How climate change will intensify infectious disease
By Shaina Eagle, Global Disease Biology ‘24 & Tammie Tam, Molecular and Medical Microbiology ‘22
Authors’ Note: We decided to partner on this paper after discovering a mutual passion for studying infectious diseases. As editors of a scientific journal and science students, we learn about the effects of climate change on our world regularly. It seemed like a natural progression to explore the effects of climate change on infectious disease.
Introduction
A changing climate impacts all living organisms—including the ones you can’t see. While climate change has made a name for itself through its more visible effects, it is equally affecting a hidden dynamic force—infectious diseases. Climate change is altering the movement of existing pathogens, fostering the emergence of new pathogens, and in turn, changing host-pathogen interactions. As the level of greenhouse gasses, like CO2, increases, shifts in temperature and precipitation patterns are producing more frequent and intense climate disasters from the raging wildfires burning the West to the floods drowning Southeast Asia [1, 2]. Besides damages from climate disasters, humans are actively destroying habitats and expanding the ecosystem boundaries where humans and the wild interact [4]. As a result, climate change is speeding up biodiversity loss, as zoonotic pathogens are spilling over from one host species to another which is threatening more species, including humans [5]. At the same time, pathogens adapted to warmer, more humid climates are creeping into historically cooler, dryer zones [3]. As sea levels rise, Arctic ice and permafrost thaw and release ancient microbial foes [6]. Consequently, infectious diseases are expected to be on the rise.
By the disease triangle model, an infectious disease event occurs when the right host, pathogen, and environment interact with each other [7]. Climate change is expected to affect all three of these factors. If even one part of the disease triangle is thrown off, the disease cannot take root. However, if complementary components are introduced and complete the disease triangle, the disease can take off and spread. The latter is what researchers are concerned about with how climate change may affect the prevalence and emergence of infectious diseases. For instance, if a new pathogen moves into a region where there is a compatible host and optimal environment, it can devastate an ecosystem unprepared for it. Similarly, if a host is weakened because it becomes unsuitable to the changing environment, an existing pathogen can wreck the current population of the host species and the health of the ecosystem.
While the basis of how infectious diseases arise can be simplified by the disease triangle model, infectious diseases come in a range of different combinations of causative pathogens, host species, transmission methods, and severity of symptoms. For instance, pathogens can be bacterial, viral, parasitic, or fungal and can infect plants, animals, and/or humans. How well they affect their host species, however, depends on the strength of their host’s defense. Once the pathogen is established in a host population, pathogens can be transmitted through many means within and between species, such as: direct contact, aerosolized particles, or through an insect vector acting as the intermediary agent transmitting the pathogen between individuals. Due to all these different factors, climate change will not affect all host-pathogen interactions in the same way, presenting different challenges for scientists to tackle. As a result, researchers are working to predict and understand how different aspects of climate change are affecting different host-pathogen interactions that will impact human society. These aspects include plant pathogens on agriculture, wildlife pathogens in zoonotic events leading to the transmission of disease between animals and humans, and environmental changes on existing human pathogens.
Climate Change Effects on Plant-Pathogen Interactions in Agriculture
Climate change is negatively affecting both ends of plant-pathogen interactions, allowing plant pathogens to pose a significant threat to global food security. While predictive models anticipate an increase in crop yield over the next few decades, they often do not consider the detrimental effects of emerging plant pathogens that may hinder such progress [8]. Plant immunity is expected to be less efficient at higher temperatures, which poses an issue as plants will potentially have to face new pathogens as the planet warms [9]. As temperatures increase with latitude, pathogens adapted for higher temperatures are expected to move poleward, especially those that travel through airborne dispersal or on insect vectors [10].
Climate Change can compromise Plant Immunity
Although plants mainly have nonspecific defense mechanisms capable of fending off a variety of pathogens, climate-change-induced abiotic stressors, such as temperature, may negatively impact a plant’s ability to fight against both existing and novel pathogens. In plants, there are two main lines of immune defense. When plant cell surface receptors detect common features shared by all pathogens known as pathogen-associated molecular patterns (PAMP), PAMP-triggered immunity (PTI) is induced, which initiates a signaling cascade that produces reactive oxygen species to damage the infected cells and upregulates resistance genes to inhibit microbial growth [9, 11]. When receptors within the plant cell detect virulent proteins called effectors, effector-triggered immunity (ETI) is induced, causing resistance genes to be upregulated, and a form of apoptosis called hypersensitive response occurs [9, 11].
The rising temperature and shifting precipitation patterns characteristic of climate change can compromise plant immunity. There have been a few studies on how temperature affects PTI, where elevated temperatures may impair some aspects of PTI but enhance it in other ways [12]. While researchers are still looking into PTI, ETI is better studied and can provide a better idea on how climate change can affect plant immunity. Increasing temperatures and humidity alters ETI-related genes and suppresses the hypersensitive response [9, 12]. For example, tomatoes infected by the fungal pathogen Cladosporium fulvum develop leaf mold, and typically, effectors injected into tomato leaf cells activate ETI which upregulates resistance genes specific against C. fulvum. However, under high temperatures greater than 30oC, ETI is unable to be properly activated [9]. Furthermore, at humidity levels greater than 95 percent, the tomato is not able to respond by ETI and efficiently upregulate its resistance genes against C. fulvum effectors [9]. Therefore, higher temperatures and humidity may find plants to have unfavorable odds against plant pathogens under climate change.
Climate Change can introduce new Plant Pathogens
Armed with a less effective immune system, plants may also have to face new pathogens to which they are not adapted. Typically, plant microbes, including existing plant pathogens, compete against new plant pathogens and prevent them from establishing. However, with climate change, plant microbes face a changing environment which they are not adapted to, allowing new pathogens more suited to the environment to sweep in. For instance, the bacterial pathogen Agrobacterium tumefaciens is responsible for crown gall disease in many plant species like fruit crops, but when exposed to temperatures greater than 32oC, its virulent genes are downregulated, rendering it nonpathogenic [9]. While this seems great for these fruit crops, they now face the threat of new pathogens that can fill roles vacated by native beneficial and pathogenic microbes that can’t survive well in the new environment. Although new pathogens may not be adapted to the plant hosts of the region, it is possible for them to acquire virulent genes from existing pathogens through horizontal gene transfer, the mechanism where bacteria can share pieces of DNA with other bacteria [13]. Meanwhile, plants can’t adapt as quickly and are limited now by an immune system that has adapted to familiar pathogens but not novel pathogens, providing ample opportunity for the new pathogen to proliferate.
Climate Change can Exacerbate Existing Vector-borne Plant Diseases
Since effectiveness of immunity and susceptibility to new pathogens under climate change do vary by plant species, some plants like cassava, which is a starchy root vegetable grown throughout the tropics that provides nutrition for over half a billion people, are quite hardy and resistant to stressors like changing temperature and precipitation levels [14, 15]. Yet, plants, such as cassava, that are susceptible to diseases transmitted by insect vectors still face a different challenge brought about by climate change. For example, cassava is affected by two major pathogens across Africa, cassava mosaic virus and cassava brown streak virus, which are transmitted by the insect vectors, whiteflies and mealybugs, respectively [16]. As temperature increases, the populations of whiteflies and mealybugs boom, leading to the destruction of cassava crop and ultimately resulting in famine and a collapsed economy for communities that rely on the crop for food and income [17].
Combatting Effects of Climate Change on Plant-Pathogen Interaction
As illustrated, climate change impacts many aspects of plant-pathogen interactions, many of which are still unknown but it’s certain from current findings that the impact is most likely large. Fortunately, much of the predicted effects of climate change on plant-pathogen interactions have yet to take root, so it’s pertinent to employ techniques to prevent and manage any negative effects that are already in place. Besides cultivating crop strains resistant against specific pathogenic species, humans have a huge hand in staving off diseases in crops through the use of pesticides and fungicides. To manage and prevent disease, crop growers can switch between different fungicides or use multi-site targeting fungicide to minimize the chance of developing resistance among pests and pathogens [18]. Climate change may also affect pesticide and fungicide uptake. As CO2 concentration increases, plants are expected to grow bigger, so more pesticide and fungicide will be necessary for better uptake [18]. Ideally, once these strategies are properly in place, plant pathogens will no longer be a threat to global food security.
Climate Change and Wildlife Infectious Disease
Besides threatening global food security, climate change is producing more natural disasters that are intensifying the habitat destruction and biodiversity loss that was initiated by human-driven forces such as urban expansion and wildlife trade. This has increased the prevalence and transmission of existing and novel wildlife infectious diseases [19]. Additionally, with increasing temperatures, pathogens are expanding into new territories. As a result of the increasing interaction between humans and wildlife, zoonotic diseases, a subsection of wildlife diseases capable of infecting humans, are expected to increase in frequency and infect humans at a higher rate.
Climate change is great for ticks and mosquitoes
All pathogens are adapted to living at certain temperatures. For pathogens that have evolved to live in warmer climates, they may find themselves moving northward as the temperature there rises due to climate change. This particularly affects pathogens that are transmitted by arthropod vectors, which have previously been kept at bay by colder winters and lower average temperatures in the global North [25]. Arthropod vectors, such as ticks and mosquitoes, may harbor new diseases that Northern hosts have never encountered before, and consequently do not have immunity to. Blood-sucking vectors transmit diseases between different species by first feeding on an infected host, and then transferring the disease with a bite directly into the bloodstream of a naive host, which can be a human or another animal [26]. As pathogens adapt to the changing global climate, species across the globe will be threatened.
The thermal mismatch hypothesis explains that species adapted to the cold are at high risk from infectious diseases as their habitats warm, and vice versa [20]. The risk of this increases as parasites and other wildlife pathogens are adapting to survive a wide range of environments. The Arctic is one region especially susceptible to fluctuations in temperature and the spread of disease. The Arctic’s temperature is increasing nearly double anywhere else on the planet, and an unusually warm summer in the Arctic would put local species and the humans that rely on them at risk of zoonotic diseases [21]. Encephalitis, a disease that causes inflammation of the brain, is spreading northward into Arctic Russia as temperatures warm and the ticks that carry the disease can survive for longer periods of the year [21]. Similarly, Lyme disease, normally found in climates like those of the upper Midwest or Northeast of the United States, is now reported in areas of the Russian Arctic, due to a tick species better suited to the cold climate [21].
Shorter, warmer winters and longer, drier summers are easier for cold-blooded ticks and mosquitoes to survive. And as temperatures rise globally, vectors’ viable habitat expands, and thus, so does the range of disease, as mosquitoes and ticks will bring vector-borne diseases into previously temperate locations. The ranges of many vector-borne diseases will shift to higher latitudes and altitudes, where they previously were not found or could not survive. Furthermore, the seasons of transmission in historically warmer and more tropical climates will lengthen [22]. Certain aspects of the ticks’ reproduction, such as developmental cycle and egg production, speed up as temperature increases [22]. This is significant because the number of ticks maturing to be capable of spreading disease and further reproducing will increase, and as tick numbers increase, so will the risk of disease.
Increasing temperatures are expected to increase vector abundance as well as their survival. Changes in precipitation rates will also affect the transmission of vector-borne diseases. More rain creates more puddles, which serve as the perfect breeding ground for mosquitoes, while drought will increase the number of containers storing stagnant water, which if not properly stored can also serve as a vector breeding ground.
Zoonotic diseases and spillover
Over time, thousands of bacterial, viral, and fungal pathogens that once circulated within host species spilled over into the human population, causing illness. Increasing interaction between humans and wildlife and the loss of biodiversity characteristic of climate change will put human populations at the risk of increased emergence and transmission of zoonotic diseases.
Zoonotic diseases are those that are transmitted between animals and humans, such as rabies, Lyme disease, and COVID-19. The transmission of zoonotic diseases, zoonotic spillover, is a significant public health concern for humans as nearly 75 percent of emerging infectious diseases [20] originate from wildlife reservoir species. Reservoir species are those through which a disease circulates without killing it off entirely, thus allowing it to spread to humans if direct or indirect cross-species contact occurs.
The rates of zoonotic spillover are increased in areas where humans live in close vicinity to wildlife. Factors such as deforestation, land-use change, and increasing population density push humans closer and closer to wildlife species’ habitats [23]. These areas, known as boundary zones, are areas where two or more different ecosystems meet. It has long been hypothesized that boundary zones are associated with the emergence and spillover of zoonotic disease, because they support increased contact of humans and wildlife species as well as species that are more likely to transmit zoonotic pathogens. These bridge species are generalist, meaning that they can move through a wider variety of ecosystems and encounter a wider variety of pathogens. This in turn increases the diversity of zoonoses that have the chance to spill over as well as the rate of spillover in and around these ecosystem boundaries [23].
As discussed, areas of high biodiversity, such as boundary zones between ecosystems, are often attributed to the emergence and spread of zoonotic disease. However, decreasing biodiversity has also been acknowledged as increasing the spread of pathogens in human populations. A new study explains that the reason for this apparent contradiction is that species that are more likely to be host species of zoonotic pathogens are more commonly found in areas where humans live [24]. It is the diversity of host species such as bats, rodents, and livestock that influence zoonotic emergence and spillover, rather than total species diversity. With decreasing biodiversity, the species that are left behind—such as those with small bodies and fast life histories (early maturation, high rates of reproduction, and mortality)—are those likely to transmit zoonotic pathogens [24]. There is also a dilution effect, when the buffer of non-reservoir species declines, meaning that the transmission of zoonotic diseases is increased.
Climate Change on Existing Human Pathogens
Besides the downstream effects of plant and wildlife infectious diseases on human society and health, climate change is expected to also directly affect the human population by impacting existing human-pathogen interactions. In the Arctic, ice and permafrost is melting at an unprecedented rate due to rising temperatures, reviving dormant pathogens, such as anthrax and smallpox, and introducing old and unknown human diseases [6]. Warmer water and more frequent storms are also generating outbreaks of water-borne infectious diseases such as cholera [27]. With warmer winters and hotter summers, climate change is affecting seasonal weather patterns and thus driving the prevalence and severity of certain seasonal infectious diseases like the flu [28]. These are just a few examples, as there are many more climate-related environmental changes and human infectious diseases being similarly affected.
Arctic ice melting and permafrost thawing brings new and familiar threats
Every decade as the ocean’s temperature rises by 0.13oC, the Arctic ice melts by about 13 percent on average, which is thereby accelerating how fast the nearby Arctic permafrost, or frozen soil, is thawing and reviving dormant microbes [29, 30, 31, 6]. From the thawing permafrost, researchers have found novel viruses and bacteria but none so far that can infect humans [6]. For now, scientists are only aware of known human pathogens that may emerge. In 2016, an anthrax outbreak in Siberia has been linked to thawing permafrost releasing hardy anthrax spores. Besides anthrax, scientists are also worried about other known human pathogens, like smallpox, being released. Since the 1970s, the deadly smallpox has been considered eradicated. However, smallpox may still remain on frozen corpses as the virus can withstand freezing conditions [32]. Although scientists have not been able to isolate viable smallpox viruses, they have been able to extract their viral DNA from previously infected frozen corpses [32]. Nonetheless, the thawing permafrost in the Arctic may still contain threats from old and new human pathogens that have yet to be revealed as researchers continue digging into the matter.
