by Allison Pardieck
for Human Evolution
Disorders that affect the human brain are some of the most difficult to understand, diagnose, and treat. Among the most mysterious of these are those caused by a pathogen only recently defined. Prions, infectious agents that begin as functioning proteins, have astonished researchers by causing fatal brain degeneration in a small number of individuals. They are believed to be one of the only pathogens to have a purely mechanical method of reproduction, and represent a rare but serious danger to the human population. Prion diseases may be ancient, and the human body seems to have evolved a genetic prophylactic method against developing the diseases in any of their transmissible methods.
The first thing to understand is that the prion is not inherently harmful. Prion proteins (known as PrPC) occur normally within the healthy body and exist in every cell, but are far more abundant in the brain. Although their purpose is not completely understood, they are believed to be involved in assisting the nervous system by maintaining the myelin sheath that protects neurons. Prion proteins are useful to the body’s homeostasis, protecting neurons and the nervous system, and they are thought to have more uses that have not yet been discovered. The Journal of Neuroscience has reported that prions might be an essential part of “developmental plasticity,” allowing the brain to change in structure and expansion as its owner gains new mental experiences. 1
Prions only turn into fatal infectious agents when they become abnormal. In these cases, the protein has taken on a misshapen form, and the cause of this aberration is not entirely understood. The infected human body’s prions increase in number as the first aberrant protein adheres to others and forces a “chain reaction that propagates the disease and generates new infectious material.” Studies have been completed in transgenic mice which have supported this hypothesis, but the results of these experiments are not absolute as of yet.2 Rampant abnormal folding of prion proteins in the brain leads ultimately to a form of transmissible spongiform encephalopathy—disorders that permanently damage the brain by eating holes in it (giving it a sponge-like appearance) and have different rates of infection, forms of transmission, and onset of symptoms depending on the type of TSE the body has contracted. Found in both animals and humans, they are always fatal, and often lead to a debilitating delirium and loss of mental faculties towards the end of the disease.
Researchers remain unsure about how the normal presentation of prion proteins is able to transform spontaneously into its infectious state and subsequently multiply through infecting other prions, although physical examination of the prion structure bolsters this theory. Researchers are also unsure as to why a change in the structure of the prion protein from normal to damaged would result in the degeneration of brain tissue found in prion disease patients. One theory about this lies in the prion’s original purpose in the nervous system: apoptosis, or programmed cell death. Prions appear to normally carry out this task; it is possible that the aberrant form of the protein turns this mechanism that is useful for brain development into a weapon against its host.
The evolution of the prion itself raises serious questions about its existence. As a protein, it contains no nucleic acid genome. No previously known pathogen has been thought to exist without nucleic acids, as that enables the pathogen to reproduce. It was a fascinating realization found in the research of prions that raised evolutionary questions, but also more immediate fears of epidemics.
There is a theory that postulates that the infectious nature of prions did not evolve on its own. Proteinaceous infectious particles do not contain a genome to code for pathology, however some researchers suggests that prions may become a pathogen due to exposure to foreign nucleic acids. Called the virino hypothesis, this theory relies on the knowledge that different strains of prion disorders exist, transmit differently, and result in different symptomatic patterns. Strains of a pathogen result from changes in the nucleic acid sequence; however, no nucleic acid has been positively identified as being related to prions, and prions, after becoming infectious, do not show vulnerability towards introduced methods of treatment which disrupt nucleic acid sequencing. 2
Prions, due to their protein nature, are notoriously hard to get rid of. Their lack of nucleic acids makes them resistant to ultraviolet radiation, which is known to disrupt other pathogens; however their apparent lack of DNA is not enough to explain the prions’ persistence. The ashes of destroyed individuals infected with prion disorders are also found to be dangerously infectious, surprising researchers. 3 Recently, it was found that infected prions can be found in the skin of patients who died from variants of transmissible spongiform encephalopathy. This is advantageous in diagnosing the disorder (which could previously only be done through brain biopsy), but raises concerns about tools that break the skin possibly becoming vectors for the disease. In a study following the one that discovered that prion evidence resided in the skin, the researchers isolated the recovered prions, and introduced them directly into the brain of mice bred to be susceptible to the disease that primarily affects humans; the animals became infected, although it was found that those injected with prions coming from the skin became sick much slower than their counterparts who had been infected with material directly from the deceased human’s brain. Hospitals, where tools are disinfected and reused constantly, are not prepared to disinfect tools against prion contagions, as they are known to adhere to the common stainless steel used in the tools.
