheritance and account for polymorphic variances, which in turn account for millions if not billions of pieces of a genomic puzzle within every domain, that may fit together in proportional ways. Sequencing of entire genomes has allowed scientists to identify the form and function of genes as well as how mutations can effect functional processes. Mutations that are at least partially heritable are a requirement for Charles Darwin’s three criteria for evolution by natural selection. Mutations have been proposed to occur as a result of genetic information being “shuffled” through the processes of meiosis and mitosis, as well as gametogenesis which results in inheritance through reproduction. It has been said that mutations arise spontaneously. I think that there is some order to mutational origination based upon the process of pathogenesis, that has up until more recent times remained an obscure or unmeasurable factor, where for instance, viral elements actually integrate within human genomes, creating mutations such as point mutations, insertions and deletions. As we can map mutations in genes in the present, we can also look at how pathogens may have influenced derived mutations, with evidence pointing to fossil DNA going back millions of years ago. There must be some more significant process that drives mutations, where random chance may be involved but nevertheless effected by the presence of genetic “ingredients” hijacked from pathogens or foreign invaders. Perhaps, the “ingredients” that progenitors have “hijacked” create some of the “menu” by which traits are selected or “ordered” in filial generations?

Some mutations may be caused by identifiable mutagenic factors such as carcinogens and radiation. Now, taking this fact into account, consider that if the genomes of all domains may come to be understood in their totality, we
might observe the evidence for how pathogens create and drive selection pressures for mutations that are then passed on through mendelian inheritance. Therein, breaking down the genomes of all domains is only part of the requirement to further our understanding of disease processes. The other part is that we need to understand is how and what genetic variances, frequencies, and mutations, not only arise but influence the production and function of proteins in harmful or disruptive ways.

The up and coming field of protogenomics employs a variety of techniques to separate and isolate proteins from cells. These proteins are the byproducts of DNA, which makes RNA, which makes proteins; The central dogma of modern genetics. Where polymorphism’s exist in most all life forms, protein products and how they influence biological functions are extent beyond the realm of what is completely understood in the present. Mutations that represent polymorphic differences within some variants in a population, may lead to different manifestations of disease whereby some variants can be adversely effected by some pathogenic entity, and others may not be adversely effected by the same pathogen. I suspect that if we can understand the relationships between for instance, certain prokaryotic families to eukaryotic families and populations, we may begin to really embark on a whole new path that alights not only the processes of disease, but also the evolutionary changes that are for or against the manifestation of diseases. In that, we can take a look at novel mutations such as the CCR5 delta-32 deletion mutation and the influence it has in resistance to infection by the Human Immunodeficiency Virus (HIV) and try to find a way to “select” that resistance mechanism in other numbers of an unaffected population.

Identifying the structure and function of proteins has in the past revealed much about human genetics including the discovery of DNA’s double helical structure by James Watson and Francis Crick in 1953 and additionally, the identification of the “transformation principle” that is Deoxyribonucleic acid by Avery, MacLeod and McCarty in 1944. I think that molecular technologies that explore single-nucleotide polymorphism’s can be incorporated alongside proteomics to explore complex structures and functions of proteins as congruent to the identification of complex trait or multiple loci genetic maps. There is significant understanding about the forms of proteins but we are going to learn more and more about their functions which are pinnacle to understanding several areas of the life sciences as proteins are the functioning units in all living organisms. We can explore through new technology, how complex trait genes are expressed or silenced in relationship to proteins. Perhaps, through proteomic applications we will even come to better understand the complexity and involvement of the human epigenome because proteomics studies the proteome which is the entire range of proteins expressed by a genome where the genome “interacts” with the epigenome. I suspect that some pathogenic agents may influence genetic and epigenetic patterns in inheritance, and so this is an important idea for further exploring evolutionary developmental changes in populations of living organisms. This type of advanced biotechnology allows researchers to look at the functions of proteins under specified conditions during specific timeframes, which could help to reveal how, when and where, the epigenome interacts with the genome. This is significant, especially as the proteome is larger then the human genome because for all of the genes in the human genome, there are several more protein products that each gene codes for. The same goes for other living organisms.

Up until now, I think we could say that the sequencing of the Human Genome and other eukaryotic, prokaryotic and archaea organisms, has influenced some of the most astonishing breakthroughs in the field of genetics and other biological sciences. I think that the field of proteomics will lead to new revelations in our understanding of how proteins are expressed, even in post-translational modifications in living organisms and in pathogenic populations. Great things are in the process of being discovered and understood more empirically. By mapping not only the form but the polymorphic functions of proteins in relationship to their genetic backbones, we can again, learn a great deal about the disease process and perhaps develop early detection or predispositional evaluation methods in conjunction to what is indicated already by genetic markers that point to certain dispositions toward disease. This type of study may be best attempted by fusing together the field proteomics and genomics, called protogenomics, a field that I think will weigh in heavily on the topic of virulent disease prevention strategies that may even come to influence the development of prescriptive treatments such as antibiotic use, in the 21st century and beyond, as necessary intervention in the face of evolving antibiotic and treatment-resistant pathogens.