Cholera, algal blooms, and changing tides
Besides melting ice, the warming ocean, home to many water-borne pathogens, is changing tidal patterns and intensifying and increasing the frequency of storms. Moreover, warmer water is also promoting algae bloom, which the bacterial causative agent of cholera, Vibrio cholerae, can be found in [33, 34]. As a result, hurricanes, which are becoming stronger due to warming water, are driving V. cholerae to wash up onto shores and coastal cities and contaminate water sources [27, 35]. Since V. cholerae is transmitted through contaminated food and water, hurricanes and algae blooms have both been linked to cholera outbreaks. During infection, V. cholerae proliferates in the human intestine and produces a toxin that causes diarrhea, vomiting, dehydration, a drop in blood pressure, and, if left untreated, can lead to death within 18 hours [36]. In communities that lack a stable health system, a treatable disease such as cholera may end up fatal when hospitals and clinics are overwhelmed by multiple coinciding disease outbreaks such as COVID-19 [37].
Influenza seasons become more severe
On a more global scale, the effects of seasonal changes is expected to worsen the severity of the flu season. Influenza is commonly known for its mild nature and annual appearance in the winter. While a warmer winter may create a milder flu season by making transmission of the virus less effective and thus affecting less individuals, more individuals are set to become susceptible to the flu the next season due to the lack of acquired immunity during the previous season, allowing the following winters to see more severe and earlier flu seasons [28]. Interestingly, during the warmest winters experienced, the 2017-18 flu season had the highest influenza mortality rates in recent history [38]. To account for this, scientists found that climate change is also affecting rapid weather variability in the fall preceding flu season, which is correlated with severe flu seasons [38]. Although COVID-19 restrictions in the past year have led to a dramatic decline in flu cases during the flu season, flu cases are picking back up once again, so the public must continue to remain vigilant and vaccinated if they want to avoid future severe flu seasons [39].
Conclusion
There is no more obvious of an example of the interactions between climate change and infectious disease than the last two years. Questions still remain regarding the origin and circulation of SARS-CoV-2 leading up to its explosion into a global pandemic [40], but a World Health Organization investigation distinguished bats as the virus’ reservoir host and identified a wet market in Wuhan as a probable center of outbreak [40]. Many of the underlying causes of climate change, such as deforestation and loss of habitat, are also linked to the emergence of infectious diseases. Researchers suspect the outbreak of COVID-19 could be connected to deforesting the tropics, changing agricultural practices, and increasing contact between reservoir and intermediate species, as well as wild animals and humans [41].
With no corner of the globe untouched by COVID-19, a clear and thorough understanding of how climate change and infectious disease affect each other is necessary for mitigating this pandemic and preventing the next one. Ultimately, any action taken towards reducing climate change will likely have a positive impact on reducing the risks of emerging infectious diseases. Recognizing that climate change and global health are interconnected is necessary for avoiding any future disastrous consequences.
Infectious disease emerges at the intersection of host, pathogen, and environment—and climate change is interacting with all three. This presents a multifaceted challenge, as a solution for plant immunity to fungal pathogens likely will not be the same as a solution for the increasing transmission of vector-borne wildlife viruses. Climate change, from rising greenhouse gasses to biodiversity loss, is dredging up new diseases and making existing ones worse. As host susceptibility, pathogen survival, and environment structures change, it would not be surprising to see more global pandemics in the future.
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Phonological Assistance, Contextual Effects, and Generalizability in Bilingual Language Acquisition: A Review Study
By Jenny Geng, Psychology ’21
Author’s note: As a psychology major Class of 2021 alumni with a focus in developmental psychology, Jenny Geng has been probing into various research topics centered around bilingual language development. Her bicultural identity as a Mandarin-English bilingual has positioned her to speculate the interwoven relationship between sociocultural context and bilingual language development. This motivated her to conduct a literature review that aims to inspect bilingual language acquisition through a broader scope that takes into account facilitators from language-learning settings. She hopes to provide insight for bilinguals and language learners who have similar curiosities as she has by giving a general overview of critical facilitators in the bilingual language learning process.
Introduction:
Phonological representing and processing impact bilingual language acquisition at a more complicated and interrelated level compared to monolinguals. Even as young as 4-months-old [1], bilingual learners develop two separate language systems to comprehend their complex linguistic environment [4], and the relationship between these features of language systems has been a point of interest. Previous research in this field has mainly focused on the influence of phonological development in differentiating the process of phonological categorization in bilingual and monolingual learners [3,5,12], and in facilitating the language acquisition in another language [11]. On the other hand, research has also incorporated the importance of language context in bilingual language acquisition. Contextual interference, as concrete as semantic context and as broad as social context, can obstruct or bolster language acquisition for bilinguals and is considered to be an inseparable part of the language learning process. This review will first illustrate the phonological assistance in acquiring two languages and the relationship between two phonological systems. Subsequently, the review will examine the role of contextual effects in bilingual language acquisition in both semantic and social contexts.
Caption: Contextual and Phonological Factors are Essential to Bilingual Language Acquisition
Phonological assistance in bilingual language acquisition:
Phonological awareness in bilinguals refers to the capability of recognizing the small sound units in both languages [7], and this awareness not only assists bilinguals to differentiate between two languages but directly affects language-learning process across different scripts [2,9]. Von Holzen et al. investigated the phonological facilitation in monolingual and bilingual language recognition, and found that compared to monolingual toddlers, bilingual children can successfully identify the changed-consonants in both L1, the first/native language and L2, the second language [11]. In the study, authors recruited German-English toddlers (N=31) and German monolingual toddlers (N=23; female:10) from the same city in Germany. They used the Intermodal Preferential Looking Word Recognition task to investigate two experimental conditions: recognition of mispronounced words, and recognition of changed-consonants. During trials, target-distractor word pairs were presented on the screen followed by a fixation point, and a camera was placed above the screen to record children’s looking preference: whether they fixated longer on target word or distractor word. The results showed that both bilingual and monolingual toddlers can successfully recognize the mispronounced words, but only bilingual toddlers showed clear recognition in changed-consonants. One interpretation of this result is that bilingual toddlers’ phonological knowledge in L1 facilitated their recognition in L2 [11], which implies an exchange of knowledge between German and English language categories. In addition, the authors concluded that this exchange activity is largely due to the overlapping labels between German and English, which suggests a possibility of phonological interference between L1 and L2 in task-switching [11]. This cognate facilitation raises the question of whether phonological assistance can only be observed in bilingual speakers who speak cognate languages and the extent to which this occurs. Further experiments of language acquisition in bilinguals who speak non-cognate languages (i.e., Chinese-Spanish; German-Korean) are needed to fully understand phonological assistance and its potential selectivity.
The phonological overlapping observation by Von Holzen et al. is largely due to the similar nature of L1 and L2: both German and English belong to Indo-European cognates which share overlapping labels. This similarity in linguistic features limits the generalization of the experiment. To fill out this gap, Lin et al. ‘s investigated the facilitation of phonological awareness in Chinese-English bilingual reading acquisition. The research group found bidirectional phonological transfer from L1 and L2 despite the language proficiency level: Bolstering the phonological awareness in one language facilitates the reading comprehension in the other language [7]. In this case, by bolstering phonological awareness in Chinese, participants showed improvement in English reading comprehension. This finding is significant because it indicates that there is an exchange of communication between two language systems, and the process of acquiring two languages relies on this exchange. As articulated by Lin, Chinese rime & tone awareness significantly facilitated English word reading through phoneme awareness, and vice versa [7]. Notably, their experiment was conducted in the U.S. where English is the dominant language. This imbalance in practice time, language inputs, or other contextual effects influences the simultaneous process of acquiring two languages. This highlights the importance of language settings embedded in the social-cultural environment in the process of bilingual language acquisition, and to what extent can it obstruct or facilitate the language-learning process.
Contextual effects in a semantic and social context:
Language environment plays a critical role in language acquisition, especially for bilinguals who require adequate inputs for both languages. In laboratory settings, Kaur investigated how different semantic contexts vary category interference in Bodo-Assamese bilinguals. The result showed a significant three-way interaction amongst List Type, Bilingual Proficiency, and Target Language, indicating the subscription level of the semantic effect differs in three conditions. This study, by manipulating language settings, aims to explore the various cross-language effects in the dynamic L1 and L2 processing [6]. To capture the big picture of contextual effects and the systematic influences in bilingual language acquisition, a greater scope of language environment has to be taken into account. To accomplish this, O’Toole et al. utilized the longitudinal approach to investigate the L1 acquisition in a minority context for Irish-English bilingual children. By accessing data from caregivers and children, the authors found that contextual effects have a significant impact: Even for households where Irish is primarily spoken, the Irish vocabulary for bilingual children is still low. Despite the naturalistic language setting of this study and its understanding of the causes for delayed language acquisition, the problem of minority languages is extensive. The dominant social status of English limits the variety of language types and puts more languages at risk of disappearing, just like Irish. Gaeltacht, where the experiment was conducted, has its demographic specialty. Its intergenerational transmission problem cannot be generalized to other regions (i.e., Japan, Mexico, etc.), and the result of this study also faces a similar generalization issue.
Kaur recruited Bodo-Assamese bilinguals (N=52; female: 23) and conducted two experiments for the purpose of testing word naming in both L1 and L2. The author accessed data from language background questionnaires and two versions of the Objective Naming Test. Across two experiments, three independent variables were introduced: Cognate Status (cognate vs. noncognate), List Type (categorized vs. randomized), and bilingual proficiency level [6]. The results in the first experiment testing for word naming in L2 showed that participants took a significantly longer time in naming categorized words compared to randomized words [6]. This indicates category interference when the word list is semantically organized. In the second experiment, the results showed a significant interaction between Cognate Status and List Type: the cognates were named significantly slowly in L1 for the categorized list, compared to noncognate words. This indicates that the Cognate Status didn’t affect word naming directly, reinforcing semantic context bolsters the cognate factor. Both experiments showed significant category interference effects and highlighted the role of semantically-related context in L1 and L2 word naming. Nevertheless, examining the language processing by meditating semantic context only on a phonological level is not sufficient to understand the whole topic. Contextual effects in bilinguals are not limited to semantic variations and can be investigated in a broader range.
O’Toole et al. used the longitudinal approach and recruited Irish-English children (N=21) under 36 months and their main caregivers. They employed the ICDI checklist and a brief version of PaBiQ-IT [8], and asked caregivers to complete these checklists every four months. Caregivers were asked to retrospectively report the frequency of speaking Irish and English in the households in five levels: always, usually, sometimes, rarely, or never. Interestingly, the results demonstrated that children’s vocabulary acquisition of Irish was not significantly influenced by any frequency levels of spoken Irish in the households. In fact, main caregivers reported that using Irish usually and mostly in homes was not significantly better than rarely using Irish in terms of improving children’s Irish vocabulary. Researchers pointed out this result as a concern as the contextual effect of English outside the households outweighs the in-home Irish inputs. In addition, the authors articulated the prevalent language use in English in a social context: children used more English nouns, greetings in English, and English had a higher social status than Irish with a cultural lens. Notably, the participants recruited in this study had relatively higher socioeconomic status (SES). Although SES does not significantly correlate with the Irish vocabulary acquisition [8], it inevitably questions the generalizability of the study. Considering the relatively small sample size (N=21) and the uneven distribution of SES, the results are not able to be generalized to other bilingual speakers and demographic dimensions.
Generalizability of phonological facilitation:
One may challenge the universality of phonological facilitation in bilinguals: does it only apply to typical-developing children? In other words, do hearing-imparied children share a similar language acquisition trajectory with normal-hearing children? Sabri et al. developed a longitudinal case study to investigate the phonological development in an Arabic-English child, named JS, with bilateral cochlear implants (CLs). By comparing JS’s phonological development with monolingual Arabic speakers, Sabri et al. found that JS acquired her phonological inventory for both L1 and L2 and eventually reached 87% accuracy for phonological inventory [10]. Children with CLs resemble the language acquisition trajectory of typically-developing children, and in this case, JS successfully acquired phonological differentiation in Arabic and English [10]. This finding supports the universality of phonological facilitation in bilingual language acquisition and crossing over the pre-requirement for typical-developing children. The detailed record of the language acquisition process of a person is thought-provoking in a way that it replaces data with personal experience. Yet, despite the result of these case studies, additional evidence of children with CLs is needed to determine the generalizability of phonological facilitation in bilingual language acquisition.
Discussion:
Two factors that support the language learning process for bilinguals were reviewed in this paper. First, phonological facilitation in bilingual language acquisition has been widely studied over the past decades. A rich collection of studies provides evidence supporting phonological development in bolstering bilingual language acquisition, and the interrelated phonological systems which involve knowledge exchange between L1 and L2. Subsequently, contextual factors impact language acquisition by the range of language inputs, practice, and how semantically related the context is. By manipulating the semantic context, Bodo-Assamese bilinguals experienced recognizing latencies when the word list was categorized [6]. On a broader scope, social context also impacts bilingual language acquisition based on the imbalanced inputs for L1 and L2.
Conclusion:
Although a wide body of research reveals significant phonological facilitation for acquiring a second language, the majority of studies target bilinguals whose first language is cognate with Indo-European languages (i.e. English, German, etc.). This language default leaves minority languages with fewer groundworks to be researched and hinders the generalizability of this topic. Hence, more research needs to focus on investigating diverse bilingual speakers to solidify the generality of phonological facilitation.
On the other hand, O’Toole et al. articulated that even with a decent amount of practice time in the household, Irish-English bilingual children still received inadequate Irish language inputs and have lower Irish vocabulary compared to English [8]. More studies are needed to reveal the critical role of contextual factors in bilingual language acquisition. In a broader scope, a rich number of studies recruited typical hearing developing children to prove validity for the generality of phonological differentiation. This approach is biased by excluding atypical language development – such as hearing impaired children, and more studies should examine language acquisition processes in atypical-developing bilinguals.
References:
- Albareda Castellot, Bàrbara, Ferran Pons, and Núria Sebastián Gallés. “The acquisition of phonetic categories in bilingual infants: New data from an anticipatory eye movement paradigm.” Developmental science 14, no. 2 (2011): 395-401.
- Castles, Anne, and Max Coltheart. “Is there a causal link from phonological awareness to success in learning to read?.” Cognition 91, no. 1 (2004): 77-111.
- Faingold, Eduardo D. “Prepositions and adverbs: Similar development patterns in first and second language acquisition.” The Development of grammar in Spanish and the Romance Languages (2003): 54-69.