Researchers found that cloned prions, when grown in tissue cultures, can become increasingly diverse in their new environment. “Mutational events” cause the proteins to evolve at an elevated pace, and “selective amplification” begins in the cells. Essentially, they can evolve rapidly without the benefit of a genome. 4 This raises additional questions about how these proteins are able to become infectious and propagate without a genome that can code for this behavior. A burgeoning theory is that perhaps prions originated earlier in organism evolution than was previously thought possible:
The rather unique properties of prions and their presence in very different kinds of living species suggest that this type of molecule was created at a very early stage of evolution and may even represent a relic from a time where peptide evolution was ongoing and RNA/DNA did not yet exist. 5
Carleton Gajdusek, a researcher credited occasionally with discovering prions—although not with naming them—believed that “there is a nanoscopic bit of clay or silica in the prion that captures the form of the protein after the rest of the structure has been incinerated.” He referred to the protein copies that he described as “atomic ghost replicas,” and theorized that these are the agents that infect prions with the abnormal folding, resurging the infection cycle. 6
Most human degenerative brain disorders found to be caused by prions fall under the name Creutzfeldt-Jakob disease. It is classified differently than other prion disorders by its sporadic nature, although it can also occur hereditarily. Five to ten percent of CJD cases are caused by a genetic mutation, and an estimated less than one percent of cases is thought to come from exposure to infected tissue from another person or substance ingested. 7 There are about three hundred cases in the United States per year, and most die within a year of developing symptoms. The symptoms of CJD are dementia, anxiety, blurred vision or blindness, insomnia, difficulty speaking or swallowing, and sudden jerking muscle movements. It has gained some attention from researchers as being strikingly similar to Alzheimer’s. Stanley Prusiner, a leading prion researcher credited with ascribing their name, tracked the creation of prions to a gene on human Chromosome 21, whereas Alzheimer’s is associated with a risk factor on Chromosome 19. Prusiner came to the conclusion that the two disorders were “not a single underlying disease but a single disease principle.” 8
Although not proven, there is a general theory that there is a link between sporadic CJD and ingesting meat from cows that have been infected with another prion disease called bovine spongiform encephalopathy, known colloquially as mad-cow disease. This theory gained traction during the British epidemic of the variant CJD that was tentatively traced to the consumption of meat; the majority of cases with variant CJD were teenagers, whereas normally the individuals who develop CJD randomly tend to be about sixty years of age. 9 Bovine spongiform encephalopathy affects the brains of cattle, causing the animal to exhibit confusion, listlessness, and an inability to function towards the end of the disorder. Like all prion disorders, it is ultimately fatal to the organism affected. Some investigation into the cause of the small epidemic found that it was likely caused by cows that became sporadically infected, and when they perished were destroyed and ground into bone meal that was fed to the healthy cows, continuing the cycle of infection and causing the panic.
The theorized cause of the BSE epidemic is strikingly similar to that of a prion disease found in an isolated population in the 1950s. Kuru, a word used by the Fore linguistic group of Papua New Guinea to describe the unstoppable shuddering of the disease’s victims, likely started as a sporadic case of CJD in one person that transmitted to the individuals who ingested the corpse. The cycle of kuru in this population of the Eastern Highlands Province likely began in the early 1900s. 10 Although the indestructible nature of infected prions likely would mean that improper handling of infected corpses would have been enough to make those involved ill, transmission was facilitated most effectively through ingesting infected flesh during ritual funerary practices. Occasionally, the brain of deceased individuals in the Fore linguistic tribe would be removed from the skull and eaten, usually by the women and children of their family. 11 Following the colonialist invasion of the previously undiscovered tribe, endocannibalism within the community was discouraged by the proselytizing foreigners, and incidence of the disease declined to an negligible percentage of the population.