Now that the above introductory discussion has been presented, I would like to take a turn in discussing antibiotic and disease resistance, as well as the evolution of viral pathogens.

We have spent some time focusing on the effects of bacterial resistance to antibiotic use and its greater implications within the context of evolutionary development. During my studies I have come to learn that infectious agents drive human and other mammalian evolution by processes in line with that of Darwin’s criteria of Evolution by Natural Selection. I mentioned these criteria previously but what is meant by the requirement for survival in that some number of the populations must survive and reproduce a mutation in greater numbers? There are many environmental factors that come into play and create stressors on living organisms. A stressor or pressure may be a predator that kills some of the population and not others (predation) which often, overtime, leads to speciation. It is the source of pressure that weighs on survival factors. In explaining and understanding the incidence of antibiotic resistant bacterial prevalence, it helps to view the antibiotic as the predator that kills some of the bacterial population, allowing some variants to survive and reproduce in greater numbers thereby passing on the resistant trait that is at least partially heritable to bacterial replicants.

In “Hunting Fossil Viruses in Human DNA” (2010) Carl Zimmer discussed the identification and implication of fossil evidence revealed in the human genome, that tells us the story of a possible co-evolution between human genes and viruses. Further, he implicates that viruses have come to be transgenerational through integration within mammalian genomes which means that the structural composition and of course functional role of genes may have been influenced and most importantly, selected. When traits are selected they expanded through a population. The viral elements that integrate within the genome may cause an active infection but also impress latent effects that can become the molecular remnant of something that functions very differently then it had during a lymphoproliferative stage, such as we might observe in
the case of mononucleosis in digression to EBV. It is to say that successive generations may not experience the active effects of such viral integration that may otherwise cause mortality and morbidity. For fatality to result from viral infection would defy the third criteria for evolution by natural selection. A virus must integrate within the genome in order to be passed on through reproduction. It does not mean that the effect of integration is directly selected but that where viral elements integrate along sites that have already been selected, they are passed on to filial generations in reproduction where mutations remain subject to other factors for conservation or in being selected against. A provirus is an example of such where there may even be a negative effect, such as the development of cancer due to oncoviral infection where a provirus integrates along a tumor suppressor and(or) oncogene to cause a default in the process of normal cellular division or proliferation occurring through mitosis.

A sort of synergy exists between the elements that exist in viral pathogens and genes, we might even call it a symbiotic relationship. The borna virus, is a good example. The borna virus is an Endogenous non-retroviral RNA virus. Endogenous means that the virus originates within a tissue, organism or cell and it may come to have an effect on the form of genes and(or) their function. Theoretics aside, evidence indicates that the borna virus did actually replicated in the human host, by invading the cell nucleus and then passed on through germ cells (spermatozoa and Oocytes). In a general sense, when effected germ cells existent in progenitor species come together during gametogenesis, the viral information is often distributed in the genomic structure (i.e. chromosomes) of filial generations. The genome of the offspring is impressed by the provirus, that is the latent or hidden derivative of the borna virus that has successfully integrated within the genomic structure. This integration had and(or) continues to take place where reverse transcriptase activity occurs or is coded in Long interspersed repetitive elements or Long interspersed nuclear elements (LINE). I suspect this type of process could mechanize a sort of epigenetic effect within some locus of expression, even causing epigenetic silencing, linkage, epistasis, or perhaps a null effect or deletion mutation. Apart from my speculation, the borna virus has been identified in “replacing” the function of reverse transcriptase activity along (Line-1), where DNA copies of RNA are synthesized and inserted into the genome. From generation to generation the virus’ DNA would mutate and it would eventually loose its ability to mutate, effectively becoming disabled. Hunting Fossil Viruses in Human DNA, Carl Zimmer (2010).

In consideration to the above, one may even wonder if these viral remnants act an input and output of susceptibility to other viruses where interaction between protein sequences “overlap” a domain. In fact this sort of inverse relationship seems possible when considering the findings of Dr. Keizo Tomonaga, a virologist at Osaka University who discovered, by accident, that four segments of human DNA had clearly descended from the borna virus. His theory is that the borna virus didn’t actually invade mammal genomes but that the genomes kidnapped them (“captive viruses”), suggesting again, that the properties of human genes and viral genes are synergistic. Tomonaga suggests that the LINEs (that sometimes make copies of themselves) grabbed the genes of the borna virus and reinserted them back into the genome. If this is so the case, then it is possible that LINEs have grabbed the genes of

other viruses and perhaps have utilized some of the genetic material composing those viruses in useful ways.

