Prions: introducing a complex scientific controversy to a biology classroom.
Prion diseases (Causes of)
Brain damage (Risk factors)
Virus-vector relationships (Analysis)
|Author:||Zaitsev, Igor V.|
|Publication:||Name: The American Biology Teacher Publisher: National Association of Biology Teachers Audience: Academic; Professional Format: Magazine/Journal Subject: Biological sciences; Education Copyright: COPYRIGHT 2009 National Association of Biology Teachers ISSN: 0002-7685|
|Issue:||Date: Nov-Dec, 2009 Source Volume: 71 Source Issue: 9|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
It has been almost 50 years since Thomas Kuhn, in The Structure of Scientific Revolutions, posited that science does not progress by the steady accumulation of knowledge, but rather by a system of competition among paradigms. They vie for supremacy through greater parsimony, explanatory power, and popularity among the community of scientists (Kuhn, 1962). The current controversy concerning the identity of prions (PrPs) (proteins devoid of the nucleic acid) as the infectious agents of transmissible spongiform encephalopathies (TSE) elucidates all the issues involved in just such a debate.
While modern biology high school and university textbooks cover many scientific controversies that have been resolved decades and even centuries ago, they fail to cover current scientific disputes. This article is intended to address such an omission by introducing the prion controversy in biology classes in high schools and colleges.
In 1982, biochemist and neurologist Stanley Prusiner proposed a hypothesis concerning infectious proteins. He identified them as abnormal prions, proteinaceous infectious particles capable of converting normal prions (naturally present proteins in mammals) into an abnormal form causing a fatal disease of the central nervous system (CNS) in both animals and humans. Heretofore, it had been accepted that infections could be caused only by protozoans, fungi, bacteria, rickettsia, viruses, or viroids. Only nucleic acids, informational polymers, were known to be able to duplicate themselves, not proteins. For the discovery of prions which Prusiner posited can cause TSE, he received a Nobel Prize in 1997.
Were Prusiner's hypothesis correct, our understanding of the organic world would be changed forever. However, Laura Manuelidis (2007), one of most dedicated scientists in this field and the head of neuropathology at the Yale School of Medicine, contends that "prions thereby became canonized, although careful review of data revealed many discrepancies." Indeed, even Nobel Prize winners can err (Allchin, 2008), including Prusiner, and prions thus remain in the realm of a hypothesis (Manuelidis, 2007).
Despite overwhelming opposing data published in The Lancet, Science, Virology, The Journal of Virology, Journal of Cellular Biochemistry, Viral Immunology, Journal of NeuroVirology, Proceedings of the National Academy of Sciences, and many other scientificpublications, most, if not all, biology textbooks in the U.S. present prions asthe primary cause of TSE. While there are scientists convinced of the ability of abnormal prions to cause infections, there are other scientists who, based on their observations and experimental data, do not think that prions could become infectious. Manuelidis suggests that prions may simply be part of the late stage of a disease, not part of the cause (Mihailova, 2007), and PrP infectivity is questionable, and perhaps non-existent (Manuelidis, 2007).
* Cannibalism & the Rise of TSE
Since students seem more engaged when instructors incorporate examples from popular culture into classroom discussions (Pryor, 2008), one might start a consideration of prions with mention of Kurt Vonnegut's science fiction novel, Cat's Cradle (1963), before introducing Deadly Feasts (1997), a shocking nonfiction case history of the discovery and epidemiology of the fatal disease TSE. Certainly, truth is stranger than fiction if one were to contrast Richard Rhodes' documented study and any of Vonnegut's science fiction novels. Cat's Cradle, concluding in an apocalyptic climax, concerns the ability of a nucleant that can turn water into ice, just as an abnormal prion can allegedly turn its host prions into abnormal forms, resulting in this fatal brain pathology. Deadly Feasts begins with a description of a burial ceremony that the women of the Fore tribe used to practice in New Guinea, "the last wild place on earth." Sixty or more native women with their babies and small children, the family of a deceased woman, would gather to bury her in their stomachs rather than abandon her to rot in the ground. "Why should we throw away good meat? It is not right," one woman told an anthropologist (Rhodes, 1997). The mourners would eat body parts, including "the bones, which they charred in the open fire to soften them," "even the feces would be eaten, mixed with edible ferns and cooked in banana leaves" (Rhode, 1997). Fore woman recalled that cannibalizing the corpses of their kindred "started within the lifetime of the oldest grandmother." "I eat you," was a Fore greeting (Rhode, 1997). The deceased who died of leprosy or diarrhea were not consumed.