- Genesee, Fred. “Early bilingual development: One language or two?.” Journal of child language 16, no. 1 (1989): 161-179.
- Höhle, Barbara, Ranka Bijeljac-Babic, and Thierry Nazzi. “Variability and stability in early language acquisition: Comparing monolingual and bilingual infants’ speech perception and word recognition.” Bilingualism: Language and Cognition 23, no. 1 (2020): 56-71.
- Kaur, Sugandha. “Word Naming in Bodo–Assamese Bilinguals: The Role of Semantic Context, Cognate Status, Second Language Age of Acquisition and Proficiency.” Journal of psycholinguistic research 46, no. 5 (2017): 1167-1186.
- Lin, Candise Y., Chenxi Cheng, and Min Wang. “The contribution of phonological and morphological awareness in Chinese–English bilingual reading acquisition.” Reading and Writing 31, no. 1 (2018): 99-132.
- O’Toole, Ciara, and Tina M. Hickey. “Bilingual language acquisition in a minority context: using the Irish–English Communicative Development Inventory to track acquisition of an endangered language.” International Journal of Bilingual Education and Bilingualism 20, no. 2 (2017): 146-162.
- Rispens, Judith E., Catherine McBride-Chang, and Pieter Reitsma. “Morphological awareness and early and advanced word recognition and spelling in Dutch.” Reading and writing 21, no. 6 (2008): 587-607.
- Sabri, Manal, and Leah Fabiano-Smith. “Phonological Development in a Bilingual Arabic–English-Speaking Child With Bilateral Cochlear Implants: A Longitudinal Case Study.” American journal of speech-language pathology 27, no. 4 (2018): 1506-1522.
- Von Holzen, Katie, Christopher T. Fennell, and Nivedita Mani. “The impact of cross-language phonological overlap on bilingual and monolingual toddlers’ word recognition.” Bilingualism: Language and Cognition 22, no. 3 (2019): 476-499.
- Xue, Jin, Xiaolan Hu, Rong Yan, Hong Wang, Xi Chen, and Miao Li. “Onset Age of Language Acquisition Effects in a Foreign Language Context: Evidence from Chinese–English Bilingual Children.” Journal of psycholinguistic research 50, no. 2 (2021): 239-260
Inconsistency in climate change education across K-12 grades
By Vishwanath Prathikanti, Anthropology ‘23
Author’s note: I, like many around the world, was alarmed when the Intergovernmental Panel on Climate Change released its sixth assessment report in August 2021 and delivered news of rapid and intensifying climate change. As an undergraduate with a research focus on science education, I was almost equally alarmed to find that the National Center for Science Education reported that 40% of middle and high school teachers teach climate change inaccurately. Furthermore, climate change isn’t required to be taught, or addressed in any capacity, in any state. In an era where climate change is becoming an existential threat to humanity, I wish to highlight the faults in climate change education and explain how it must improve.
In schools across the United States, teachers are teaching subjects such as arithmetics, the Revolutionary War, Shakespeare’s plays, and, more recently, climate change. However, not all teachers teach climate change, and the ones who do may be teaching it wrong.
Before we discuss climate change education, it is important to understand exactly what has caused the degree of climate change in the past few decades. All credible scientists agree that climate change is happening, and it’s human activities that are responsible for causing it. Our atmosphere is designed to keep heat from the sun inside; it’s why we don’t completely freeze at night when the sun isn’t directly on us. Greenhouse gasses, such as CO2 and methane, help our atmosphere keep this heat in. Since the mid-twentieth century, humans have been significantly increasing the amount of greenhouse gasses in our atmosphere, either by driving cars that produce carbon dioxide, raising livestock, which produce methane, or cultivating soil, which produces nitrous oxide [1]. This results in more heat being trapped in the atmosphere, causing increased floods and droughts, the destruction of coral reefs, and the displacement of animal populations.
Considering the fact that the United States had the second greatest carbon footprint in 2021, it is imperative that the next generation understands the reality of climate change [2]. If nothing is done to address climate change, irreversible damage will be dealt to the Earth, such as animal and plant populations going extinct and even human settlements being destroyed or simply deemed uninhabitable due to worsening weather conditions. People must be educated on the severity of climate change so that they may mitigate or prevent such catastrophic events.
What does climate change education look like now?
Despite climate change being an existential threat to humanity, climate change education isn’t actually required to be taught in schools. Topics discussed in school are left for states to decide, and in many states, including California, teaching climate change is not mandated, despite it aligning with state science education standards [3, 4]. This leads to varying levels of quantity and quality regarding climate change education, as it often falls into the hands of individual schools or teachers themselves to determine how much time they spend and the level of depth when discussing climate change.
A study done by Eric Plutzer and colleagues found that of their sampled high school and middle school teachers, around 75% spent at least an hour per academic year on climate change (87% of high school biology and 70% of middle school science teachers) [5]. Plutzer and colleagues note that this small amount of time dedicated is worrisome by itself, but the quality of education is cause for more concern. Thirty percent of teachers emphasized that recent rises in climate were due to “natural causes” and 12% failed to emphasize human causes. Strangely, 31% admitted to teaching that recent climate change is caused by human activity, but also that many scientists believe it is due to natural causes [5]. Plutzer and colleagues stipulate it may be an attempt to convey both sides of the argument. This is alarming when coupled with the fact that 97% of climate scientists agree that humans are causing global warming and climate change. According to NASA, “international and U.S. science academies, the United Nations Intergovernmental Panel on Climate Change and a whole host of reputable scientific bodies around the world” have expressed this fact [6].
Sarah B. Wise, a professor at University of Colorado Boulder, conducted a similar study earlier, though limited the sample to Colorado public school teachers. Wise found that while 87% of teachers addressed climate change, the method was much more variable as indicated by a free-response section. According to Wise, many teachers only have an “informal discussion” rather than an organized lecture. Meanwhile, among those that did include a formal lesson plan, more than ⅔ of them indicated the lesson was mainly on “emphasizing the ‘nature of science’ (e.g., how scientists gather evidence, arrive at explanations, and engage in peer review) … and acknowledging or discussing the presence of public controversy and skepticism around the topic of global warming” [7]. These methods of teaching climate change often give way to imagining holes in the idea that humans are responsible for climate change. For example, if a student hears the notion that some scientists disagree on climate change, and the nature of science requires us to have skepticism, their perception of climate change being driven by humans weakens.
While many teachers make sure to emphasize the scientific consensus, the fact that the number is only 54% should be cause for concern.
Why is climate change taught this way?
Plutzer and colleagues suggested that teachers may cover certain aspects of climate change and avoid others due to misinformation in their own lives. While 97% of scientists agree that human activity has been responsible for climate change, the public perception of climate change scientists’ knowledge is poor. According to a 2016 Pew Research poll, only 33% of Americans believe climate change scientists understand whether climate change is occurring or not, 28% believe scientists understand the causes, and 27% believe scientists agree that it is caused by humans [8].
When teachers were asked directly in Wise’s study, answers were a bit nebulous. The vast majority reported that a discussion of climate change would not “fit into their curriculum or standards” for various reasons, some being a lack of time, and others citing a limitation of the curriculum itself. Interestingly, unlike a subject such as evolution, very few teachers indicated they felt pressure to avoid teaching the subject by a student or member of the community. Even when teachers were directly discouraged from teaching the subject, free responses indicated it did not affect their decision to include it in the class, through an informal discussion or otherwise.
That being said, the political aspect of climate change should not be ignored. While the extent of the politicization of climate change is a somewhat complicated issue, it is undeniable that many believe climate change is a political subject, and like all political views, it is important to share “both sides” in school. While teachers were found to generally teach climate change, as discussed prior, the discrepancy was with whether they would emphasize human activity or natural causes as the main driving factor. While scientists have recognized there are patterns of climate change that occur naturally, it is also clear that after the mid-twentieth century, when cars became a family staple and humans started producing more greenhouse gas emissions, temperatures spiked much higher than they ever did naturally [9]. It is therefore commonly agreed that in the past few years, human beings are the ones mainly responsible for the increase in temperature.
Wise found that 85% believed teaching both sides was important. When asked why, 25% of teachers said it was because both views held scientific validity and 50% said it was to promote “critical thinking” and “independent decision-making.” Only 25% believed students should learn both, but school curricula should emphasize the scientific consensus that human activity is the driving force [7].
When they asked similar questions to their sample, Plutzer and colleagues found that those who believed it’s “not the government’s business to protect people from themselves” were also most willing to teach both sides [5]. In this sense, Plutzer and colleagues claimed the issue was based more on personal values of the teachers than any formalized curricula that may have been forced onto them.
What needs to be changed
It is clear that education on climate change in America must be made more robust; not only must climate change be required in school curriculums, but it should also emphasize the fact that there is a scientific consensus that human activity is the main cause. Climate change must be standardized at the state level, or at the very least, be mandated to teach. Until there is an established curriculum for climate change, the way it is presented will remain up to teachers.
While some might argue a solution is to educate teachers and allow them to retain power over the way climate change is taught, because of the personal motivations at play, Plutzer and colleagues do not believe this would solve the issue [5]. In an interview with Time Magazine, Plutzer said, “The goal of climate skeptics is very similar to the goals of evolution skeptics. They’re not attempting to prove their point; they’re merely hoping to raise doubt — enough doubt to delay [changes to education] policies” [10].
Instead, Plutzer and colleagues suggest the process of educating teachers will need to draw on science communication research, and specifically help science teachers “acknowledge resistance to accepting the science and addressing its root causes.” A failure to approach educators properly may actually lead to the strengthening of views that seek to teach both sides equally [5].
Until personal biases in teachers regarding climate change can be resolved, some researchers have turned towards extracurricular activities and games to increase climate change knowledge and bridge the partisan gap. Juliette Rooney-Varga and colleagues created a simulation for secondary (grades 6-12) and post-secondary students in which participants role-play as UN delegates who are tasked with saving the world from climate change. The researchers found that of the 2042 participants, 81% reported an increase in their desire to “combat climate change.” In particular, they pointed out the effectiveness in convincing Americans who were “somewhat or strongly opposed to free-market regulation.” This label applied to 40% of all participants, who, prior to the study, indicated lower beliefs “that climate change is caused by human activities,” “lower levels of knowledge about CO2 accumulation dynamics,” and lower levels of “a sense of Urgency” [11]. After the study, their views on climate change “showed no statistically significant differences” when compared to their fellow Americans who favored government regulation.
Similar to how schools still face difficulties teaching evolution, it is unclear exactly how much resistance teachers, schools, and textbook authors will face when incorporating a stronger climate change curriculum into K-12 education. However, with the help of educators and researchers with a desire to foster better science communication, the next generation of students may be better equipped to address climate change in society.
References:
- NASA. The Causes of Climate Change. Accessed January 30, 2022. Available from: https://climate.nasa.gov/causes/
- World population review. Carbon footprint by country. Accessed Jan 30, 2022. Available from: https://worldpopulationreview.com/country-rankings/carbon-footprint-by-country
- Johnson S. October 18, 2019. Teachers and students push for climate change education in California. Ed source. https://edsource.org/2019/teachers-and-students-push-for-climate-change-education-in-california/618239
- U.S. Department of Education. The Federal Role in Education. Accessed January 30, 2022. Available from: https://www2.ed.gov/about/overview/fed/role.html
- Plutzer E, Mccaffrey M, Hannah AL, Rose J, Berbeco N, Reid AH. February 12, 2016. Climate confusion among U.S. teachers. Science. 351(6274):. 664-665. https://www.science.org/doi/10.1126/science.aab3907
- NASA. Do scientists agree on climate change? Accessed January 30, 2022. Available from: https://climate.nasa.gov/faq/17/do-scientists-agree-on-climate-change/
- Wise SB. January 31, 2018. Climate Change in the Classroom: Patterns, Motivations, and Barriers to Instruction Among Colorado Science Teachers. Journal of Geoscience Education. 58(5): 297-309. https://www.tandfonline.com/doi/abs/10.5408/1.3559695
- Pew Research Center. October 4, 2016. Public views on climate change and climate scientists. Available from: https://www.pewresearch.org/science/2016/10/04/public-views-on-climate-change-and-climate-scientists/
- Denchak M, Turrentine J. September 1, 2021. Global Climate Change: What You Need to Know. Natural Resources Defense Council. https://www.nrdc.org/stories/global-climate-change-what-you-need-know
- Worland J. February 11, 2016. Why U.S. Science Teachers Struggle to Teach Climate Change. Time. https://time.com/4214388/science-teachers-climate-change/
- Rooney-Varga JN, Sterman JD, Fracassi E, Franck T, Kapmeier F, Kurker V, Johnston E, Jones AP, Rath K. August 30, 2018. Combining role-play with interactive simulation to motivate informed climate action: Evidence from the World Climate simulation. PLoS ONE 13(8): e0202877. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202877
The psychedelic renaissance: a review on microdosing, the routine use of low-dose psychedelics as a therapeutic
By Reshma Kolala
Abstract
Psychedelic drugs are far from what is considered to be conventional medicine. An infamous history of misuse has stigmatized psychedelics, making it difficult to garner support for its use as a potential therapeutic tool. However, among working adults, taking low doses of psychedelics has recently gained popularity in its ability to boost productivity, reduce anxiety and depression, and enhance overall well-being. Only a few studies have investigated these benefits in a controlled, randomized setting, all of which produced promising results. However, the data is far from sufficient, and significant further study is warranted before psychedelics may become a mainstream nootropic supplement.
Introduction
Psychedelic drugs such as lysergic acid diethylamide (LSD), psilocybin, and N, N-dimethyltryptamine (DMT) are notorious for their ability to induce a hallucinogenic episode or an altered state of consciousness. These effects are brought about by visual, psychological, and auditory changes following the intake of a recreational dose. In recent years, however, the profile of psychedelic drug usage has shifted to microdosing. Psychedelic microdosing is the use of low doses of hallucinogenic drugs on a chronic, relatively regular schedule. On average, users take about one-tenth to one-twentieth of a typical, recreational dosage every two to three days [1]. Anecdotal reports have shown that users experience enhanced creativity and productivity as well as improved cognitive function [2]. In an online questionnaire, Hutten et al. (2019) observed that the primary motivation for microdosing is performance and mood enhancement, symptom relief, and curiosity [3]. Despite encouraging reviews from users, there is minimal empirical evidence to support the commercialization of psychedelics for clinical purposes. The following review evaluates the practice of microdosing by examining its efficacy, application, safety, and relevance to the social and health challenges faced by individuals presently.