Now in his article, “Hunting Fossil Viruses in Human DNA”(2010) Zimmer mentions that the neurotropic borna virus is one of many viruses that infects mammals and birds. To digress for a moment, birds, insects and humans share a unique relationship in that vectors such as mosquitoes have been known to pass viruses between species so this connection is not surprising. He continues that some species effected by this virus are asymptomatic and therefore the effects of the infectious agent are mostly abstruse with specified exceptions. For instance, behavioral effects in horses have been observed, manifesting as wild fits where these normally tame animals might kill themselves by smashing their own skulls or even by starving themselves. For this reason, scientists postulate a correlation between the borna virus and human behaviors indicative of disorders such as schizophrenia. But when I come to discuss the role that has recently been identified about protozoa effecting human behaviors and as pathogens or parasites behind disorders like schizophrenia, we may gain even more insight as to how behaviors are influenced by pathogenesis. The idea that pathogenesis can lead to mental illness or play a role in behavior may actually be one met with much controversy just as the idea that humans descended from primates was during the time in which it was first suggested even up until the present; A controversy over the idea that humans are in less control over their behaviors would likely arise but to think of the implications that identifying pathogens responsible for influencing behaviors would have in terms of leading to any inhibition of certain pathogens action could lead to cures for a latter of mental illnesses.

An alarming hypothesis (should it be taken as conclusive) is that some 40 million years ago the borna virus infected our monkey-like ancestors. Presently, viruses are found in about 8% of the genome of every person on earth, according to the reference for the article, Hunting Fossil Viruses in Human DNA (Zimmer, 2010), that is, Endogenous non-retroviral RNA virus elements in mammalian genomes. Endogenous non-retroviral RNA virus elements in mammalian genomes. (Honda, 2010) That measurable 8% is traced back namely, to retrovirus infections. “To put that number in perspective, that’s seven times more DNA than is found in all the 20,000 protein-coding genes in the human genome.” Hunting Fossils Viruses in Human DNA (Carl Zimmer, 2010)

In 2001, the entire human genome was sequences by scientists and shortly thereafter, several segments of human genes were observed to have a resemblance to genes in retroviruses. Although scientist have established an interconnection between about 100,000 viral elements (mostly originating from retroviral infection) imprinted within the human genome, respectively, this discovery about the borna virus as a counterpart of the human genome is a unique finding in that this type of non-retrovirus that is member of the Bornaviridae family within the Mononegavirales order, has never been identified in the human genome previously.(ii) Inference derived in this fact is central to the notion that many other viruses have yet to be discovered in the human genome.1 Think of the implications this may have, where form and function come to be identified; What else can be uncovered about disease of known and(or) unidentified origin and in that, plausible treatment(s)?

The borna virus is not the only example of fossil viruses, illuminated via gene mapping and referencing to the databases containing the sequences of the human genome. Zimmer points out that, “Now fossil virus hunters are moving beyond the human genome and taking advantage of the growing number of mammal genomes piling up in online databases and helping to flesh out the evolutionary history of viruses going back tens of millions of years.” The collective results of these related and independent investigations have revealed that humans and other species are more viral than previously thought.

What I find to be most pertinent to the topic of viral pathogens (or as I would like to refer to them as “pathogenes”), over every other pathogen that I will discuss, is that viruses are technically, non-living vectors whereas, prokaryotes, archaea, and protozoa are living. I reiterate, viruses are the only pathogenic taxon containing genetic material that is not alive, per se. This is unique to the fact that viruses must invade host organisms in order to survive and reproduce at a greater rate which has implications for the evolution of viruses in and of themselves. For one, it might mean that a virus’ best chance to evolve is when it does not kill the host(s) that it exploits ensuring that it survives and reproduces in greater numbers. Theoretically, this can apply to viruses as this is the a basis for evolution by natural selection in living organisms. Essentially, I am assuming that in order for a viral population to evolve in a host organism it is optimal that the host is not exploited to a point of death. To flip that coin, it also seems plausible that some viral pathogens may evolve through exploiting a host toward fatality and dually being passed on to another host which may allow for evolutionary changes to progress in both the host and viral populations. A virus may evolve as it multiplies in cells and reproduces. Is there a limited advantage but nonetheless an advantage, for viral pathogens, that is gained by integrating within the host genome, either during active infection and(or) thereafter as a provirus that is reproduced in filial generations, in that it never becomes completely obsolete? To my way of thinking, the answer is likely yes. This must be a quintessential driving force of not only evolution in humans and animals but possibly in evolution between Prokaryotes, archaea, and protozoa or what I call a “pathogen-to-pathogen route” where for instance eubacteria may be exploited for a viral population where, a symbiotic advantage is posed in each population. I think that when we look at how eukaryotes, prokaryotes, and archaea are related, we should search for a pathogenic phylogeny amongst all domains and subsequent taxonomies.