By 1950, a disease called kuru (KOO-roo), which means shivering with cold or fear, had killed women in every Fore village. One of the most pronounced symptoms would be unprovoked laughter. Because of this, the disease became known as "laughing death." The victims would lose their ability to walk, shiver uncontrollably but not from cold or fear; their speech would become blurred. Finally, their ability to swallow would be so impaired that their relatives would have to chew food for the dying victims and force it down their throats. Such symptoms were considered to have been caused by bewitchment. Nevertheless, the flesh of women killed by sorcery was considered dean enough to be eaten by other women. Fore men were blamed for practicing sorcery on their women and children, and were hated and feared by natives of New Guinea. Medical researchers who encountered Fore women's symptoms at first thought they were dealing with a new form of encephalitis. The part of the brain of these Fore patients primarily damaged was the cerebellum. Postmortem examinations revealed multiple holes in this part of the brain. Surprisingly, there was no inflammation as in encephalitis. Interestingly enough, after the cessation of cannibalism, kuru gradually disappeared (Gajdusek, 1977).
Another mysterious disease involving brain damage without apparent inflammation was discovered in Germany in 1913 by a young physician, Gerhard Creutzfeldt. He had a patient whose cheerful personality had abruptly changed. No longer wanting to eat or bathe, she began screaming that she was possessed of a devil and that she was dead and wanted to sacrifice herself. At the same time, the woman had sudden outbursts of laughter, distracted speech, tic-like jerks in her arm, fluttering facial muscles, altered reflexes, and tremors that started up whenever she made a voluntary movement. In her last hours, the woman's swallowing was impaired and she went into a deep stupor. Creutzfeldt, recognizing that this was a new disease, reported his findings in a German medical journal. Alfons Jakob read Creutzfeldt's paper and contacted him because he too had lost patients with similar symptoms. Thus, this disease was named Creutzfeldt-Jakob disease (CJD). One of the most surprising characteristics of the kuru and CJD was that there was no apparent inflammation to the damaged brain. In 1957, a neuropathologist at the National Institute of Health, Igor Klatzo, was the first to associate kuru with CJD, in correspondence with virologist Daniel Carleton Gajdusek. Thereafter, research veterinarian William Hadlow realized that scrapie, the degenerative brain disease he had studied in sheep, was also very similar to kuru and CJD in humans. Studying sheep brain sections under the microscope, Hadlow identified cerebellar holes and sponginess as also occur in the brains of kuru and CJD victims, while it also affected the cerebral cortex in CJD, but not in kuru victims.
If kuru and CJD have the same nature as scrapie, those fatal human neurodegenerative diseases might also be infectious, and, of course, would raise public health concerns. In Gajdusek's lab, in the 1960s, brain tissue from kuru victims had been homogenized and inoculated into those of chimpanzees. Within a couple of years, the animals showed the first signs of inactivity, shaking and trembling, and uncoordinated movements, quickly followed by further physical deterioration. The brains of the sacrificed laboratory animals were sectioned, and with further histological analysis, it was evident that their brain pathology was indistinguishable from that of the kuru victims. Indisputably, the disease had been shown to be transmissible. If it could be passed on to chimpanzees, it could be passed on to humans. The connection between kuru and cannibalism was no longer in question. CJD was not confined to New Guinea, but was occurring throughout the world. British cows had a long history of having been fed protein supplements made from scrapie-infected sheep offal and even infected dead cows. Richard Rhodes called it an "industrial cannibalism" (Rhodes, 1997). It should not have been surprising that those cows developed symptoms somewhat similar to those of infected sheep, which today is known as "mad cow disease" or bovine spongiform encephalopathy (BSE). Consumption of contaminated beef led to spreading deadly infection to humans. Neither cooking, nor chemical disinfectants, nor irradiation deactivate the infectious agent and, at the present time, there is no treatment for TSE. Scientists are racing to identify the precise agent of the fatal disease, as the controversy of possible sources is still unresolved. TSE continues to spread throughout the world, killing people who eat the tissue of cattle infected with BSE, children treated with human growth hormones, patients in surgery (transplants, transfusion, use of contaminated surgical instruments), herds of sheep, cattle, deer, elk, and mink. (See Table 1.)
* Prions or Not Prions--That Is the Question
Primary experiments have shown that the causal agent of TSE is capable of passing through bacterial filter. It causes no apparent inflammation, raises no fever, nor indicates any other signs or symptoms of an immune response. Moreover, this agent was highly resistant to such insults as boiling and even autoclaving. It was also resistant to disinfection with chloroform, carbonic acid, strong formaldehyde, and UV light. No bacteria grew in scrapie-infected tissue, and none was visible under the light microscope.