Microdosing as a therapeutic tool
History of clinical psychedelic drug use
The clinical use of psychedelics to treat mood disorders is not an unfamiliar avenue for hallucinogenic drugs. The discovery of LSD in the 1940s, and its wider distribution in the 1950s, began a new era of research into psychoactive compounds. Psychedelics were considered useful as a supplemental treatment to facilitate successful therapies. This prompted further research, leading to nearly 1,000 clinical studies being published by 1965 [4]. These studies reported positive therapeutic outcomes in patients suffering from various mood and substance abuse disorders. However, a cultural shift in recreational psychedelic drug usage during the 1960s and 1970s led to a relabeling of psychedelic drugs. These hallucinogens became synonymous with rebellious and dangerous behavior, leading to the criminalization of psychedelics in the United States. This severely restricted research into psychedelics as a therapeutic, causing interest and funding to diminish and ultimately stalling further advancement.
The demand for an alternative approach
Microdosing is portrayed as an alternative to traditional antidepressant or anti-anxiety medications. The prescription rates of medications treating behavioral and mood disorders remain alarmingly high, most notably in the United States. Despite this, there has been minimal improvement in the efficacy of these medications in the last few decades. These medications are slow to act, have several adverse effects, and only show improvement in ⅔ of patients [2]. This has encouraged patients to seek alternative methods of treatment, such as microdosing. Despite known unwanted effects, standard antidepressants, or SSRIs (selective serotonin reuptake inhibitors), continue to be prescribed because of the large volume of controlled, clinical trials that demonstrate their safety and efficacy. The same cannot be said for psychedelic use however, due to the controversial nature of funding research into illicit drugs, particularly those that cannot be patented by pharmaceutical companies. Therefore, the substantial anecdotal support for microdosing, notably their reported lack of relative side effects, cannot be reliably concluded. However, amidst logistical challenges, the increasing prevalence of microdosing unveils a new niche of therapeutics that target individuals who may be unreceptive to traditional modes of treatment for mood and anxiety disorders.
Chronic, low-dosage psychedelic treatment (microdosing)
Few studies have investigated the effects of microdosing in ameliorating depression and anxiety symptoms in controlled, randomized trials. One of these is a UC Davis study where DMT was administered at sub-hallucinogenic levels (1 mg/kg) on a chronic, intermittent schedule to rats (Cameron et al. 2019). This was opposed to a standard high dose (10 mg/kg) which is known to induce symptoms of anxiety. These rats were subjected to tests that quantified their anxiety levels and behavioral responses. DMT was specifically chosen for this study because of its chemical architecture, as it possesses a core indole-containing structure, present in LSD and psilocybin. These indole-containing hallucinogens are analogues of the neurotransmitter serotonin, which is known to influence mood and behavior. DMT is also known to influence rodent behaviors often affected by depressive symptoms, such as sociability, mood, and anxiety. The results indicated no significant difference between the control group and the treatment group in their ability to produce anxiogenic effects or reduced anxiety symptoms. In a test traditionally used to measure the efficacy of antidepressants, rats treated with DMT exhibited antidepressant-like responses without any impairment to working or short-term memory or social interaction. This study corroborates reports that microdosing in humans alleviates depressive-like symptoms [2]. However, anxiety reduction, enhanced sociability, and enhanced cognitive function self-reported by users in the study conducted by Hutten et al. (2019) was not observed.
Nonchronic low-dosage psychedelic treatment
Anxiogenic effects were observed, however, in a controlled, randomized study that proposed psilocybin as a treatment to reduce anxiety and depression in patients with advanced-stage cancer. Ross et al. (2016) concluded that a single dose of psilocybin (0.3 mg/kg) produced significant, immediate, and sustained (up to 7 weeks after the dose) reduction of depression and anxiety symptoms [5]. However, this study did not practice microdosing, in contrast to the study conducted by Cameron et al. (2019). In another double-blind, controlled study, patients with obsessive-compulsive disorder (OCD) were administered up to four doses of psilocybin, ranging from mildly hallucinogenic to moderately hallucinogenic (100ug/kg-300ug/kg). Results indicated that patients experienced an acute reduction in OCD symptoms immediately after treatment, at all given dosage levels [6].
Although the studies conducted by Ross et al. (2016) and Moreno et al. (2006) target different populations, both studies showed promising benefits after psilocybin treatment [5,6]. However, in both studies, psilocybin was administered minimally, not often enough to be considered microdosing. In sum, psychedelic psilocybin treatment has shown promising results when administered minimally and at low doses.
Risks of microdosing
The safety risks associated with short-term or long-term microdosing are unclear, although research into the safety of recreational psychedelic use (~10 mg/kg) suggests that it is relatively safe. In a rating study conducted by European Union (EU) drug experts, van Amsterdam et al. (2015) concluded that, based on current data, alternative substances such as tobacco and alcohol are significantly more harmful than psychedelics in a physical and societal aspect [7]. This is attributed to the addictive quality of tobacco and alcohol, and their ability to induce long-term health disorders such as lung and heart cancers.
Longitudinal studies done with higher, recreational doses have demonstrated that long-term usage of psychedelics is associated with reduced psychological distress [8]. However, it is known that both low and high doses of DMT can alter the neuronal structure of the brain, promoting structural and functional plasticity [9]. These effects were observed long after DMT was cleared from the body. The effects of psychedelic use may also have metabolic effects. The data collected by Cameron et al. (2019) indicate that the male mice who were administered low doses of DMT had a reduced appetite yet gained significantly more weight. Metabolomic profiling of these mice revealed no significant differences in serum steroid levels, implying the interplay of unknown factor(s) in microdosing.
Conclusion
Recent publications regarding microdosing and general low-dose psychedelic drug use reveal several disparities between animal trials and human reports making it difficult to recommend microdosing based on current empirical evidence. Although psychedelics as a therapeutic show promising preliminary results, further research must be conducted to determine their clinical relevance. Future studies should explore the effects of a microdose and recreational dose within the same study and use a broader range of psychedelics such as non-indole-containing compounds. Additionally, researchers may want to vary the frequency of doses within a study, ranging from frequent (Cameron et al. 2019) to infrequent administration, (Ross et al. 2016) and aim to design longitudinal studies to determine the long-term effects of practicing microdosing. By investigating alternative approaches to enhance cognitive function and minimize mood disorder symptoms, researchers can provide further insight into the future of more comprehensive, personalized healthcare for all adults.
References:
- Polito V, & Stevenson, RJ. 2019 February 6. A systematic study of microdosing psychedelics. PLoS One. [accessed 2021 May 12]; 14(2). https://pubmed.ncbi.nlm.nih.gov/30726251/. https://doi.org/10.1371/journal.pone.0211023
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The Role of Microglia in the Two Hallmarks of Alzheimer’s Pathology
By Nathifa Nasim, Neurobiology, Physiology, and Behavior ‘22
Author’s note: While in the Jin lab at the MIND Institute, I was introduced to the intersection between inflammation and neurodegeneration, specifically in the context of Alzheimer’s disease. My interest in this relationship has primarily been in manipulating inflammatory pathways to investigate the effects on the disease. However, I wanted to step back and understand how they connected, and compile a review on microglial activation as a bridge between the two.
Introduction:
Alzheimer’s, the most common form of dementia, is a neurodegenerative disease characterized by progressive loss of memory and cognitive function. It is still largely untreatable: the last drug approved by the FDA was released nearly two decades ago. Currently, there are only a few available treatments, all of which deal with alleviating symptoms rather than affecting any of the underlying pathology [1]. There are two primary hallmarks of Alzheimer’s disease: amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques are formed from aggregations of small amyloid beta protein (Aβ); these amyloid beta are the product of cleavage of amyloid precursor proteins found in the membrane of neurons. Neurofibrillary tangles, on the other hand, form from tau protein, which stabilize neuronal microtubules and therefore allow for transport from the cell body to other parts of the neuron. Hyperphosphorylation of tau (a signaling mechanism) leads tao its detachment from the microtubule and aggregation into neurofibrillary tangles [2, 3].
Both amyloid plaques and NFTs are implicated in neurodegeneration and cognitive loss. Amyloid plaques are thought to be precursors that trigger a cascade culminating in neurodegeneration. On the other hand, the loss of support for microtubules in NFTs leads to impaired axonal transport, resulting in synaptic loss and neuronal dysfunction in an Alzheimer’s brain [2]. This review will explore an emerging aspect of Alzheimer’s research, microglial activation, as a means of mitigating both of these pathological characteristics of the disease thereby providing a potential avenue for approaching treatment.
The Role of Microglia:
In order to approach microglial activation, it is necessary to establish neuroinflammation’s role in neurodegeneration. Neuroinflammation refers to the central nervous system’s immune response, activated in response to trauma, pathogens, or the amyloid protein aggregations of Alzheimer’s, among others [2, 4]. It is a necessary immune response, but an overactive or continuous inflammatory response can be harmful, as evident in the body’s release of anti-inflammatory mediators alongside pro-inflammatory cytokines [2, 4]. Proinflammatory cytokines (proteins that are critical for immune signaling) such as IL-1β, IL-6, IL-18 and tumor necrosis factor (TNF), have various adverse effects on neuronal function including neuronal death, synaptic loss, and synaptic “pruning” or stripping [2, 5]. Therefore, unmitigated neuroinflammation can drive neurological disease, and is implicated in the pathology of all neurodegenerative diseases [4].
The main instruments of neuroinflammation are microglia: non-neuronal phagocytic cells that are the primary proponents of the brain’s immune response. Microglia recognize potential pathogens or irritants through receptors, and in response phagocytose and/or degrade the irritant while releasing cytokines, chemokines and interferons, immune signaling proteins [2]. There are two microglial activation states which dictate the inflammatory response: the “M1” or pro-inflammatory state associated with exacerbating neurodegeneration, and the “M2” or anti-inflammatory state [2, 4]. It must be noted that this binary is simplified, and currently under research. The overactivation of the inflammatory response can be linked to the M1 state of microglia. When inflammatory mediators such as IL-1β were released by microglia, they amplify the inflammation by activating more microglia, creating a positive feedback loop of neuroinflammation characteristic of a diseased state.
Based on their role in neuroinflammation, researchers have looked to microglia as key players in Alzhiemer’s pathology. Numerous research studies have indicated that microglial activation is increased in Alzheimer’s by observing increased expression of microglial receptors in the diseased brain [3, 6]. An example of this is a study that utilized [11C](R)-PK11195, a carbon labeled ligand specific to phagocytic cells. The ligand’s specificity to microglia was increased, allowing it to serve as an indicator for microglial activation. They found a significant increase of microglial activation in Alzheimer’s patients. Furthermore, the pattern of microglial activation physically mirrored the disease’s progress in the brain in terms of atrophy, among other indicators [5]. The research is supported by previous studies as well, all of which suggested that microglial activation is an early event in neurodegeneration, as it was present in mild/early cases of Alzheimer’s [3, 5]. The immune response appeared to escalate into causing more damage as the disease progressed [3].
Amyloid Plaques:
Decades-old research has confirmed the involvement of microglia in Alzheimer’s by demonstrating that microglia cluster around amyloid plaques. There is a progressive increase of activated microglia closer to dense plaque buildup, as well as a linear increase of activated microglia as overall plaque numbers increase [7]. As previously mentioned, amyloid precursor protein splicing leads to a beta amyloid protein; a derivative of the splicing, sAPP-α, has been shown to activate microglia. As microglia are activated by irritants, this falls in line with the general defense role of microglia. The sAPP-α protein, especially an Alzheimer’s-causing isoform which is more likely to aggregate, acts as a threat and thereby activates microglia. As an assumed consequence of the microglial activation, the same study verified that the presence of sAPP-α also increased inflammatory protein expression [8].
Tau Protein Involvement:
In addition to amyloid plaques, microglia have more recently been linked to the other hallmark of AD, neurofibrillary tau tangles. Similar to amyloid plaques, a linear pattern between NFT’s and activated microglia has also been shown [7]. Further supporting this connection, experimental depletion of microglia has led to decreased tau propagation [9]. Interestingly, although inflammatory mediators observed in one study were increased in patients with tau tangles and neurodegeneration, this was not the case in patients with only amyloid plaques. This highlights the importance of tau in microglial activation, as well as the difference in microglial relations between the two [3].
The interconnection between microglia and tau is proposed to be due to microglial phagocytosis of damaged neurons containing misfolded tau. The tau is secreted in exosomes, and these “seeds” of misformed tau protein are capable of inducing other tau to misfold and aggregate [6, 9, 10]. Although the exact mechanism of microglia engulfing tau is unclear, this theory fits with the overall degenerative pathology of Alzheimer’s in that microglia “prune” already damaged neurons and then engulf them. This increased tau phagocytosis and consequent release of misfolded tau increases overall NFTs, thereby further aggravating the disease state.
Tau, Amyloid and Microglia:
Microglia may also play a role in the pattern of tau accumulation and growth in the Alzheimer’s brain. Typically, as the disease progresses, NFTs “grow” in specific patterns or stages, culminating in the neocortex, the part of the brain devoted to higher cognitive functioning. This accumulation of plaques and NFTs in the neocortex is theorized to be the cause for dementia [6]. The propagation of tau, however, is still not fully understood—research is being conducted on whether microglial activation could be a cause. The current understanding of Alzheimer’s pathology via the amyloid cascade hypothesis suggests that amyloid plaques precede other aspects of Alzheimer’s pathology and neurodegeneration, and that tau tangles occur as a result of the “cascade” [2]. However, a recent study proposed that microglia could be the key player in this cascade. Microglia are theorized to act on Aβ, thereby increasing tau propagation, although they are not directly implicated in tau spread. Studies have shown a correlation between activated microglia with the development of cognitive impairment and dementia, supporting the theory that microglia are responsible for the tau propagation patterns seen as AD progresses [6]. This bridge between tau and amyloid via microglia-driven inflammation is further elucidated by another study. Researchers propose that microglial activation, intended to clear amyloid, additionally activates kinase pathways, specifically p38MAPK, directly/indirectly increasing tau phosphorylation, leading to neurofibrillary tangles [11].
Figure 1. In the healthy neuron, tau stabilizes the neuron, but in the diseased state, the phagocytosis of misfolded tau culminates in the formation of more tau misfolding when it is released. For amyloid, specific cleavage sites result in oligomers prone to aggregation which ideally is phagocytosed by the microglia
Potential Influence on Treatment:
Based on the role of microglia in immune activation and its implication in Alzheimer’s pathology, inhibition of microglial activation could theoretically be neuroprotective against the disease, among other neurodegenerative diseases in which neuroinflammation plays a key role. Research published earlier this year expanded on this idea. Based on increased expression of a receptor in activated microglia found in Parkinson’s, a neurodegenerative disease similar to Alzheimer’s in that it is also marked by cognitive deficits, the researchers proposed utilizing the agonist NLY0. Not only did the administration of the agonist block microglial activation, it also reduced inflammatory mediators that in turn activate astrocytes, another glial cell, preventing the cycle of neuroinflammation to neurodegeneration. There were also reduced Aβ plaque numbers in an Alzheimer’s model, and perhaps as a result, improvements in cognition such as improved memory [1].