Oncoviruses promote tumorigenesis in humans and animals and serve as another well researched topic that broadens the understanding as to how viral pathogens may drive evolutionary change or at least meet the criteria that allow for selection to unfold.

Oncoviruses are cancer causing viruses. The study of Cancer causing viruses in animal models has given scientists an understanding as to how viruses influence changes in cellular division and growth, through the process of proliferation, where normal cells transform into cancer

cells. Viral DNA infects the nucleus of infected cells where it seems to randomly integrate into the host genome producing a provirus. Most cancer-causing viruses found in animals are retroviruses which are made up of RNA, often referred to as acute transforming retroviruses. Some animal viruses may be passed on in breast milk, blood and germ cells.2

Viral oncogenes can by default, change normal cells into tumor cells through the process of tumorigenesis and by utilizing the machinery of a host cell. Viral oncogenes may create the rapid growth and division of host cells based on the action of viral promoters. Retroviruses mechanize the development of cancer in animal populations in two ways. In one capacity retroviruses mechanize the development of cancer in animal populations when proviral DNA randomly integrates near proto-oncogenes and influences transcriptional activity through strong promoters and enhancers within the provirus. This causes higher levels of transcriptional proteins or rate related differences in cellular proliferation. Another way in which retroviruses mechanize the development of cancer in animal populations is by integrating through replication of a host proto-oncogenes where new viral oncogenes undergo mutation as a result of viral transfer.

One may think that it is not important to the study of evolution to look at the effects of oncoviruses in tumorigenesis where cancer may lead to mortality and therefor the mutagenic changes cannot be passed on to filial generations (in that reproduction is a requirement for selection) however, mortality does not result in all cases. Where humans survive cancer, they may go on to reproduce and pass on proviral proto-oncogenes called oncogenes or proviral tumor suppressor genes that lead to heritable factors in tumorigenesis. In contrast, a provirus may not integrate nearby proto-oncogenes or tumor suppressor genes in progenitor populations but may still be passed on to filial generations where the provirus is integrated within the genome and relocation of the provirus takes place through meiosis I and II during fertilization, a precursor to reproduction. After reassortment and distribution of parental genetic material in meiosis I and II, a proviral gene may continue to be integrated within the genome of offspring, and if it should locate along an allele nearby a tumor suppressor gene or proto-oncogenes, the development of an oncogene may result. This means that a trait for tumorigenesis by way of oncoviral pathogenesis may exist and even create a de novo mutation in an unaffected individual that can still pass along the trait that leads to cancer as a heritable condition. Also, if cancer results in mortality it leads some number of unaffected individuals to survive and reproduce, possibly passing on traits that are resistant to oncogenic viruses leading to tumorigenesis.

I have talked about acute transforming retroviruses in reference to animal populations but no acute transforming retroviruses have been found in Humans. Instead, viral agents in DNA have been identified as a factor in the development of human cancers. Specifically, DNA oncogenic viruses have been identified in Humans. The World Heath Organization’s International Agency for Research on Cancer estimated that in 2002, 20% of human cancers were caused by infection, of which 10–15% are caused by one of seven different viruses. (Parkin, 2006) Some of the oncogenic viruses identified in humans are the Human papilloma virus (HPV), Kaposi’s sarcoma-associated herpesvirus (KSHV or HHV-8, Epsein-Barr

Virus (EBV or HHV-4), Human Mammary Tumor Virus (HMTV) and Merkel cell polyomavirus (associated to Merkel cell cancer and Human T cell leukemia virus-1; HTLV-1). HTLV-1 is also linked to infection with Hepatitis C and the development of hepatocellular carcinoma.3

HIV is a form of a herpes retrovirus that causes AIDS. This virus weakens the immune system in infected humans putting persons with AIDS are at greater risk of developing cancers caused by oncogenic viruses.4 One form of cancer associated with HIV and namely the herpes virus 8 (HHV-8) and KSHV, is called Kaposi sarcoma (KS), a form of skin cancer (Chang et al., 1994). Patrick Moore, Yuan Chang, Frank Lee and Ethel Cesarman identified Kaposi sarcoma-related herpes virus in 1994 by using representational differences analysis(RDA) that compared the differences in the genomic sequences of cDNA samples.5(Chang et al., 1994) HIV infection has also been linked to non-Hodgkin’s lymphoma. Lymphatic cancers associated to HIV infection can effect the central nervous system, liver, bone marrow and gastrointestinal system. (Opportunistic Infections and AIDS-Related Cancers, 2006)