Could the causal agent of TSE be a virus, "a piece of bad news wrapped in protein," as Peter Medawar once quipped (Rhodes, 1997)? Many scientists reject this, citing its resistance to UV light, which is known to kill microorganisms by damaging their nucleic acids. An experiment done in the 1960s on the homogenate of a scrapie brain with enzymes, known to damage nucleic acids, demonstrated no reduction in infectivity while homogenates with enzymes, known to damage proteins, reduced infectivity by more than ninety percent. So is the infectious agent a protein? At first, a positive answer to this question sounds like science fiction, since, as far as we know, infections are not caused by proteins, but by microorganisms. We know that in order for them to multiply, nucleic acid is required. According to the current fundamental principles of biology, proteins cannot replicate themselves, causing infections as nucleic acid can. Prions lack any nucleic acid and, therefore, violate the "universal" rule of protein synthesis. Francis Crick did not want to overlook the possibility of an exception, noting that discovery of an exception "will shake the whole intellectual basis of molecular biology" (Rhodes, 1997). Even so, one must not jump as yet to a quick conclusion. The infectious agent could be either a virus whose genome is protected from UV light inside a sturdy coat of protein, or a virus that is super efficient at repairing radiation damage to its genome.
At this time, let us recall what Kurt Vonnegut's Cat's Cradle is all about. In this science fiction tale, a scientist creates a nucleant capable of turning all the water on the planet, including the water in human cells and blood, into ice. In 1995, Byron Caughey and Peter Lansbury borrowed Vonnegut's scientific fantasy for the title of a paper, "The Chemistry of Scrapie Infection: Implications of the 'Ice-9' Metaphor" (Lansbury & Caughey, 1995). Vonnegut's fictitious nucleant is a "seed" capable of converting nearby fluid water to crystalline form. Gajdusek visualized a similar infective process at work in the TSE. He proposed that a nucleant crystal of abnormal PrP was the TSE infectious agent. According to his hypothesis, the abnormal prion is capable of converting a normal prion into the abnormal conformation. Prusiner coined the name "prion" and enthusiastically pursued the proof of this hypothesis and, thus, was rewarded a Nobel Prize.
The functions of prions in a healthy individual are still unclear. Some researchers suggest that they might play a role in the cell death and neural excitability. All mammals produce host prions in both diseased and healthy individuals. Prions are expressed across the entire CNS, especially in the hippocampus, striatum, and frontal lobe. The unique sequences of amino acids in a prion make it possible for these molecules to have two different, stable tertiary structures. One type, called a cellular ("healthy") prion protein ([PrP.sup.C]), has functional structure folds with many [alpha]-helices. The abnormal prion protein ([PrP.sup.Sc]) has many [beta]-plated sheets. They are the same protein but just folded differently. [PrP.sup.Sc] is amyloid fibrils assembled in large structures. Prusiner's team of research scientists suggest that [PrP.sup.Sc] converts [alpha]-helices into [beta]-plated sheets (Pan et al., 1993) and thus transmits TSE (Prusiner, 1998). Let us consider some scientific data that contradicts rather than supports Prusiner's prion hypothesis:
1. It has been established that one of the major routes of transmission of TSE is along the gastrointestinal tract in which an infectious agent invades the mucosa and, thereby, infects the Peyer's patches. However, recently it has been shown that the PrP is rapidly destroyed by alimentary track fluids (Jeffrey et al., 2006). If so, it makes the ability of "infectious PrP" to implant further, crossing the blood-brain barrier, almost impossible. The viral hypothesis does not contradict this new finding since we know that enteroviruses are capable of withstanding acid and proteolytic secretions.
2. The presence of hundreds of different strains of TSE in different species also challenges the prion hypothesis. The presence of strains is one of the characteristic features of an infectious agent with a nucleic acid. These strains have been successfully passed from one species of animals to another, and even back to the original species (e.g., sheep to mice, then mice to sheep), preserving their singular strain identity, despite PrP differences between sheep and mice (reviewed in Manuelidis, 2007). The presence of different forms of PrP in those species during infection does not satisfy the first of Koch's postulates that states that a pathogen must be invariably present, in a constant form, in every case of the disease. Consequently, how can protein particles behave as various strains while they display different identities in a single strain of the disease?