Conclusion:
Alzheimer’s disease is characterized by inflammation, through which microglia, as proponents of the brain’s immune response, are implicated in the development of the disease. The two main hallmarks of the disease — amyloid plaques and neurofibrillary tangles — are both associated with increased levels of activated microglia. However, in both cases, it is difficult to determine whether increased microglia are present as a result of neurodegeneration or whether they contribute to neurodegeneration. Nonetheless, emerging research places microglia as an important component of the amyloid cascade, by which Aβ and NFTs are connected. Neuroinflammation triggered by the need to clear amyloid plaques may lead to hyperactive kinase activity, hyperphosphorylating tau and leading to NFTs.
Given microglial involvement, further research is needed to investigate the potential of microglial inhibition in the treatment of Alzheimer’s, amongst other neurological diseases. However, the established interplay between microglia and Alzheimer’s pathology provides an important avenue in which to investigate related treatment options while illuminating the connection between inflammation and neurodegeneration.
References:
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Effects of Aerobic Exercise Training on Longevity in Aging Adults
By Hastings Lorman, Human Development
Author’s Note: This paper was written as a term paper for my HDE 117 class in which my professor, Dr. Carey, suggested that I submit this paper to the Aggie Transcript. Not only did I write this paper for my class, but I wrote it for myself as one of my goals while taking this class was to improve my writing skills. I chose to write on the effects of aerobic exercises on longevity because of my personal interest in successful aging and general health and well-being. The topic is similar to a previous term paper I wrote for HDE 100C which was The Effects of Aerobic Exercise on Executive Function. I earned a C+ on that paper and I saw this assignment as a redemption and a way to build my research and writing abilities. I hope that the reader is able to take away information on how to avoid or minimize the risk of chronic, degenerative diseases in adulthood. I also hope to introduce the reader to the concept of exercise as medicine.
ABSTRACT
Physical health and cognition are determinants of mortality. These factors are also measurements to discern if aerobic exercise influences longevity. Aerobic exercise is a treatment that has been extensively studied and has been shown to have a positive effect on healthy aging and longevity, such as, lowering mortality in older age, improving VO2 uptake, and increasing lean body mass, which can facilitate greater physiological function in aging adults. Physical activity can ameliorate adverse symptoms resulting from cardiovascular diseases such as high blood pressure, diabetes, and stroke compounded by the presence of Alzheimer’s Disease. An active lifestyle has been linked to greater cognitive function and improved mood. Those who exercise have, on average, greater brain volume which can stall the deteriorating effects of neurological conditions to lengthen one’s life expectancy. The implementation of aerobic exercise and healthy lifestyle practices is a key factor contributing to overall successful aging and mitigating risk of morbidity [1].
Introduction
Physical exercise is a highly effective and often prescribed treatment for a plethora of physical and mental health conditions. There is a strongly reviewed association between daily, moderate exercise and improved health, which becomes more imperative for successful aging. [2]. Healthy aging involves maintaining high function of physiological and cognitive abilities while resisting major diseases such as high blood pressure or Alzheimer’s disease [3]. One means of extending longevity in aging adults is a consistent aerobic exercise regimen such as brisk walking or jogging. By following a succinct, cardiovascular workout routine repeated multiple times a week, multimorbidity, the presence of two or more chronic illnesses, significantly improved.
Procedure
Table 1. The effectiveness of individualized aerobic exercise training combined with telephone-based motivational interviewing on physical activity amount based on mixed model analysis [4].
In a longitudinal study, designed to test an aerobic exercise treatment for aging adults, participants were found to have an increase of muscle protein synthesis leading to greater lean muscle and body mass. Physical exercise as a prophylactic was linked to combating frailty. Participants were selected for age and health condition [5]. Aging adults were defined as being 65 years or older and were most often suffering from pre-existing chronic conditions such as cardiovascular diseases and Alzheimer’s due to the subjects being residents of rehabilitation centers. Studies were also selected for individuals who did not already exercise on a regular schedule.
One-hundred fifty minutes of aerobic exercise a week is the recommended benchmark for healthy aging [6]. Physical exercises used as treatment were brisk walking and jogging, on a treadmill or outdoors, and cycle ergometer. Aerobic workouts were performed outdoors with weekly check-ins or completed in a lab or rehabilitation center. Aerobic exercise treatments were structured to be an hour long occurring 3-5 times a week for 12-18 weeks long. Physical and psychological measurements were taken before and after the training routine.
Activities were recommended to either be intentional, such as exercises done with the purpose for gaining health benefits, or for leisure, such as walking to destress. Since lower muscle mass is associated with cancer-related disease, researchers paid attention to increases in muscle mass and VO2 uptake, which can determine brain function and metabolic health [7-8]. More vigorous exercises were allowed but subjects were encouraged to participate in moderate physical activities [9].
RESULTS
Improved cardiovascular measures positively correlates with greater VO2 uptake, a leaner body mass (measured by BMI), and improved endurance in aerobic exercise [10]. Greater cognitive function is correlated to a decrease in depression after receiving an exercise treatment. Participants exhibited a decrease in high blood pressure, which is a predictor of chronic health conditions. Alzheimer’s patients after exercising on a weekly basis had greater brain volume. Aerobic exercise can help aging adults retain their autonomy in daily life by reducing the naturally occurring physiological stress that accompanies longevity.
Effects on Physical Health
Consistent aerobic exercise can improve different measures of health such as weight, energy and pre-existing conditions such as Type II diabetes and other cardiovascular diseases. Moderate aerobic exercise can have anti-inflammatory effects on the aging body and provide significant relief for chronic pain [11]. Exercises such as walking and jogging on a weekly basis contribute to an increase in peak oxygen consumption by 10 to 15 percent when targeting frailty, the physical and cognitive decline that develops with age [5]. Subjects who adhered to the exercise regimen were reported to have a lower BMI, a greater heart rate reserve, and a lower blood pressure reading after 12 weeks [4]. For people struggling with cardiovascular diseases such as Type II Diabetes, exercise can be used to help alleviate symptoms, produce healthier measures of fitness, and contribute to an increase in longevity [12].
Lack of physical exercise is linked to an increase in noncommunicable diseases such as diabetes and respiratory diseases. In addition, lack of physical exercise can increase hypertension and obesity. Twenty percent of deaths in the United States are due to obesity and Type II Diabetes [9]. The Copenhagen City Heart Study contributed additional evidence to the benefits that aerobic exercise can have on physical health and, in turn, life expectancy. The study concluded that those who are physically active have at least a 30 percent lower mortality risk when compared to inactive participants [13]. Non-joggers treated with an exercise regimen of light to moderate jogging had a significantly lower mortality rate than the sedentary control to prevent the accumulation of diseases that can contribute to high morbidity risk.
Aerobic activities can also improve the quality of life in aging adulthood. Capacity for movement and strength drastically decrease after 65 years, but the addition of aerobic activities in daily life can lead to better blood pressure and bone density [14]. This can help alleviate physical strain from activities of daily living [15]. Aerobic exercise is especially crucial for women, who, on average, experience a more drastic loss in bone density after twenty years. An active lifestyle should be prescribed as medicine and should be performed as a prophylactic and preservation of current ability. Along with reinforcing bone density in older age, aerobic exercise is also linked to retention of muscle mass [16]. As life becomes more sedentary for the aging population, health professionals urge aging populations to keep as mobile as possible. Short durations of exercise can help limit the physiological effects of aging and reduce the impact of chronic disease on activities of daily living [17].
Routine exercise can reduce the risk of many debilitating conditions that can become more prevalent at an older age, such as certain types of cancers and osteoporosis. Exercise benefits are directly linked to intensity and quantity of the workout. Aerobic exercise can also increase measures of fitness such as muscle tone, flexibility, and cardiorespiratory function. Oxygen carrying capacity decreases with age which correlates with a 5 to 10 percent decrease in physical ability. The risk of sarcopenia, a decline in muscle strength and volume, increases with age which is why physical fitness becomes more imperative for successful aging [18].
Effects on Cognition
Aerobic exercise has led to improvements in memory processing and improvement in pre-existing neurological conditions such as Alzheimer’s Disease and dementia. The progression of Alzheimer’s Disease has been linked to a decrease in brain volume in the entorhinal cortex and hippocampus [19]. These brain regions are correlated with episodic memory which stores personal experiences of previous events [20]. Brisk walking on a regular basis significantly slows the growth of brain atrophy in Alzheimer’s, reducing the amount of nonfunctioning years of a patient’s lifespan.
Those with mild cognitive impairment are expected to live 3.5 years (male) and 4.1 years (female) after receiving a diagnosis. Aerobic exercise cannot stop the biological clock, an organism’s natural time and physiological cycle, nor can it reverse the effect of dementia. However, aerobic exercise can extend quality of life and extend the functioning years of those with memory diseases [27]. Biological age, the measurement of age based on biological health, is a more accurate predictor of mortality than chronological age [28]. Leukocyte telomere length, a biological age marker, appeared to be nine years healthier in active participants compared to sedentary ones [29]. Aerobic activities can compress the prevalence of symptoms in aging adults [18].
Aerobic exercise is associated with activation of brain-derived neurotrophic factors (BDNF), promoted by the mild stress caused by physical activity. The exposure to mild stress with the purpose to build tolerance and improve cognitive function, known as the process of hormesis, is associated with greater neuroplasticity and thus successful aging [3]. Structural connectivity is not only correlated with better cognitive, overall operational processing, and executive function, working memory and self-regulation, but also with the prevention of Alzheimer’s and dementia. Exercise can help slow down the loss of gray matter and brain volume, contributing to greater longevity in those with degenerative conditions.
As brain volume begins to decrease with age, moderate exercise has been shown to increase cortical thickness in preclinical Alzheimer patients. Decrease in brain volume is one of the most present symptoms of Alzheimer’s, and an active lifestyle could combat the progression of memory loss. Aerobic exercise specifically benefits homeostatic functions such as brain plasticity and neurogenesis [3]. Physical exercise can attenuate amyloid, an abnormal protein made in bone marrow, which can lead to greater cognition. The presence of amyloid beta proteins, an inactive part of the protein amyloid, is linked to memory diseases such as Alzheimer’s [22].
Risk of heart failure along with Alzheimer’s disease greatly increases with age due to rapid myocardial dysfunction and a higher rate of perfusion and inflammation. These risk factors can be worsened by cardiovascular diseases and can lead to cognitive impairment. The progression of Alzheimer’s is linked to a greater risk of stroke due to a buildup of amyloid beta proteins between brain cells. Cognitive decline is found in both conditions and is believed to be linked to the presence of amyloid beta protein build up to form plaque in the brain which affects myocardial function [23]. Likewise, heart disease is linked to the deposition of amyloid plaque into the heart which leads to swelling and stiffness of the soft tissue [24]. Exercise has been shown to improve some of the cognitive deficits brought upon by Alzheimer’s such as executive function. Cognitive test scores measuring memory, attention, and mood significantly improved after a physical exercise treatment consisting of cycling or psychomotor activities administered 2 to 6 times over the course of 7 weeks [25].
Exercise is significantly correlated to improvement in mood for people with memory conditions such as mild cognitive impairment and dementia. Adherence to an exercise regimen has decreased dependency on others for activities of daily living (ADL) along with increased mood and feelings of self-efficacy. Depression can cause both physiological and psychological stress leading to rapid degeneration due to worsening cognitive symptoms. Physical activity along with environmental enrichment can induce hippocampal neuro-genesis resulting in greater benefits than either physical activity or an enriched environment alone. Aerobic treatments stimulate neural pathways found in the hippocampus, an area of the brain that decreases in function in those with neurodegenerative diseases, leading to greater retention of cognitive operation [25].
Fig. 2. “Vicious circle” of inactivity and positive effects of regular physical activity [18].
Fig .3. The links between physical inactivity, abdominal adiposity, inflammation, and disease [11].
Fig. 4. Hypertension. A linear dose–response association exists between leisure-time physical activity (LTPA) and risk for hypertension [11].
Discussion
Aerobic exercise should be prescribed to aging adults to preserve cognitive function with the purpose of extending longevity and improving quality of life. Exercises such as walking or jogging are non-invasive treatments that produce significant improvements in blood pressure, body mass, and cognition. Direct implementation of exercise is crucial for healthy aging and early intervention is associated with a lower risk of developing adult-onset diseases later in life [26]. Participants who have experienced many life stressors were able to find health benefits through routine exercise, especially when combined with other life pillars such as adequate nutrition, well-being, and sleep. Public health professionals and researchers encourage the public to use exercise as medicine [11]. There are currently no FDA-approved medications for functional decline [30]. Aerobic exercise is now being regarded as a lifestyle medicine to combat chronic diseases that can develop later in life.
The goal of aerobic exercise is compression morbidity which is reducing the number of years one is disabled and extending the ability to perform ADLs in older age. Successful aging consists of both biological and psychological measures. Causes of death have shifted from infectious diseases to age-related chronic diseases meaning that personal wellness and successful aging are becoming more salient with age. Absence of disease has appeared on surveys measuring feelings of content throughout aging and is a key factor in emotional wellness as well as physical [28].
Aerobic exercise should be done in consideration to the individual. Exercises performed should not negatively impact other physiological functions and can be uniquely designed for the individual’s ability. The CDC recommends 150 minutes per week such as 30 minutes of walking 5 times a week or 75 minutes of vigorous exercise per week such as running [31]. Aerobic exercise is prescribed as safe and doable for most individuals regardless of socioeconomic status or other sociological categories which makes it a more equitable treatment than pharmaceuticals or invasive surgeries. Aerobic exercises do have barriers that should be accounted for such as access to an appropriate location, lack of time, and disease-specific symptoms that infer with the ability to participate [4].
Conclusions
The aging population of this generation is healthier than any previous cohort. To ensure the health of this generation and those to come, aerobic exercise must be incorporated into the weekly routine of the general population. It is important to consider exercise as medicine and as public health policy. With increasing longevity, older populations should place a greater focus on physical independence and the maintenance of well-being in old age. Social institutions, starting as early as primary school and as late as retirement home should encourage walking and light jogging for aging adults to maintain health and foster longevity. Education and encouragement to engage in practices that contribute to successful aging should be promoted to further ensure the health and longevity of future generations. Aerobic exercise is a crucial factor in healthy aging and elicits health benefits that decrease the likelihood of early morbidity.
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Clearing the Cellular Landfill: The Use of Chaperone-Mediated Autophagy to Treat Alzheimer’s Disease
By Reshma Kolala, Microbiology, ‘22
Author’s Note: Alzheimer’s disease is one of the most common neurodegenerative disorders, affecting nearly 1 in 9 individuals aged 65 or older. Available current therapies fail to address the underlying pathophysiology of the disorder, focusing on the amelioration of neuronal symptoms that result from Alzheimer’s disease. I was immediately intrigued by the proposal that an existing mechanism for cellular waste removal, chaperone mediated autophagy, could be reinvigorated to remove toxic protein aggregates that are characteristic of an Alzheimer’s diagnosis, thereby targeting a significant contributing factor to the disease. This finding paves the way for new therapies that prevent or delay the onset of Alzheimer’s disease.