HIV infects host cells through blood-to-blood contact and through seminal and vaginal secretions. In the 1980’s it was found that HIV transmission had occurred via blood transfusions. The rate in which the viral pathogen exploits host cells is rapid and millions of divisions can occur in one day; That is millions of new viral captive cells can be reproduce extremely rapidly which also leads to rapid mutations in viral populations. This rate of viral reproduction challenges treatments aimed at slowing the progression of neoproliferation and cures because treatments target the virus in host cells, which sometimes kills off some number of viral cells but leaves other mutated cells to survive in the host and reproduce more virulent variants within the population. The fact that HIV has shown to integrate nearby proto-oncogenes or tumor suppressor genes is what leads to cancerous growth. This shows just how deeply this virus penetrates the host on a molecular, genetic level. There is currently no cure for HIV and to understand the evolutionary history of HIV and its pattern of evolutionary change may help us control this disease. Taking an evolutionary perspective on HIV has led scientists to look in three new directions in their search for treatments and vaccines.6 However, there have been incidences where even vaccinations for other viruses have not prevented infection because they prevent only certain variants of viral pathogens from being passed from host to host, or host cell to cell, which allows only the more virulent mutated viral elements to survive. Evolved forms of the diseases that were intended to be prevented, such as observed in the emergence of more virulent strains of pertussis, are a result of vaccinations acting as a selective pressure. Also, vaccinations introduce genetic information from pathogens, into a host, including viral pathogens which are known to integrate within the human genome. How do we know that we are not created a whole new spectrum of mutations or diseases by administration of vaccines? Vaccines geared at preventing the Human Papilloma Virus, HPV-16 and HPV-17 strains have actually been linked to the development of cervical cancers in which they were intended to prevent. Anthrax vaccinations administered to soldiers during the Gulf War have led to an 80% incidence of autoimmune diseases as observed in the case of Gulf War Syndrome. Atherosclerosis is an inflammatory disease effecting structures of the heart, where some vaccines have triggered the over-stimulation of the immune system, such as the H1N1 vaccine with adjuvants used to boost immunity
development based on a the subsequent hyper-stimulation of Macrophages according to Dr. Mae-Wan Ho, a Geneticist and Director of the Institute of Science in Society in London, England, who assessed the Cardiovascular Risks from H1N1 Swine Flu Vaccines. (Cardiovascular Risks from H1N1 Swine Flu Vaccines. Ho, Mae-Wan. 2009) In other cases, vaccinations may have led directly to mortality. I am not in adamant support of vaccines as a solution to halting or ceasing the spread of infectious disease and strongly suspect that they may lead to other health-related problems. Nonetheless, the companies who make vaccinations such as Novartis and Sanofi Pasteur procure billions of dollars annually for their vaccination products, so of course, they will overlook significant adversities. This is not to degrade their achievements but to say that perhaps the process of vaccination is premature and driven by capitalist incentives, where industries also stand to lend benefit to governmental fiscal requirements through taxation, and where the FDA which regulates vaccination production is part of that governmental body. Clearly, there may be some indication for ethical concerns that have not been more closely looked at.

Historically, serious infections of epidemic or pandemic proportions such as the “Black Death” or smallpox have been discussed by Carl Zimmer in “Evolution: The Triumph of an idea” (Evolution: The Triumph of an idea. Zimmer. 2001. pp. 268-271). The Black Death has been estimated to have killed one to two thirds of Europe’s population in the 1400’s. Those that survived, may have as a result of a genetic mutation that might have already existed in the population, and it may also have as a result, come to exist more prevalently thereafter. Whether this specific mutation was existent prior to or after the black death, I think it is possible that the mutation may have arose as a result of pathogenic information, integrating within the human genome but not causing harm to certain variants based upon some specific genetic disposition. So I think it is both, predisposition and the integration of new genetic material from pathogens that work to drive new mutations to become more frequent in a population. This is just one possibility I have explored. A reason why this historical recount is pertinent to the discussion of pathogenesis is that it is suspected by some scientists that the surviving variants were partially resistant or completely immune to Plague, and since these individuals were the ones that survived, they reproduced in greater numbers and their variants or offspring having survived to reproduce may have passed on the trait and the mutation should have in turn increased in frequency to some degree. An interesting correlation that may explain why some numbers of the population were not susceptible to selection pressures during the plague or possibly smallpox exposures, may relate to the fact that a mutation specifically known as the CCR5-delta32 deletion mutation was present.7 The discrepancy as to whether the the CCR5-delta32 mutation emerged as a result of historic plague or smallpox exposure is ongoing. Some accounts say that this mutation is believed to have come about as a result of past exposure to the bubonic plague or black death, caused by a Gram -negative bacterium called Yersinia pestis, that swept across europe. As it turns out, the bacterium Yersinia pestis (which cases bubonic plague) attaches to white blood cells. It is believed that this bacterium, as well as the HIV virus, infect hosts that have no
mutation in the CCR5 gene. The great significance of the CCR5-Delta32 mutation is that it has caused some of the human population to lack a specific protein on the surface of their cells which creates immunity or resistance to the Human Immunodeficiency virus (HIV) because the presence of this protein is required for invasion by the viral pathogen that causes HIV and AIDS. In such cases, there is no “communication” between select populations of human gene pools and the viral genetic material. Recently it has also been hypothesized that this mutation creates immunity to other viruses such as the mosquito borne West Nile Virus.8