Symptoms that surround kuru are similar to CJD, but are noted to have evolved some due to the disease’s isolation within the population. They included pain in the extremities, increasingly severe coordination issues, difficulty walking, headaches, and increasing loss of control in one’s muscles, resulting in the spasms that the Fore people noted as the defining feature of the disease. Incubation of kuru within a person who had become infected on average was around one decade, however incubation periods of up to five decades have been reported. After the first case appeared in the early twentieth century, a peak mortality of over two percent of individuals in the population was found in some of the villages, and some villages “became largely devoid of young women.” 12
Among the obscure and even more rare instances of prion disorders is Gerstmann-Strussler-Scheinker disease. Unlike sporadic instances of prion diseases, GSS disease is almost exclusively inherited. GSS was discovered to be inheritable on a dominant allele of an autosomal gene; there would be half a chance that a child of any gender would develop the disorder if born to at least one parent who developed GSS. 13 Symptoms included ataxia, bradyphrenia, dementia, slurring speech, abnormal eye movements, rigid muscles, blindness, and deafness. Sufferers of GSS developed symptoms typically between thirty-five and fifty years of age, and usually survived an average of five years after diagnosis. 14
Another disorder that is related to GSS in methods of transmission is fatal familial insomnia. FFI is inherited, although it can rarely manifest in a sporadic manner. It targets the thalamus and parts of the medulla oblongata that manage motor control, resulting in a progressive loss of neurons. Symptoms manifest typically in middle age, the average victim being fifty-one years old; this helps the disorder to continue onto the next generation by striking its victims after natural childbearing age. However, it has been known to begin to present in patients as young as eighteen years old and as old as seventy-two. Its progression manifests as increasingly debilitating dementia, hypothermia, hyperthermia, ataxia, and worsening insomnia. As a result of the insomnia, phobias, weight loss, lack of appetite, hallucinations, and delirium emerges. 15 Death of the affected person usually comes as a result of the total inability to sleep.
As with most pathogens, the human body appears to have developed a defense against the spread of prion infection. John Collinge and researchers examined the prion genes of people known to be afflicted with CJD. In his first study, he found that of the two copies of the PRNP prion gene that the sufferer had inherited from their parents, both had the genetic code for the amino acid called valine in codon 129, making them homozygous for that important portion of the gene; he found this in forty of his forty-five patients. 16
Another researcher, Michael Alpers, conducted tests on members of the Fore tribe who had not fallen from kuru, although they had participated in the ritual funerary practices that involved cannibalism of the deceased. In the women studied, most of them had a heterozygous polymorphism. On one of the genes inherited, there was a methionine in place of one of the valines. Blood tests of the surviving Fore people showed “the highest percentage of heterozygotes of anyone in the world.” Based on multiple following studies, the correlation between heterozygosity for that amino acid and decreased likelihood of contracting or developing CJD has been accepted. This theory, first developing in the early 1960s, gained additional evidence following the BSE outbreak in Great Britain in the 1990s. Although exposed to an estimated 640 million doses 18 of BSE in their food supply, only 178 individuals died of vCJD: 19
There was something in heterozygosity that altered the shape of the prion to make it less effective at spreading within the body...More recent research shows that there are people [with heterozygosity] who have a prion mutation but never get sick, or at least die of old age-related diseases before they get sick. 20
An explanation for the extreme difference is that the majority of the British population consisted of heterozygotes, and was less susceptible to the disorder. “All clinical cases of variant Creutzfeldt-Jakob disease to date have been in MM [methionine-methionine] homozygotes,” states a research article presented in the New England Journal of Medicine. 21 The heterozygous advantage is similar to that of the genes associated with sickle cell and Tay-Sachs disorders.
The advantageous variant of codons 127 and 129 is represented globally, in every population. It is found in different percentages in various ethnic groups; for instance, Japan has a heavily homozygous population, 22 and the Fore tribe, in the areas with the highest exposure, has a high number of heterozygotes. The favorable polymorphism is most common in the Eastern Highlands Province of Papua New Guinea, and women who were born into this community after ritual cannibalism faded from use were not as likely to have heterozygosity as their ancestors.