“Imagine someone has taken your brain and it’s an old file cabinet and spread all the files over the floor, and you have to put things back together,” describes Greg O’Brian, an award-winning political writer who was diagnosed with Alzheimer’s Disease in 2010. The disorienting feeling described by O’Brian in an interview with Medical Daily is familiar for those diagnosed with Alzheimer’s disease. “My former life no longer exists, and it’s up to me to create a new life,” explains Chris Hannafan in an interview with PBS Newshour, a year after his Alzheimer’s diagnosis. Alzheimer’s disease is a progressive brain disorder that leads to memory loss, developmental disabilities, and cognitive impairment. The cause of the disorder appears to be a culmination of a variety of complex factors that arise as we age, such as the degeneration of neuronal pathways, immune system dysfunction, the buildup of β-amyloid protein, among others [1]. Due to its composite nature, a cure for the neurodegenerative disorder continues to elude the scientific community and treatment remains focused on palliative care, medical care that is focused on relieving and mediating the symptoms of the disorder.
Of the several factors that contribute to an Alzheimer’s diagnosis, scientists have recently focused on a cellular process known as chaperone-mediated autophagy (CMA). Autophagy is a critical and versatile cellular mechanism that allows our cells to degrade or eliminate any unnecessary or damaged components [2]. “Without autophagy, the cell won’t survive,” notes Juleen Zierath, a physiologist at the Karolinska Institute in Stockholm, in an interview with Nature. The autophagy process may vary in each cell and is tailored to meet the demands of a specific cells’ workload. CMA refers to a specific form of autophagy that maintains the delicate balance of proteins in the brain through the use of chaperones. Chaperones or cellular “helpers,” lock onto faulty proteins to prevent buildup before being degraded by the cell. Similar to other cellular processes in our body, CMA is naturally less efficient as we age. This may be attributed to the accumulation of dysfunctional proteins and a compromised ability to respond to stressors over time [2]. When the age-dependent decline of CMA is paired with a neurodegenerative disorder such as Alzheimer’s disease, it has been proposed that the age-related inefficiency of CMA is accelerated. This leads to toxic aggregations, or clumps, of damaged proteins that upset the balance of proteins in the brain and entrap functional proteins, generating more blockage. Without CMA, our cell’s cleanup mechanism, this cellular landfill continues to build and begins to interfere with other critical biological processes.
In April 2021, Dr. Ana Maria Cuervo and her team of researchers at the Albert Einstein College of Medicine published a breakthrough study that investigated the relationship between inefficient CMA and the progression of neurodegenerative diseases in a mouse model of Alzheimer’s disease [3]. Cuervo, the co-study leader and co-director of the Institute for Aging Research at Einstein, noted that “these [mice], similar to the [Alzheimer’s] patients, have decreased memory, develop depression and [have] lack of engagement in general.” Using these mouse models, the first step of the study was to confirm that CMA does, in fact, have an impact on the balance of proteins in the brain. To investigate this, researchers generated a CMA-deficient mouse model through knockout, or removal, of the gene that encodes CMA. When compared against the mice with normal CMA levels, the CMA-deficient mice exhibited characteristics that align with rodent models of Alzheimer’s disease. These characteristics included reduced short-term memory, abnormal motor skills, and other dysfunctional behaviors. By interfering with the cells’ ability to regulate proteins, this finding proves that the proper balance of proteins in the brain contributes to the maintenance of stable neurological function.
The link between CMA deficiency and abnormal neurological symptoms may also be reversed, further emphasizing the importance of CMA in the brain. In a second experiment, researchers examined whether they could observe deficient CMA in mice that were already diagnosed with early Alzheimer’s disease. The results revealed lower levels of CMA activity in the mice that were afflicted with early Alzheimer’s disease. Ultimately, these findings indicated that in the early stages of Alzheimer’s disease, CMA activity is decreased and is likely contributing to the harm caused by aggregated proteins.
With a more concrete understanding of how CMA plays a role in neurological disorders, Cuervo and her team of researchers created a drug that could be used to treat the CMA-related symptoms observed in Alzheimer’s disease. Her vision for this new drug was that “if [we] could increase the removal of these proteins or the cleaning process that occurs normally inside the brain, it might be enough to eliminate toxic proteins.” This pharmaceutical re-energizes a component of the CMA apparatus, allowing a more efficient clearing of protein debris that may otherwise create blockages and eventually manifest in neurological symptoms. In a typical Alzheimer’s patient, “the sheer amount of defective protein overwhelms CMA and essentially cripples it,” Cuervo continues. Essentially, since the levels of faulty protein are markedly higher in Alzheimer’s patients, the CMA process must be functioning optimally. This new drug, CA, acts as a CMA enhancer by interacting with a
receptor, a type of cellular gatekeeper. In a healthy individual, chaperones, or cellular “helpers,” lock onto faulty proteins and guide them to a specific compartment within the cell, the lysosome. A single cell can have hundreds of lysosomes, each of which is tightly sealed from the rest of the cell due to its highly acidic contents. Once the chaperone, faulty protein in hand, has reached the lysosome, it docks to the compartment and releases the protein into the lysosome to be digested. The entry of the faulty proteins into the lysosome is monitored by various cellular gatekeepers present on the surface of the lysosome, one of which is the LAMP2A receptor. Throughout one’s life, the production of the LAMP2A receptor is constant. However, with age, the deterioration of LAMP2A receptors is accelerated. CA specifically targets this challenge by “[restoring] LAMP2A to youthful levels, enabling CMA to get rid of defective proteins so they can’t form those toxic protein clumps” as explained by Cuervo. By increasing the number of LAMP2A receptors, or gates, on the lysosomal surface, researchers were able to increase the channeling of faulty proteins into the lysosome which acts as the garbage disposal of the cell.
This new treatment, despite still being in its early stages of testing, provides an optimistic glance at potentially revolutionizing treatment for those suffering from neurological disorders that are caused by protein aggregation. Although it may be a while before Alzheimer’s patients are free from the daily burden of reorganizing their mental file cabinets, this study sheds light on a previously underscored cellular process and reveals a new avenue for Alzheimer’s research to explore. As Dr. Cuervo concludes, “this [finding] can be considered as an important step forward, or as a very good proof that enhancing cellular cleaning can be a way to develop therapeutics or interventions that can cure Alzheimer’s disease.”
References
- Armstrong RA (2013). What causes alzheimer’s disease?. Folia neuropathologica, 51(3), 169–188. https://doi.org/10.5114/fn.2013.37702
- Bejarano E & Cuervo, AM (2010). Chaperone-mediated autophagy. Proceedings of the American Thoracic Society, 7(1), 29–39. https://doi.org/10.1513/pats.200909-102JS
Bourdenx M, Martín-Segura A, Scrivo A, Rodriguez-Navarro JA, Kaushik S, Tasset I, Diaz A, Storm NJ, Xin Q, Juste YR, Stevenson E, Luengo E, Clement CC, Choi SJ, Krogan NJ, Mosharov EV, Santambrogio L, Grueninger F, Collin L, Swaney DL, Cuervo, AM. (2021). Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell, 184(10), 2696–2714.e25. https://doi.org/10.1016/j.cell.2021.03.048
mRNA Vaccines: A Safe and Effective Technology
By Elexia Butler, Human Biology, ’23
Author’s Note: This article was written to reveal how the COVID-19 vaccines are produced and how they are a safe technology used to help reduce the number of sick individuals. Throughout the article, I will discuss the safety and efficacy of mRNA vaccines as well as the limitations that scientists overcome. I chose this topic because mRNA vaccines are a “new” technology that many of us don’t understand and has led to a larger social debate. The controversy surrounding mRNA vaccines stems from people’s questions regarding the vaccines’ safety and necessity. After reading this article, I hope the reader is able to take away the fact that the mRNA vaccines are safe and effective.
Abstract:
As the world begins to settle after the past year and a half of operating with the COVID-19 pandemic, we look to mRNA vaccines to help return to a sense of normalcy. With both Moderna and Pfizer leading the market of mRNA vaccines since April 2021, we have seen a large decline in cases [27]. However, many people across the country are still skeptical of this “new” mRNA vaccine technology [8] and remain hesitant about getting the vaccine. Additionally, the COVID-19 vaccine controversy has left many individuals wondering if the vaccine is truly a safe way to fight the spread of COVID-19 or not. Currently, 54.7-59% of Americans have been fully vaccinated, but based on a PBS poll 24% have chosen to not receive any dose of the vaccine [40-41]. The goal of this article is to demonstrate the safety of mRNA vaccines, their development, limitations, and potential for treating future diseases.
Introduction:
Messenger RNA (mRNA) vaccines are not a new technology, in fact they have been researched for years. mRNA is a small genetic molecule that encodes specific proteins [33]. The discovery of mRNA in 1961 sparked an entire field of research related to gene regulation [1-5].
Traditional vaccines work by introducing an antigen (a foreign substance that is recognized by the immune system) to elicit an immune response and cause the body to produce antibodies against that antigen [13]. For nucleic acid vaccines (DNA and RNA vaccines), rather than directly injecting the antigen, the instructions for producing the antigen are introduced into the cell [14]. The cell can then use these instructions to “make a protein—or even just a piece of a protein—that triggers an immune response inside our bodies” [16]. In the case of COVID-19, Pfizer and Moderna mRNA vaccines encode the instructions to make a viral spike protein from SARS-COV-2 (the virus that causes COVID-19). The spike protein won’t cause sickness on its own, it trains the immune system to defend against the real SARS-COV-2 virus [38]. While research has been conducted on both DNA and RNA based nucleic acid vaccines, it has been shown that RNA vaccines are able to elicit a stronger immune response and are likely safer [15]. The technology of mRNA vaccines became increasingly promising as scientists used the speed of production of the technology to develop a safe and effective mRNA vaccine to their advantage [50-51]. One of the many reasons the Moderna and Pfizer vaccines work is the way they modify the stability of the mRNA and establish a method for efficient delivery, allowing for a strong immune response when administered [17, 45-47]. Though hesitancy remains surrounding the COVID-19 vaccine, the Moderna and Pfizer vaccines are both effective and have significantly reduced the infection rate of COVID-19 [27]. This hesitancy has been fueled by reports of conspiracies as well as possible health effects, which all have been proven false and will be discussed later in larger detail.
Figure 1. This diagram demonstrates how the SARS-COV-19 vaccine was produced and how it elicits an immune response. Through the mRNA being introduced into the body, the cells gain instructions on how to produce the spike protein and forms antibodies.
Proof of Principle:
The COVID-19 mRNA vaccine has brought hope to the medical field because they are effective and can continue to develop. With this technological advancement, it is important to maintain a certain standard of success to build confidence in the vaccines. The Food and Drug Administration (FDA) has set a standard for success of “at least 50%” efficacy, or the prevention of the spread of infection due to the vaccine [18, 53]. The Moderna and Pfizer mRNA vaccine clinical trials exceeded this standard, granting them Emergency Use Authorization (EUA). The application of the mRNA vaccine demonstrated an effectiveness of “90% for full immunization and 80% for partial immunization” [10]. A study, conducted by the CDC in March of 2021, was used to assess the real world application and effectiveness of the vaccine in a potentially infectious setting. As reported by the CDC, the group of vaccinated first responders and essential health care workers were prevented from infection. This study showed that the Moderna and Pfizer vaccines are highly effective in the real world.
Along with this, there have been observational studies that show the vaccines have reduced the amount of transmission and need for hospitalization [9, 23]. Through a recent study by the Center of Disease Control and Prevention (CDC), it was concluded that the “SARS-CoV-2 vaccines significantly reduce the risk for COVID-19–associated hospitalization in older adults and, in turn, might lead to commensurate reductions in post-COVID conditions and deaths.” [9]
The vaccines have created an opportunity for the world to return to a somewhat normal reality through the concept of herd immunity. Herd immunity is the idea that a “large portion of a community becomes immune to a disease … As a result, the whole community becomes protected—not just those who are immune” [30]. In other words, as more people get vaccinated, the transmissibility of SARS-COV-2 will be significantly reduced. Proof of this comes from the CDC as they discovered that in 1000 working days, infections among unvaccinated individuals (1.38 infections) were significantly higher than both fully vaccinated (0.04 infections) and partially vaccinated individuals (0.19 infections) [10]. To put it simply, the COVID-19 vaccine works. The vaccine has protected individuals throughout the past 6 months, and now that it is readily available we are seeing a massive decline in cases [27].
Figure 2. This diagram demonstrates how herd immunity functions in our society. As shown, the more people that are vaccinated, they are less likely to become infected.
Versatility:
Researchers have started studying possible applications of mRNA vaccines to diseases such as AIDS and other incurable diseases. It has been difficult to make regular vaccines due to the fact that there are so many mutations and strains, however the mRNA vaccine has been able to sidestep that by teaching the body to make antibodies and proteins. Before the modern advancements of mRNA vaccines that the COVID-19 vaccine brought forward, there was no efficient and effective way to deliver mRNA into the cell [31-32]. According to Mu et al. until these recent developments, there were major bottlenecks that hindered such research because mRNA is very unstable and can easily denature [31-32]. With new research, Moderna has begun trials on various mRNA vaccines, including one for HIV and AIDS [29].
Along with HIV, there has been research into using mRNA vaccines to treat cancer. Two types of vaccines have been proposed for cancer: preventative vaccines and treatment vaccines. Preventative vaccines attempt to protect the body from viruses that can potentially lead to cancer. HPV and Hepatitis B are two infections where vaccines have been made in an effort to prevent these infections and stop the development of cancer [43]. In this method, the body “mount[s] an attack against cancer cells … Instead of preventing disease, they are meant to get the immune system to attack a disease that already exists” [43]. Treatment based vaccines, meanwhile, are more personalized to an individual’s genome [49]. To implement this, there must be an understanding of the individual’s specific cancer genome [49]. Scientists identify the mutated genes that are responsible for the tumor growth in the individual. They then encode and inject the mutant mRNA into the body, providing the individual’s immune system with instructions to create the mutated protein. This mRNA enables the body to identify and attack the cells with markers for the mutated gene, which are not present in non-cancerous cells. Moderna implemented a similar approach and found that the method reduced tumor size in 30% of human participants when combined with checkpoint inhibitors, a drug which activates proteins to regulate the immune system when attacking cancer cells [49, 54]. Through the use of an mRNA vaccine, this allows the body to fight the tumors on its own rather than using harsh chemical mixtures, like chemotherapy, to stop the growth of the cancer.