Accumulative research has indicated that some humans, about 20 percent of the global population have a deletion mutation in the CCR5-Delta32 allele, where CCR5 is a protein that encodes the protein of the surface of red blood cells in rhesus positive blood groups, while rhesus negative blood groups have been found to correlatively represent the percentage of the population that is resistant to the Human Immunodeficiency Virus (HIV) and Advanced Immunodeficiency Syndrome (AIDS) Virus.

According to various research accounts and some more inconclusive documents, rhesus negative blood group variants in the human population seem to more frequently inherit a delta 32-CCR5 mutation where the result is that the D-antigen is not produced on red blood cells as surface proteins. The semipermeable membranes of these variants cells are more “constricted” so to speak, and are not big enough to allow viral invasion of host cells as a result.

The protein CCR5, is a C-C chemokine receptor type 5 that encodes the human CCR5 gene. The gene that codes for CCR5 is situated on human chromosome 3 at position 21.9 Only 1% of Caucasian individuals is homozygous for the CCR5-Delta 32 allele. CCR5 also called CD195, is a beta chemokine receptor or cytokine receptor that binds to cytokines by chemokine ligands, RANTES, MIP-1α and MIP-1β. A seven transmembrane structure and relationship to G-proteins allow for signal transduction and intracellular signaling in human cells. This chemokine receptor coupled with G-protein receptors are found on the surface of leukocytes but also this gene is expressed on T cells, dendritic cells, macrophages and microganclia. This gene is suspected of having a role in immune functioning though mechanisms of which remain uncertain to some extent.10

Chemokines are small peptides that are potent activators and chemoattractants for leukocyte sub-populations and some nonhemopoietic cells. Again, their actions are mediated by a family of 7-transmembrane G-protein-coupled receptors, the size of which has grown considerably in recent years and now includes 18 members. Chemokine receptor expression on different cell types and their binding and response to specific chemokines, are highly variable. Significant advances have been made in understanding the regulation of chemokine receptor expression and the intracellular signaling mechanisms used in bringing about cell activation. Chemokine receptors have also recently been implicated in several disease states including allergy, psoriasis, atherosclerosis, and malaria. However, most fascinating has been the

observation that some of these receptors are exploited by the human immunodeficiency virus type 1 in gaining entry into permissive cells. They play a role in inflammation and in infectious diseases.(Blood. 2000;95:3032-3043. 2000. The American Society of Hematology.)

Another well know example of an oncogenic virus is the Epstein Barr Virus, first identified by Anthony Epstein, Bert Achong and Yvonne Barr in 1964. When a host organism is infected with EBV, there are active lymphoproliferative responses that take place in the body marked by symptoms such as swollen glands, fever and lethargy. Thereafter, active infection with EBV leads to the non-neoplastic disease mononucleosis and ultimately produces minimal or no symptomatic effects in a host if it remains dormant in resting b-lymphocytes due to an anti-apoptotic cellular response. The anti-apoptotic effects result because the virus successfully integrates within the human genome and the body no longer recognizes specific viral genes as foreign. When EBV leads to neoplastic disease (from, Neoplasia meaning “new growth” in greek) the abnormal proliferation or division of cells occurs. In time this can lead to a form of cancer called lymphoma, including Burkitt’s lymphoma. In this case, the pathogenic microRNA (miRNA) in the EBV causes chromosomal translocations at integrational loci 2;8 and 8;22 in Burkitt lymphoma. Burkitt’s lymphoma is caused by Epstein-Barr virus (EBV) where the avian myelocytomatosis (myc) oncogene is activated by chromosomal translocation T(8;14) (q24;q32) into the immunoglobulin gene locus, such as IGH at 14q32, IGK at 2p12, or IGL at 22q11, which was
seen in 75-85% of cancer individuals. In some cases, miRNA is dually associated with suppression of tumorigenesis but not in the case of EBV in relationship to Burkitt’s lymphoma.11

Something to keep in mind is that certain sub-populations undergo mutagenic changes differently. For example, where gender may play a role, it is my opinion that these observations suggest some sort of locus of integration within the sex determining chromosomes. A more specific instance is that boys with X-linked lymphoproliferative syndrome may develop high-grade, B-cell lymphomas after exposure to EBV.12 Now, theoretically, this also means that more females can survive and carry the trait for X-linked lymphoproliferative syndrome that leads to B-cell lymphomas in male offspring which means that there is a challenge to the mutation being fully selected against.