3. Infectivity and PrP titer are not proportional across strains. Many different animal models in different laboratories show that PrP presence is a poor marker for the level of infectivity, and the lack of PrP does not preclude infection (reviewed in Manuelidis, 2007). Some slow CJD strains show no detectable PrP. Baker et al. (2002) showed that living microglia from a CJD-infected brain had no detectable prions, yet contained maximal levels of infectivity. Another study shows that "PrP neither encodes nor alters agent-specific characteristics" (Arjona et al., 2004). Blocking the formation of prions by an antimalaria drug does not lengthen CJD victims' lives (Collinge, 2009). These are a few examples from many studies that do not confirm prion infectivity. Initial misleading data, suggesting that PrP is the infectious agent, had been the result of technical difficulties to purify PrP from nucleic acid present in infected animal tissue; thus, infectious preparations often contain a large amount of nucleic acids.
4. "The host can recognize a TSE agent and recruit its innate immune system to respond as early as 20-30 days after inoculation" while "PrP begins to accumulate only at 90 days post-inoculation, and is incapable of activating the same immune pathways" (Manuelidis, 2007). Lu et al. (2004) detected innate immune host responses before the occurrence of PrP changes. "These host responses are consistent with a foreign pathogen, but not host encoded PrP. The epidemic outbreak of BSE also strongly implicates an exogenous infectious agent" (Liu et al., 2008).
5. Virus-like particles in TSEs had been detected in many experimental animal tissue samples by many different laboratories (David-Ferreira et al., 1968; Bignami & Parry, 1971; Lampert et al., 1971; Baringer & Prusiner, 1978; Sklaviadis et al., 1992; Liberski & Brown, 2007; Manuelidis et al., 2007). Treatment with low concentrations of SDS removed residual PrP from these particles, but did not reduce their infectivity. On the other hand, disruption of nucleic acid-protein complexes destroyed 99.5% of their infectivity (Manuelidis et al., 1995). It has been shown that cells infected with scrapie and CJD agents produce intracellular 25-nm virus-like particles (Manuelidis et al., 2007). Their size is similar to the size of small RNA viruses. Disruption of these viral particles destroys infectivity.
The abundance of scientific data and arguments among an impressive segment of scientists, contradicting and challenging Prusiner's hypothesis, warrants continued reconsideration. By including current unresolved scientific controversies, such as the hypothetical nature of prions, for the first time in biology courses, students could be introduced to one of the most contentious unresolved disputes in the culture of a discipline so scrupulous that finding the true answer can be as hard as "nibbling on granite," as they say in Russia. The theoretical importance of the topic of infectious proteins might be compared to the eighteenth-century debates on spontaneous generation, although the task of identifying the nature of the infectious agent of fatal TSE has proven far more complicated than what had been resolved by Francesco Redi and Louis Pasteur. This mysterious agent, like a molecular ghost, is still "invisible" to us even at the most sophisticated levels of technology and molecular biology. The answers may be found as research scientists devise new ways to evaluate the TSE infection. Giving students the opportunity to think about and discuss this topic will greatly expand their background and skills, as the scientific community still searches for answers.
* Classroom Activities & Assessment
The prion controversy would be best introduced at the conclusion of the biology course. Having covered the scientific method, characteristics of living things, the structure of proteins and nucleic acids, the immune response, the nervous system, and Koch's postulates, students would then have the background to engage with the issues. Since this controversy requires the integration of biological knowledge, as well as the skills to apply the scientific method of inquiry, it could be used advantageously by biology teachers either in high schools or colleges. Introduced in a case studies format, such a scientific dispute can be considered during an inquiry-based session. To increase classroom participation, and at the same time review material covered during the course, I have devised interrupted case classroom discussion on TSE consisting of two sessions. Below is the suggested strategy in approaching the topic.
First Session: The Mysterious Disease
Introduce the details of kin cannibalism in the Fore tribe of New Guinea, but before divulging any specific information on TSE, ask, "What might be another explanation for the death of the Fore women other than sorcery?" Students should write their diagnostic hypotheses so that afterwards, they can compare them to additional information eventually provided them. Then, dividing students into groups, ask them to share and debate their hypotheses with one another.
After these group discussions, compare the symptoms of the disease in Fore women with that of outbreaks of similar diseases found in the other parts of the world. Provide the class with a list of questions detailing the way the brains of the TSE patients deteriorate. (See Table 2.)
Before moving on, point out that if we are to satisfy each of Koch's fundamental postulates (see Table 3) in experiments conducted with kuru and CJD, we would have proof not only that those diseases are infectious, but we would able to identify the infectious agent. Ask students to do some Internet research on the causative agent of CJD, and summarize their findings in a brief report.