In regards to the multitude of other infectious diseases, much of the research around mRNA vaccines has already started and will continue. With the full approval of the Pfizer vaccine and current EUA of Moderna, the opportunity for future mRNA vaccines seems promising. As noted in previous research for mRNA vaccines targeting Zika and other diseases, there was a lack of knowledge regarding mRNA vaccines that impacted the ability to create a successful vaccine [19]. Due to the recent advancements, the opportunity to revisit these vaccines is possible.
Limitations:
Several major hurdles continue to limit the broad application of mRNA vaccines which include cost, safety concerns, and instability of mRNA affecting storage.
Cost:
Due to the severity of COVID-19, funding was readily available in an effort to mitigate the spread of this deadly virus. The federal government was one of the major financial suppliers as they “pledged to give nearly $500 million to Moderna alone for its COVID-19 vaccine”, and this was able to support one of the first COVID-19 vaccines brought forward [24]. Dr. Nathaniel Wang, chief executive of Replicate Bioscience developing RNA-based treatments for cancer, said “it’s pretty hard to talk people into taking bets on this type of technology for vaccines in infectious diseases” because it is seen as “new” technology [19]. This has been gravely apparent regarding RNA vaccines for diseases like Zika [19]. These financial constraints delayed progress and it made mRNA vaccines a nonviable strategy of treatment for Zika, COVID, and other diseases previously discussed.
Safety:
The safety concerns regarding the COVID-19 vaccine have been particularly contentious in the U.S. This fear is fueled by misinformation such as rumors of infertility caused by the vaccine and other false claims that have been reported in opinion pieces online. Many of the conspiracy theories and stories that damaged the image of the vaccine originated from social media[21]. A study polled that a majority of Americans believe there was “rushed approval for the COVID-19 vaccine without the assurances of safety and efficacy” causing people to believe that the vaccine bypassed all the regulatory steps [22]. The FDA defines that “for an EUA to be issued for a vaccine… FDA must determine that the known and potential benefits outweigh the known and potential risks of the vaccine” [39]. Through years of advanced research, the trials and production of the vaccine were able to run in parallel without compromising the safety of the vaccine [50]. While there are some valid concerns specific to the COVID-19 mRNA vaccines, including myocarditis, blood clots, and potential allergic reactions, the COVID-19 mRNA vaccines have been deemed as safe and effective by the CDC [26].
Side effects:
It is possible that individuals will experience certain side effects ranging from pain, swelling in the arm, nausea and fever, along with some more serious side effects, for example myocarditis and blood clots, reported by the CDC. It is important to note that if these less serious side effects even occur they are generally present for less than a week. A small price to pay for a vaccine that has been effective in preventing the spread of COVID-19 [23]. This was shown through mouse and hamster trials, as they noted that they had full immune system responses that protected against COVID-19, similar to that of humans [57]. In another study done with rats, they focused on the vaccine’s potential impact on pregnant rats to simulate that of a pregnant woman and found that there are potential side effects on that impact fetal development, female fertility, and early offspring development, but none were observed [58].
Through a variety of trials, scientists have determined that the body has been able to perform a timely immune response to the vaccine. A measurement of this has been the body’s reaction in the form of specific side effects [52]. Only a small number of cases include more serious reactions, such as anaphylaxis (2.5 per 1 million Moderna vaccines). Most cases will only have small reactions and no long-term side effects have been recorded [34, 35]. Though the majority of people only have minor reactions, these side effects show that the vaccine has gotten into the cell and the body has identified the viral mRNA [52].
Through the immense amount of data showing the vaccine’s efficacy, Pfizer has received FDA approval while Moderna has begun the FDA approval process [36, 37]. This milestone highlights the safety and efficacy of both mRNA vaccines.
Storage:
Due to the fact that both Moderna and Pfizer need lower temperatures for stability, they require the vaccines be kept below freezing around -20 to -80 degrees C for long term storage [25]. RNA needs to be stored at lower temperature as it will degrade due to alkaline hydrolysis, (breakdowns on its own in basic conditions) and RNAse activity (a nuclease that cleaves RNA). There have been cases of COVID-19 vaccines being discarded due to improper storage [55]. This limits packaging, shipment, and regions of the world allowed to have access to these vaccines because their storage will require specialized equipment and refrigeration.
Conclusion:
The COVID-19 vaccines have paved a way for more mRNA vaccines to be brought to the medical field. If there is a steady increase in funding, researchers can begin to establish these kinds of vaccines for a variety of different diseases. By working through setbacks and finding a way to deliver vaccinations to the masses as well as bringing money to research, many of the limitations of mRNA vaccines can be mitigated in the future. The COVID-19 vaccine has proven to be quite efficacious and the recent FDA approvals are evident of this. These vaccines have been able to set a precedent of how mRNA vaccines can be used throughout health care as a protective measure. mRNA vaccines are still considered a “new” technology and will continue to be researched and applied to a wide variety of fields in the future.
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Computational Strategies in the Treatment and Analysis of COVID-19
By Surya Vishnubhatt, Biomedical Engineering, ’22
Author’s Note: The devastating COVID-19 pandemic, having resulted in the death of millions of people worldwide, has spurred innovation in countless sectors of academia, namely in the field of bioinformatics and computational biology. By using computer science techniques, researchers have been able to rapidly identify treatments and further analyze the SARS-CoV-2 virus; the following review synthesizes computational advancements in COVID-19 research through immunoinformatics, docking servers, machine learning, and microRNA analysis. This review also incorporates current computational approaches in the treatment and analysis of COVID-19 viral variants. The use of bioinformatics and computational biology, in pursuit of analyzing and treating all forms of COVID-19, has yielded fast and effective therapeutic treatments in conjunction with crucial analytical findings. With much of the United States now opening up, and the virus likely to become a global endemic, the need for fast, computational analysis of the disease, regarding its progression and spread, is invaluable in ensuring public safety.
Introduction
The COVID-19 pandemic is a global public health emergency, with the fast spreading virus having engulfed the world within a few months. The respiratory disease, as of February 2022, has resulted in the death of 5.9 million people worldwide [1]. The viral pathogen behind COVID-19 is SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). This relentless virus has a mutation rate of 9.8 x 10-4 substitutions per site per year, which refers to the replacement of a specific DNA base pair with another by means of nucleotide substitution. Given the scale of the genome (the human genome is 3.2 billion base pairs long), the mutation rate of SARS-CoV-2 allows for substantial changes to the virus’ spike protein, allowing it to evade its host’s defenses and causing new viral variants to crop up around the world [2]. As the prevalence of these variants increases worldwide, the importance of effective computational analysis of COVID-19 protein and antibody dynamics cannot be overstated.
Bioinformatics and computational biology are highly similar, interdisciplinary areas of study that use the core tenets of computer science to analyze biological data. In general, bioinformatics and computational biology are crucial in understanding and analyzing protein dynamics, primarily in regards to sequence, structure, and evolution based analysis (which tracks changes in protein composition over time) [3].
A variety of computational approaches have been and are being investigated in the hopes of better understanding how COVID-19 operates in order to develop effective therapeutic treatments. One such approach concerns the field of immunoinformatics, a subset of bioinformatics and computational biology, which uses protein structures and genome sequences to develop vaccines [4]. Other areas of interest involve the use of docking servers (which predict and model protein-ligand binding interactions) and machine learning to identify and develop COVID-19 therapeutics [5]. Further research is also being conducted in analyzing micro RNA to better understand and exploit the cellular dynamics of COVID-19 [6].
This review will investigate established computational approaches and will also explore novel research regarding COVID-19 in the hopes of stimulating further research in COVID-19 variant analysis.
A Brief History of COVID-19
The SARS-CoV-2 virus emerged in December of 2019, first reported in Wuhan, China. The unique virology of SARS-CoV-2 allowed for its rapid progression and spread. The virus itself is covered with spike proteins on its surface; each spike protein consists of three monomeric units which bind to human ACE2 receptor cells [7]. ACE2 receptors are present on the surface of human muscle cells, primarily in the lungs, and act to mediate vascular constriction and inflammation. During COVID-19 pathogenesis, the SARS-CoV-2 spike protein can bind to the human ACE2 receptor, invade the cell, and proliferate, leading to lung damage. The spike protein has an incredibly high affinity for the ACE2 receptor due to contact interactions which occur at the interface between the receptor binding domain of the spike protein and the ACE2 receptor, contributing to the widespread nature of the disease [8].
Figure 1: The SARS-CoV-2 infection mechanism.
Currently, in the United States, vaccines have been created for the original viral strain, namely the double dose Pfizer and Moderna (mRNA based) vaccines and the single dose Johnson and Johnson (adenovirus based) vaccine [9]. These vaccines stimulate the host to synthesize a non-pathogenic version of the spike protein, which triggers an immune response and is then targeted by host-specific antibodies (generated in response to the host-mediated spike protein), rendering immunity to the major COVID-19 strain. However, with the rise of new variants, most notably, the omicron B.1.1.529 strain, the effectiveness of mRNA (e.g. Pfizer and Moderna) vaccines are diminishing from 95% efficacy to 35% efficacy, with booster shots required to increase efficacy to 75% [10, 11]. Similarly, the Johnson & Johnson adenovirus based vaccine declined from 94% to 85% efficacy in adenovirus based vaccine therapies in individuals who received booster shots [12, 13].
Applications of Bioinformatics and Computational Biology in COVID-19 Research
The field of bioinformatics and computational biology deals in the collection and analysis of biological data, namely genomic and proteomic data, in the hopes of better understanding disease pathogenesis [3].
3.1 Immunoinformatics and COVID-19 Vaccine Development
The field of immunoinformatics is a subset of the field of bioinformatics and computational biology. Specifically, it uses computational, analytical, and mathematical data tied in with computer science processing techniques, to formulate predictions about immunity and vaccine development [14]. In the immunoinformatics-based approach to COVID-19 vaccine development and drug discovery, it is important to note that only the receptor binding domain (RBD) of the SARS-CoV-2 spike protein is in contact with the human ACE2 receptor, making the RBD the major functional region of the virus. Accordingly, the major immunoinformatics-based approaches to COVID-19 antibody development target the RBD of the spike protein, preventing its attachment to the ACE2 receptor [15].
There are two major methodologies of vaccine discovery through immunoinformatics: reverse vaccinology and structural vaccinology [4]. Reverse vaccinology analyzes expressed genomic sequences in order to identify various antigens as potential vaccine targets, as these identified antigens are, ideally, to be synthesized and subsequently targeted by the host immune system. Meanwhile, structural vaccinology uses 3D protein models to engineer immunogenic conformations of antigens in the hopes of eliciting antibody responses against pathogenic attack [16, 17]. Structural vaccinology is not explicitly used in COVID-19 drug discovery, but is incorporated within modern reverse vaccinology techniques [4].
A new study used reverse vaccinology programs as well as novel computation techniques such as the Molecular Mechanics Poisson-Boltzmann Surface Area calculation approach, to design a COVID-19 antibody protein that can provoke a wide array of host immune responses [18]. This immunological approach, in its emphasis on reverse vaccinology, has also been successfully implemented in the design of a multi-epitope subunit vaccine, triggering immunity in both humoral and cell-mediated contexts [19]. Using DNA/PCR visualization software, researchers observed that the multi-epitope vaccine has highly specified, targeted responses to pathogenic invasion via host-mediated immune response [19, 20].
3.2 COVID-19 Docking Analysis
The SARS-CoV-2 docking procedure binds the pathogen to the host’s ACE2 receptors. It is a key point of interest for many researchers who aim to disrupt this binding configuration to prevent COVID-19 infection [21]. Free energy simulators can be used to visualize the stability of various binding configurations of proteins to ligands with a lower binding free energy value indicating a more stable protein-ligand configuration. Using these computational free-energy simulators that bind ligands to the spike protein, potential antibodies can be developed to block or destabilize host-virus interactions [22]. A variety of preliminary studies have been able to identify potential therapeutic compounds from which drug development can progress.
Furthermore, COVID-19 binding can be simulated by docking servers which model how small molecules, peptides, and antibodies bind to potential targets on SARS-CoV-2. In 2020, a team from China created a free meta-server to predict COVID-19 target-ligand interactions to promote drug discovery [23]. This server has been used in a variety of studies. One study used the server to test docking scores of a variety of potential antiviral agents and found that scalarane-based sesterterpenes (a biochemical) showed promise in developing COVID-19 vaccines [24]. Another study, using the same server, identified teicoplanin, an antibiotic, as a potential source of drug design in combating SARS-CoV-2 infection [25].
Several other studies have used docking servers to analyze potential plant-based therapeutic targets; including the compounds of the Boerhavia diffusa, the phytochemicals of the Phyllanthus amarus and Andrographis paniculata, and hesperidin [26-28]. These compounds were initially chosen due to their therapeutic properties and have been previously used to treat a wide array of diseases. Upon further analysis, resulting simulations show that these chemicals can destabilize the ACE2-spike protein complex, thus rendering host immunity [28]. In addition, in silico molecular docking techniques were used in identifying the antiviral drugs Remdesivir and Mycophenolic acid acyl glucuronide as potential candidates to be repurposed towards COVID-19 treatment, due to their preferential binding to the main protease of SARS-CoV-2. This preferential binding can then be used to disrupt the binding of SARS-CoV-2 to human ACE2 receptor cells [29].
3.3 Machine Learning and COVID-19
The field of machine learning is a branch of computer science which trains an algorithm to “learn” through feeding it enough data such that it can make logical predictions about a variety of different sets of conditions [30].
Reverse vaccinology can be combined with machine learning practices to design COVID-19 vaccines. The machine learning tool, known as Vaxign-ML, incorporates biochemical and physicochemical characteristics into its reverse-vaccinology analysis [31]. This platform can then be incorporated with machine learning algorithms, to identify “cocktail” vaccines, consisting of structural and non structural proteins (a protein that is encoded but not part of the viral body), which stimulate an immune response to COVID-19 [32].
Another aspect of machine learning in COVID-19 research involves a more external approach to attacking the problem. Researchers from the Sri Ramaswamy Memorial Institute of Science and Technology were able to train a machine learning algorithm to analyze abnormal chest x-rays and CT scan data in patients exhibiting signs of COVID-19. The study yielded a 93% recall score of CT scan images and 88% precision in analyzing chest x-ray images [33]. Similar machine learning algorithms were used in a different study to analyze abnormal features in the CT scan data of patient lungs. This study yielded an accuracy of 91.94% in diagnosing COVID-19 infection [34].
3.4 MicroRNA (miRNA) and COVID-19 Analysis
MicroRNAs or miRNAs are pieces of RNA which act to regulate gene expression post-transcriptionally [35]. Researchers from Italy and Singapore found that various miRNAs are regulated by the spike protein of SARS-CoV-2 and the human ACE2 receptor in conjunction with the enzyme histone deacetylase (HDAC). Through computational analysis, using in silico methods and the query miRNet analytics platform, these researchers were able to identify that HDAC inhibitors limited interactions between the spike protein and the ACE2 receptor [36]. Further studies confirmed the effectiveness of HDAC inhibitors as a preventative drug to restrict SARS-CoV-2 entrance into the host, using a wide array of laboratory tests and culture analyses [37]. Using similar methodologies, another study constructed its own computational meta-analysis framework to identify how host miRNAs bind to SARS-CoV-2 RNA and suggests the repurposing of anti hepatitis C, RNA based, drugs in the treatment of COVID-19, due to its substantial binding affinity [38].