Another virus, communicable through sexual activity called the Human Papilloma Virus (HPV) may cause cervical cancer by way of a similar process. Harald zur Hausen and Lutz Gissman won the nobel peace prize in 2008 for their discovery of the HPV16 and HPV18 in the 1980’s. These two viral strands account for 70% of cervical cancers.13 Just as there are several variations in human genetic material there are variants of viral genetic material, and we can observe several variations in HPV. HPV is a DNA virus that causes transformation in cells through interfering with tumor suppressor proteins such as p53.14?
Interfering with the action of p53 allows a cell infected with the virus to move into a different stage of the cell cycle allowing the virus genome to be
replicated forcing the cell into the S phase of the cell cycle could cause the cell to become transformed. (Scheffner et al. 1990) According to a study conducted by the National Cancer Institute, HPV 16 is most common accounting for 61% of cervical cancers followed by HPV 18 accounting for 9%, while types 33, 45, 58 and 59 were each identified in one specimen. Sequencing of up to 1349 bases of the 21 HPV 16-positive isolates, encompassing the enhancer/promoter of the upstream regulatory region (URR) and the E6 and E7 genes, revealed distinct patterns of genomic stability and variability. An overall mutation rate of 5% was seen in the URR. One isolate had a large deletion of 436 bases in the enhancer; while varying combinations of 21 point mutations were identified in the remainder, impacting several YY1, NF1, TEF-1 and Oct-1 sites. More sequence variations were found in E6 compared to E7 accounting for 81% vs. 52% of isolates showing at least one mutation, which sometimes resulted in changes to the translated amino acids. Since the E6 and E7 genes encode the oncogenic proteins essential for malignant transformation, and as their expression is controlled by the URR, it is possible that some of the identified mutations altered the oncogenicity of the virus, either directly by changing amino acid sequences of the E6 or E7 oncoproteins, produced changes directly or indirectly through alterations to transcription factor binding sites in the URR. (Human Papillomaviruses and Cancer. The National Cancer Institute. 2008.; Int. J. Cancer 86:695-701, 2000.) The part of the above that I wish to emphasize is that, “ it is possible that some of the identified mutations altered the oncogenicity of the virus: either directly by changing amino acid sequences of the E6 or E7 oncoproteins, producing changes either directly or indirectly through alterations to transcription factor binding sites in the URR,” because it is a highly specified, clear example that describes some mutagenic changes in viral expression. It implies that even if viruses are a major underlaying mechanism in evolutionary change and even though they cannot live outside of a host cells, they can still evolve. I had mentioned earlier that viral evolution could benefit through integration within a human or animal genome but viral evolution most likely unfolds not only in the cells of host organisms but by passing from host to host, across species. Perhaps this is because different species have unique genetic niches that create an environment for viral genetic transitions? We have seen examples of this with the H1N1 influenza virus that originated in swine populations and crossed a barrier to infect human hosts. Similar patterns of multi-species viral crossing-over has also occurred in the case of avian influenza.

What we can observe on a larger scale as a commonality in the expressions and gene profiling where oncoviruses are concerned, is that large scale neoplastic changes are perpetuating. A study on the Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. This study directed emphasis toward the identification of cancer signatures on gene expression, by relying on statistical methods of analyzing comparative metaprofiling for 40 published cancer microarray data sets that contained 38 million gene expression measurements from more then 3,700 cancer samples. Resulting transcriptional profiles were validated through independent data sets for the profound conclusion that there is a common transcriptional profile in various forms of undifferentiated cancers, as universally activated in most cancer types. This is further indicative that there may be core transcriptional features of neoplastic transformations observed in cancer patients. This is how cancer cells continue to develop and do not undergo differentiation.15

If there is one thing that can be taken from all of this new and emerging information about evolutionary development, pathogenesis, and genetics, it is that their is significant evidence as to how viruses integrate within the human genome to create changes and drive evolution, where tumorigenesis is just one identifiable and measurable result being explored presently. These topics are entirely relevant to evolutionary importance in the medical science in that there have been selection pressures identified, mutagenic changes and mortalities in global populations. Understanding the evolutionary mechanisms involved may point research in a direction where treatments and prevention strategies can be cultivated for success. It seems that one of the best strategies for the management of disease and prevention of resistance, it to develop medications or treatments that target only the most virulent strains of a pathogen of interest so that the weaker variants are the ones that survive and reproduce thus causing less harm to the host. However, this strategy may not work in the case of HIV, since all variants of the viral pathogen exploit the host in harmful ways. This approach may decrease the incidence of disease virulence in antibiotic resistant pathogens but treatment would most likely have to evolve within an evolving target population. The evolution of pathogens would need to be closely tracked, as well as projected, for this approach to work most efficiently. I hope to see more scientists take this approach, of developing methods that are complementary to more analogous processes of selection rather then develop what we now know to be more reckless, for the moment type of approaches to developing medical interventions.