Second Session: The Virus versus Protein
At the beginning of this session, ask students what they know about the common characteristics of the prokaryotic cell, while refreshing their memory about immune responses to bacterial infection. Point out that the spiroplasma (the thermostable, small, helical bacteria discovered in the 1970s) was so small that it could pass through bacterial filters. These bacteria have often been present in cases of TSE, but not always (Alexeeva et al., 2006). This fact does not satisfy Koch's first postulate, thus ruling out spiroplasma or any other bacteria as an etiologic agent.
At this point in an inquiry-based session, present conflicting data from the two opposing groups of research scientists. In light of such information, ask if any students want to reconsider their initial hypotheses: "Why have these scientists come to such contradictory conclusions? Could it be that the hypotheses regarding TSE infections ought to be reconsidered?" One may want to give a homework assignment to research the methodology of studying TSE.
After providing the class with selected papers from leading scientific publications containing conflicting data, set up an "Abnormal PrP Trial." Announce that abnormal PrP pleads "not guilty" in causing TSE. One group of students must devise a rationale for the defense of the abnormal prion, while another prepare the prosecution's arguments. During the session, one can draw the students attention to topics covered earlier in the school year. (See Table 4.)
After the "trial," every student is expected to write an essay on the "Tentative Nature of Science and the Studies Done on TSE." In assessing their work, one must pay attention to their originality, critical thinking, factual details, and integration of biological topics.
I have observed a high level of student interest during such interruptive classroom discussions. The class becomes particularly fascinated with the unusual transmission and nature of this deadly disease. Students who were shy begin to ask questions. The class as a whole begins to question the fact that its textbooks have completely ignored the theoretical importance of the complex scientific controversy.
Many recent studies show that case studies increase student participation and improve student understanding of subject matter. However, one of the negative aspects is that it could become time-consuming. Introducing the current controversy on TSE. a teacher could "kill two birds with one stone" by covering the topic of prions from the curriculum while reviewing material for the final examination.
Below are low-power light microscope images of sections of the laboratory mouse's brain that has been affected by one of the strains of transmissible spongiform encephalopathy (TSE), a deadly disease in animals and humans.This strain had been passed from an infected cow to a human and then on to the mouse, preserving its original identity throughout transmission. The sections of the brain were taken from the same TSE-infected mouse. They have been stained using immunohistological techniques to reveal changes occurring due to the infection.
The top section is a part of the mouse's cerebrum. There are numerous activated microglial cells (red) that indicate an ongoing process known as microgliosis. On the section below, another staining of the cerebrum reveals numerous accumulations of abnormal prion proteins (also in red).This indicates a TSE infection.
In the third section of the brain, there is a brain stem and a cerebellum. While the brain stem is filled with abnormal prion proteins, there is no indication of their presence in the cerebellum. The same pattern is also evident in affected cows and humans with this TSE strain. The fact that the pattern remains the same in such transmission is characteristic of an infectious agent with nucleic acid.
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IGOR V. ZAITSEV, Ph.D., is Assistant Professor in the Science Department, City University of New York, Borough of Manhattan Community College, New York, NY 10007; e-mail: email@example.com.
Table 1. Some forms of transmissible spongiform encephalopathies in mammals. SPECIES DISEASE ABBREVIATIONS man kuru -- Creutzfeldt-Jakob Disease CJD sheep scrapie -- mink transmissible mink encephalopathy TME cattle bovine spongiform encephalopathy BSE deer chronic wasting disease CWD elk Table 2. Suggested questions for the first session. 1. In one word, what type of damage in the human body would trigger tic-like jerks, tremors, and fluttering facial muscles? 2. What is the function of the cerebellum? 3. What is the function of the cerebral cortex? 4. Why had Fore women lost their ability to walk, yet remained conscious until they died? 5. Which centers in the brain are responsible for speech? 6. If, in kuru patients, only the cerebellum was damaged, how you would explain blurred speech? 7. Does this additional information correspond to your pri mary hypotheses? 8. How would you explain the fact that, after the cessation of cannibalism, kuru disappeared? Table 3. Koch's postulates. 1. Pathogen must be invariably present in constant form in every case of the disease. 2. Infectious agent must be isolated from the host with the disease and grown in pure culture or recombinant form. 3. The cultivated agent must be able to reproduce when it is inoculated into a healthy susceptible host. 4. Pathogen must be recoverable from the experimentally infected host. Table 4. Suggested questions for the second session. 1. How would you describe a nucleic acid? 2. How many different types of nucleic acids do you know? 3. What can DNA and RNA do that proteins can not? 4. How would you explain the central dogma in biology, and who defined the central dogma? 5. How would one define protein? 6. How many structures do proteins have? 7. How could proteins be folded in a tertiary structure? 8. Why do those folds occur? 9. What drives protein folding? 10. Can the same protein have more than one shape?
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