Current Computational Efforts in COVID-19 Variant Analysis
COVID-19 variants are formed when the virus’ spike protein mutates, making it harder for the established antibodies in vaccinated people to recognize and bind to the pathogen. In some cases, the established antibodies may be able to bind well enough against the variant molecule, while in other cases, a breakthrough infection may occur and the virus is able to override the host’s defense systems [39, 40]. Currently the four major variants of COVID-19 in the United States are: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) [41].
Figure 2: A phylogenetic tree depicting the dominant COVID-19 variants as of December 2021.
By using machine learning algorithms, and comparing genome sequences, researchers were able to obtain an overall picture of the spread of variants throughout all continents [42]. Similarly, other researchers were able to track the global progression of coronavirus variants by aggregating data, concerning the worldwide evolution of COVID-19 nucleotide-substitutions, and building an open source web application known as COVID CG to reflect their findings [43]. Other population-orientated studies investigate the genetic, topological, and evolutionary progression of SARS-CoV-2 in order to understand its emergence on the global scale and how to homogeneously apply vaccines to heterogeneous populations, in the hopes of preventing the spread of COVID-19 and its variants in the future [44-46].
Figure 3: The COVID CG tool, from the end user perspective.
Other studies use computational modeling mechanisms to determine how variants interact with ACE2 receptor cells. One such study modeled a wide array of mutations to the spike protein in order to determine variant transmissibility, which can aid in establishing future safety precautions [47]. Another study was able to model the transmission dynamics of COVID-19 by computationally comparing it with dengue infection (as dengue fever and COVID-19 have similar symptoms in the earlier stages of infection) to obtain alternate insights into COVID-19 disease progression [48].
Conclusion
The field of bioinformatics and computational biology is expansive in its coverage; it can be narrowed down to analyze specific protein-to-protein interactions on the molecular scale or expanded to examine the global progression of disease. With much of the United States reopening its borders, and students returning to in-person classes, the rapid computational analysis of COVID-19 disease progression on both a micro and macro scale is invaluable in ensuring public safety.
As of January 2022, actions to curb the spread of variants have been taken in the form of booster shots and the Pfizer pill. Booster shots reintroduce the same material as the previously mentioned vaccinations to “boost” or reinforce host immunity by increasing the count of memory B and T cells [49]. Additionally, the FDA approved Pfizer COVID-19 Oral Antiviral Treatment, or Paxlovid, consists of nirmatrelvir and ritonavir, with nirmatrelivr acting to prevent viral replication while ritonavir reduces the breakdown of nirmatrelvir. Furthermore, Paxlovid has been proven to be effective against COVID-19 variants in in vitro studies [50-52]. Ultimately, due to the virus’ rapid evolution, most experts have reached a common consensus, that COVID-19 is likely to continually circulate as an endemic, with yearly vaccines needing to be developed and administered, much like the flu [53]. Like the flu, we must continually stay “ahead” of the virus and its variants. Thus, the need for fast, effective computational analysis of the disease and its mutations is essential in mitigating its potentially detrimental effects.
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Current and Potential Therapeutic Options for ALS Individuals
By Anna Truong, Neurobiology, Physiology, and Behavior, ’22
Author’s Note: I wrote this piece of work for an assignment through my UWP 104F course, and felt very connected with it. I decided my topic to be about a disease known as ALS because my father was diagnosed when I was at a young age. At the age of nine, I did not understand the gravity of becoming sick, and how much the world can change when someone important in your life passes away. I did not understand how impactful a disease was until I had the experience as a family member. ALS became a topic of interest to me since then from class presentations about interesting scientific topics to college research papers and literature reviews. This literature review is something that I am proud of because it encompasses ALS as the disease that has involved me and my family. From this review, I hope readers learn more about ALS and how the current research can pave a way for future research in the treatment of ALS.
Introduction
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that is characterized by progressive degeneration of motor neurons in the spinal cord and brain [1-5]. Motor neuron degeneration inhibits the ability of the brain to send signals to the muscles to control movement. There are two types of motor neurons responsible for this communication: the upper and lower motor neurons. Lesions in upper motor neurons prevent the signal cascade to the lower motor neurons that send another signal responsible for muscle movement. This can lead to muscular atrophy, paralysis, and eventually death [1-5]. Various injuries such as damage to the spinal cord or strokes, as well as other factors like oxidative stress induced by free radicals, contribute to the destruction of motor neurons [6]. Approximately 5 of every 100,000 individuals will be affected by ALS and the average life expectancy after diagnosis is between 2-5 years [2].
Many studies have focused on identifying the cause for motor neuron cell death and the genes involved in the development of the disease. Although bodily mechanisms by which motor neurons degenerate remain unclear, they are thought to encompass a non-cell autonomous process [3]. The purpose of this literature review is to analyze the current and potential treatments that can be effective toward individuals experiencing ALS. This article will focus on a current drug treatment called Edaravone, followed by potential treatments, astrocyte-based therapy and cell-based therapies.
Drug Treatments
Edaravone is a free radical-scavenging drug that functions to protect motor neurons from free radicals and oxidative stress damage in the central nervous system (CNS) [2,6]. Edaravone effectively acts on oxidative stress by reducing the number of free radicals to slow disease progression. With the absence of a cure, such treatment options have mainly contributed to prolonged survival [6].
ALS Functional Rating Scale
In this section, we will analyze the effect of Edaravone on disease progression through scoring of motor function by the revised ALS Functional Rating Scale (ALSFRS-R). The ALSFRS-R is an instrument designed for the clinical evaluation of functional status of ALS patients and efficacy of clinical trials [6]. It measures 12 aspects of physical function such as swallowing, breathing, and walking, scoring functioning ability from 4 (normal) to 0 (no ability) with a maximum total score of 48 and a minimum of 0.
Edaravone treatment on ALS patients
During normal disease progression, it is assumed that decline in functioning scores is almost linear [6]. When comparing ALSFRS-R scores between patients who received either placebo treatment or Edaravone treatment, there was a significantly faster decline in functional scores for those who received the placebo. This indicates a considerable loss in the ability to perform everyday tasks [2]. In conjunction with these results, a further study has shown greater improvements in ALSFRS-R scores for patients after beginning Edaravone treatment compared to the pre-treatment period [7]. The pre-treatment period lost an average of 4.7 points on the ALSFRS-R whereas the treatment period showed a smaller average loss of 2.3 points over the same time duration [7]. This indicates possible clinical efficacy for Edaravone due to its ability to effect a more gradual decline.
In addition, compared to placebo, Edaravone remains effective for up to a year, after which survival rates start to decline [2]. Edaravone’s effectiveness is also more prevalent in the early stages of ALS progression, but long-term effects of Edaravone are not yet fully evaluated so results past a year are unclear. Further limitations to these studies, including a nonlinear difference in decline between functional rates of early stages of ALS and end stages of ALS, require more research before affirming the long-term health benefits through Edaravone [2,6,7]. Therefore, as a marketed drug, it is difficult to be sure of its full effectiveness from the lack of positive results in life expectancy of the target population. On the other hand, no detrimental effects or worsening of symptoms due to Edaravone were analyzed during patient trials besides a few side effects including bruising, headaches, and hypoxia [6]. Due to these factors, Edaravone remains a partially beneficial drug.
Potential Therapeutic Options
Although Edaravone’s effectiveness is still actively being deciphered, there have been studies on whether other types of cellular targets within the brain and stem cells, such as astrocytes, could help slow down or halt disease progression and thus be effective treatments for ALS [1,3,4]. Astrocytes are a type of glial cell within the CNS that is inflamed under the diseased state [1]. Most of the following research involves the SOD1-G93A transgenic mice expressing the human SOD1 gene with G93A mutation. It is an important mouse model for studying ALS as it presents many of the pathological symptoms experienced by patients, including motor impairment and motor neuron death, allowing for an analogous simulation [1].
In the current state of medication development, the SOD1-G93A transgenic mice are utilized for their relation to astrocytes, a promising target for effective treatments. The increasing number of studies performed on astrocytes show them to be crucially involved in ALS through their influence on motor neuron fate and disease progression. The studies discussed will present multiple experiments on the SOD1-G93A transgene, and explain how elimination and/or alteration of this gene can help slow prominent signs of disease and extend lifespan [1,5].
Role of Astrocytes in ALS
Upon a specific signal within the CNS, astrocytes can transform into either their reactive A1 state characterized by promotion of neurodegeneration and toxicity or their neuroprotective A2 state which promotes healing and repair of injury [3,9]. Among ALS patients, the reactive A1 astrocytes are dominant along with the mutant transgenic SOD1-G93A, contributing toxic components that participate in ALS pathology [1].
Amongst these pathologies, researchers investigate neuroinflammation, characterized by inflammation of the nervous tissue, to prove its benefits for minimizing reactive astrocytes [1]. Neuroinflammatory stimuli like lipopolysaccharide (LPS) lead to a signal transduction cascade that can secrete immunologically active molecules like IL-1α, TNFα, and C1q that transform resting astrocytes to their neurotoxic A1 state [1]. These reactive astrocytes will lose regular functions and secrete factors toxic to neurons [1,3]. Moreover, isolated astrocytes from ALS patients were found to be toxic to healthy, cultured motor neurons [3]. This indicates the involvement of astrocytes in motor neuron death that can lead to a progressive decline of motor function [3]. Lowering the prevalence of neuroinflammation may contribute to a decrease in motor neuron death, and therefore delayed progression of ALS.
Healthy individual’s communication between the motor neuron, astrocytes, and immune cells compared to those of an ALS individual
Astrocyte-Based Therapy
To minimize neuroinflammatory effects of ALS, Guttenplan et al. determined that knockout, or the genetically modified absence of IL-1α, TNFα, and C1q in SOD1-G93A mice did not produce any reactive astrocytes [1]. This triple knockout was also linked to the possibility of neuroinflammatory reactive astrocytes becoming a therapeutic target for ALS. The triple knockout mice presented with lower levels of reactive astrocyte marker C3 and had a significantly extended lifespan of over 50% compared to regular SOD1-G93A mice [1]. Treatments that implement this mechanism of lowering neuroinflammation can contribute to a turning point in increasing efficacy rates of therapies involved in ALS.
In addition, diagnosis is primarily followed after the presence of symptoms [1]. An approach to treatment included restoring normal functionality of endogenous astrocytes through the transplantation of healthy astrocytes in patients [3]. These transplanted healthy astrocytes can provide neuroprotection through reduction of misfolded proteins in motor neurons. However, they can also transform into neurotoxic A1 astrocytes when in the diseased environment of the CNS [3]. The mechanisms through which transplanted astrocytes act continue to be thoroughly understood, yet provide a promising target for an ALS targeted therapy [1,3]. Delay in disease progression may be more effective with a combination of therapies attacking both reactive astrocytes and motor neurons compared to individual therapies [1].
Cell-Based Therapy
Another approach that has been studied as a potential therapeutic target for ALS is through stem cells. Mesenchymal stem cells (MSCs) are adult multipotent precursors that can be prompted to release neurotrophic factors released by A2 astrocytes and have shown to be beneficial in the regeneration of healthy cells [3]. Transplantation of the same individual’s MSCs induced to secrete neurotrophic factors showed early signs of safety and treatment effectiveness [3].
Furthermore, a specific stem cell therapy “Neuro-Cells”, a combination of MSCs and hematopoietic stem cells (HSCs), along with anti-inflammatory measures was administered to both SOD1-G93A mice and FUS-tg mice, a variant of the standard SOD1-G93A strain [4]. In SOD-1 and FUS-tg, inflammation contributes to disease progression, allowing for comparison investigation in these two mutations [4]. When tested on rats subjected to spinal cord injury, this mixture had an anti-inflammatory effect, thus improving motor function and decreasing concentrations of proinflammatory cytokines in the cerebrospinal fluid [4]. Muscle degeneration among FUS-tg mice was also compared during Neuro-Cell injections. Muscular atrophy was noticed to be partly rescued by the mixed stem cell therapy. To verify these results, Neuro-Cells were administered to SOD1-G93A mice. Results showed an indication of improved motor function similar to that of the FUS-tg mice, thus providing further evidence of disease counteraction [4]. These signs of efficacy and preclinical studies of transplantation of MSCs and HSCs are indicators of beneficial treatments from the usage of stem cells through reduction of motor neuron death, prolonged survival and improved motor performances [3]. Coincidingly, according to de Munter et al., stem cell therapy should be utilized as a part of the cell-based treatment of ALS due to the knowledge present already in this field [4]. Even so, more research is needed to define the anti-inflammatory mechanisms in ALS pathology and other effects that “Neuro-Cells” have on ALS.
Possible stem cell therapies that could be used to treat ALS
Discussion/Conclusion
While there are currently effective drug treatments available for ALS, there is still research being conducted on these drugs to better ensure quality and effectiveness. Edaravone’s ability to slow disease progression remains minimal or ineffective to patients who are past the beginning stages of ALS progression, and toward end-stage ALS, respectively. Decline in patients experiencing ALS occurs non-linearly with a rapid decline toward the end-stage, and so clinical effects of Edaravone may not be beneficial. Its therapeutic effects are yet to be better understood and whether or not their effectiveness is due in part to the drug. Although it is currently being used as a treatment option, Edaravone could be further improved for efficacy.
In association, potential treatment options of astrocyte-based therapies and cell-based therapies play an important role in the future of ALS. Targeting astrocytes and neuroinflammation, and utilizing stem cell therapy can provide benefits to slowing disease progression. However, much like the current drugs, there is still much to understand about other subpopulations of astrocytes and stem cells that could contribute to ALS pathology. The intertwined participation of therapies is important to note as it could provide greater benefits to patients seeking out future treatments. Although options of treatment are currently limited, these studies suggest potential therapeutic approaches that can be optimized to halt or slow disease progression. Currently, stem cells are encouraged to be part of treatment in ALS patients, suggesting its potential in reducing inflammation and therefore can be highly effective in minimizing motor neuron death. Additionally, astrocytes are becoming a major direction in the studies of ALS, due to its direct involvement in motor neuron death associated with the disease. Astrocytes may become the center of research in the near future and lead to a more efficient slowing of disease progression compared to the currently approved drugs. With more studies, the cellular mechanisms contributing to the deterioration of motor neurons involved in ALS can lead to promising treatments with greater efficacy against the disease. In due time, we can hope to see an increase in the average life expectancy of 2-5 years to much longer.
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