Citations

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2. DETECTION OF THE BOVINE LEUKOSIS PROVIRUS IN THE BLOOD AND SEMEN SAMPLES OF BULLS. Reza Asadpour. Razi Jafarei, Clinical Science, Faculty of Vet.Med. University of Tabriz, 2Faculty Veterinary Medicine, 3Clinical Science, University of Tabriz, Tabriz, Iran

3.Clonal integration of a polyomavirus in human Merkel cell carcinoma. Feng H, Shuda M, Chang Y, Moore PS. 2008. Science 319 (5866): 1096–100. doi:10.1126/science.1152586. PMID 18202256)

4.Aids Related Cancers. Gale Encyclopedia of Cancer.

5.Identified Kaposi sarcoma-related herpes virus in 1994 by using representational differences analysis (RDA) that compared the differences in the genomic sequences of cDNA samples. Schmidt, C. 2008. “Yuan Chang and Patrick Moore: Teaming Up To Hunt Down Cancer-Causing Viruses”. JNCI

Journal of the National Cancer Institute 100: 524. doi:10.1093/jnci/djn122. ; 31- “Ethel Cesarman, M.D., Ph.D. | Weill Cornell Medical College”. Med.cornell.edu. Retrieved 2010-03-17.]

/ Patrick Moore, Yuan Chang, Frank Lee and Ethel Cesarman. 1994.
6.HIV: The Ultimate Evolver. Understanding Evolution. adapted from Evolution: The Triumph of an Idea, by Carl Zimmer, © 2001, Harper Collins Publisher.

7.Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele. Alison P. Galvani, Montgomery Slatkin. Department of Integrative Biology, University of California, Berkeley, CA. Proc Natl Acad Sci U S A. 2003 December 9; 100(25): 15276–15279.Published online 2003 November 25. doi: 10.1073/pnas.2435085100. Pubmed 2003. The National Academy of Sciences. 2003.

8.HIV Protection CCR5 Chemokine Receptor Mutation. Judy Arbique. 2006. ; The evolutionary history of the CCR5-Delta32 HIV-resistance mutation. Galvani AP, Novembre J. Microbes Infect. 2005. Feb;7(2):302-9. Epub 2005 Jan 8. Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, CT.

9.CCR5-delta32: a very beneficial mutation. Andrew Lamb. Journal of Creation 20(1):15 April 2006. ; CCR5-delta32 is the deletion mutation that has become the cohort in HIV resistance amoungst certain populations. Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, et al. (1996) Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382: 722–725)

10. Partial protective effect of CCR5-Delta 32 heterozygosity in a cohort of heterosexual Italian HIV-1 exposed uninfected individuals. Enrico M Trecarichi, Mario Tumbarello, Katleen de Gaetano Donati, Enrica Tamburrini, Roberto Cauda, Christina Brahe, Francesco D Tizian. Department of Infectious Diseases, Catholic University, Rome, Italy. Department of Medical Genetics, Catholic University, Rome, Italy. 25 September 2006. Trecarichi et al; licensee BioMed Central Ltd. 2006.

11. Chimeric transcripts with an open reading frame are generated as a result of translocation to the PVT-1 region in mouse B-cell tumors. Huppi K, Siwarski D. Int J Cancer 1994; 59: 848-51.; Identification of a human translocation unit affected by the variant chromosomal translocations 2;8 and 8;22 of Burkitt lymphoma. Shtivelman E, Henglein B, Groitl P, Lipp M, Bishop JM. Proc Natl Acad Sci USA 1989; 86: 3257-60.

12. Epstein Barr virus infections in males with the X-linked lymphoproliferative syndrome. Grierson H, Purtilo DT. Ann Intern Med 106:538,1987

13. Harald zur Hausen. Autobiography. Nobelprize.org.

14. Regulation of CAK kinase activity by p53. Schneider E, Montenarh M, Wagner P. Medical Biochemistry and Molecular Biology, University of the Saarland, Building 44, 66421 Homburg/Saar, Germany Oncogene. 26 November 1998, Volume 17, Number 21, Pages 2733-2741

15. Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Daniel R. Rhodes, Jianjun Yu, K. Shanker, Nandan Deshpande, Radhika Varambally, Debashis Ghosh, Terrence Barrette, Akhilesh Pandey, Arul M. Chinnaiyan.

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