It makes sense evolutionarily for those who reside for centuries in communities where prion disorders are prevalent to have a higher number of protected alleles, but as stated earlier heterozygosity is disproportionately represented in all ethnic groups across the world. Heterozygotes are found in communities not known to have experienced prion diseases in epidemic form. A possible explanation for this protection to have become favorable across the entire world’s population is that a scourge of prion disorders happened long before recorded history, prompting a human ancestor to develop a methionine-valine polymorphism as a defense. “The [heterozygous] genes are more common than you’d expect,” stated Simon Mead, a prion researcher from University College London. It suggests that prion disorders must have struck when humans’ ancestors were within close proximity, constantly interbreeding, and engaging in risky eating habits. The age of prion disorders supports this ancient theory as well, considering that they may have been pathogens since before the later stages of peptide evolution when DNA and RNA may not have existed. Heterozygotes would have been favored in a situation that quickly destroyed the homozygotes, allowing for the favorable gene to pass on to today’s population. This and a general revulsion could have been evolution’s response specifically to consequences of endocannibalism: a common, and dangerous, practice of hominids.
One of those ancestor hominids was Homo antecessor. H. Antecessor existed at around 1.2 million to 800,000 years ago, and is considered by some anthropologists to be the last common ancestor of modern humans and Neanderthals. Others argue that that honor belongs to Homo heidelbergensis, but those who support H. antecessor believe that the features of H. heidelbergensis are too Neanderthal-like to be equidistant between them and humans. 23 H. antecessor had a larger brain size than their predecessors, a fossa between the cheek bone and the nasal passages, a flatter face, and large incisors.24
H. antecessor is widely accepted to have been an occasional cannibal. The Gran Dolina archeological site in the Atapuerca Mountains was dated to about 800,000 BCE, when the Earth’s magnetic field last switched. It is the oldest site of hominid and human remains in Europe. Here two sets of H. antecessor remains were found: a fourteen-year-old and a ten-year old. The ten-year old showed signs of malnutrition, and the bones were found near the mouth of the cave, which originally confused researchers, as that is where animals eat their prey. However, animals did not make the marks on the bones of the children:
...further research showed that the children’s bones, as well as some animal bones found nearby were dissected with a precision that exceeds the skills of non-human carnivores...two segments of finger or toe bone and a cranium had the meat scraped out of them. Other bones had been snapped so that the marrow could be sucked out...either hominids celebrated some sort of ritual that involved pulling the meat off their dead, or, more probably (because hominids of 800,000 years ago were unlikely to be capable of such symbolic behavior) they were eating other hominids for food. 25
Due to some of the bones showing signs of malnutrition, some anthropologists speculate that there was not an abundance of meat or other sources of sustenance in the area. H. antecessor may or may not have recognized their own species in death. Chimpanzees—Homo sapiens closest living genetic relative and the animal compared to hominids in deciding their intelligence millions of years after their death—do not kill their children, so the scenario that the H. antecessor adults did this is not likely. Possibly the children died of natural causes such as starvation, and the others took advantage of the situation. Possibly a rival tribe of hominids attacked the children. Regardless, evidence shows that a creature approaching human ingested the bodies of the deceased hominids: most importantly, their brains were scraped out of their craniums. If we know that H. antecessor engaged in cannibalism, we can assume that other hominids did so as well.
The most important of these hominids are the archaic humans who descended from H. antecessor, possibly yet undiscovered, who lived around 500,000 years ago. Researchers have traced the recent history of the prion protective polymorphism, and found that methionine was the original amino acid and valine began replacing it in codon 129 at around that time. 26 The theory of population genetics suggests that, for every modern human population to contain a sizeable amount of prion disease protection among them, these humans were either cannibals themselves or the valine substitution was a recent mutation from their ancestors.
This mutation would, in theory, become favorable during an epidemic of prion disease. At this time, the population of archaic humans, the fledglings of modern humanity, would be at a count of about two thousand. The most effective diseases among them would be slow, allowing transmission between hosts before and after the original host dies. Prion disorders certainly allow for that, being inheritable from parents, infectious through eating diseased meat (possibly from deceased relatives), and spontaneous at a certain age. Anthropologists know that prehistoric humans would eat meat, for they were too large and used too much energy to subsist on fruit and grains alone; they required a concentrated form of protein. This would give a food-borne pathogen an advantage against the small population of humans, “because they seek it out and put in their own mouths.” 27 In theory, the cycle of eating diseased corpses slowly became an epidemic, and the growing populace was threatened with extinction. In this situation, the methionine-valine mutation on the PRNP gene became a sudden advantage: if a hominid was exposed to damaged prions, they were less likely to affect them. Like all other traits that humans as a species possess, the codon 129 mutation was passed to the descendants of lucky hominids and spread throughout the world population as the archaic humans migrated outward. Humans never stopped eating meat, and thus this mutation was still useful among them. As researchers saw in the Fore population, heterozygosity grew in number among their people in a short period of time among the survivors, as a defense against kuru.
As research continues into the study of neuropathology and human evolution, more will be understood about the way prions have functioned in prehistory and how they will continue to function for the human population. For now, as with most evolutionary topics, the main discussions surrounding prion diseases and its sufferers will be steeped in theories. There are no pathogens discovered that is like it in the way it reproduces and how it affects the brain. It is not so much an invasion, as it is the body’s proteins turning against it. For now, CJD sufferers have little information about their disorder, and the descendants of those with familial prion diseases remain uncertain about their future. Although the body has some methods for preventing infection, it is not one hundred percent, and researchers are still unsure about the extent of the prevention.
1 Costandi, Mo. “Proteins behind Mad-Cow Disease Also Help Brain to Develop.” Nature News, Nature Publishing Group, 14 Feb. 2013, Web.
2 “What Is a Prion?” Scientific American, www. scientificamerican.com/article/what-is-a-prion-specifica/. Web.
3 Max, D. T. “Did Man Eat Man?” The Family That Couldn't Sleep: Unraveling a Venetian Medical Mystery, Portobello, 2008, pg. 195–195.
4 Li, Jiali, et al. “Darwinian Evolution of Prions in Cell Culture.” Science, American Association for the Advancement of Science, 12 Feb. 2010, Web.
5 Rode, Bernd M, et al. “Are Prions a Relic of an Early Stage of Peptide Evolution?.” Peptides, Elsevier, 27 Jan. 2000, Web.
6 Max, “Did Man Eat Man?” The Family That Couldn't Sleep, pg. 195–195.
7 Grady, Denise. “Abnormal Proteins Discovered in Skin of Patients With Rare Brain Disease.” The New York Times, The New York Times, 22 Nov. 2017, Web.
8 Max, “Did Man Eat Man?” The Family That Couldn't Sleep, pg. 191.
9 Grady, “Abnormal Proteins.” Web.
10 Max, “Did Man Eat Man?” The Family That Couldn't Sleep, pg. 205.
11 Mead, Simon, et al. “A Novel Protective Prion Protein Variant That Colocalizes with Kuru Exposure — NEJM.” New England Journal of Medicine, 19 Nov. 2009,Web.
12 Mead, “A Novel Protective Prion Protein.” Web.
13 “What Is a Prion?” Scientific American, www. scientificamerican. com/article/what-is-a-prion-specifica/. Web.
14 “Gerstmann-Straussler-Scheinker Disease.” Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, 7 Nov. 2016, Web.
15 “Fatal Familial Insomnia.” Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, 2 Dec. 2016, Web.
16 Max, “Did Man Eat Man?” The Family That Couldn't Sleep, pg. 199–200.
17 Max, “Did Man Eat Man?” The Family That Couldn't Sleep, pg. 201.
18 Max, “Did Man Eat Man?” The Family That Couldn't Sleep, pg. 201.
19 CNN Library. “Mad Cow Disease Fast Facts.” CNN, Cable News Network, 4 June 2017, Web.
20 Max, “Did Man Eat Man?” The Family That Couldn't Sleep, pg. 202.
21 Mead, “A Novel Protective Prion Protein.” Web.
22 Max, “Did Man Eat Man?” The Family That Couldn't Sleep, pg. 203–203.
23 Wayman, Erin. “Homo Antecessor: Common Ancestor of Humans and Neanderthals?” Smithsonian.com, Smithsonian Institution, 26 Nov. 2012, Web.
24 The University of Texas at Austin, Department of Anthropology. “Homo Antecessor.” Homo Antecessor | EFossils Resources, Web.
25 Max, “Did Man Eat Man?” The Family That Couldn't Sleep, pg. 206.
26 Max, “Did Man Eat Man?” The Family That Couldn't Sleep, pg. 204.
27 Max, “Did Man Eat Man?” The Family That Couldn't Sleep, pg. 204.