Science

Microplastic burden in marine benthic invertebrates depends on feeding strategies

May 8, 2024 by Cindy Dai '27

Microplastic pollution is a global issue effectively impacting all aquatic systems from the poles to tropical reefs. Current emission patterns project to around 35 – 98 metric tons of annual microplastic emission by 2030. Yet, this may only be an underestimation, as our current understanding of microplastic concentrations based on traditional sampling practices overlooks smaller debris (Lindeque et al. 2020, Borrelle et al. 2020). With this scale of rapid increase in concentrations, the implications of microplastic accumulation in marine systems have become an increasing concern. In response to this global concern, Adam Porter and his team looked towards the ocean’s floor to better understand how microplastics interact with dynamic ecosystems.

Microplastics emitted into the marine environment can adversely impact a wide range of processes from cellular metabolism to digestive functions, fertility, locomotion, and growth (Foley et al. 2018; Bour et al. 2018). Furthermore, bioaccumulation, or trophic transfer when contaminated prey is consumed by predators, magnifies microplastic burdens in organisms higher in the food chain. These above properties, in conjunction to the rapidly increasing environmental concentrations, highlight the pressing need to quantify how much microplastics marine organisms are ingesting.

Historically, our understanding of individual microplastic burdens has often assumed that levels of environmental contamination directly map onto their uptake by marine organisms. However, studies have found that this isn’t always the case. Other factors, such as feeding strategies and community composition, also impact a species’ uptake rate (Pagter et al. 2021; Bour at al. 2018).

To bridge the mismatch of environmental concentration and individual burden, Porter et al. reviewed 412 studies on marine invertebrates from around the globe to investigate how different species traits could influence microplastic uptake. First, they gathered data from each study and assigned a geographic sector to each sampling site. Next, they evaluated each observation for a variety of variables, including feeding mode, position within the sediment, and wet weight (mass) of the individual. Then, Porter’s team used statistical tests to examine the potential influence each parameter had on plastic uptake with statistical analyses tests and visualized their findings.

Geographically, the Pacific Northwest, Yellow Sea and Japan Trench, had the highest mean individual microplastic burden. In terms of animal class, the highest mean burden occurred in the Malacostraca class. Malacostraca encompasses common commercial species such as crabs and lobsters, which could have commercial implications on industries like lobster fishing and aquaculture.

Of all the outlined parameters, feeding strategies had the greatest impact on microplastic uptake. Omnivores were shown to have the highest rate of uptake, followed by predators, herbivores, grazers, suspension feeders, deposit feeders, and lastly scavengers. These findings support the bioaccumulation theory, one of several hypotheses concerning microplastic uptake patterns (Wang 2014). According to the bioaccumulation theory, microplastics enter the food web through primary consumers like suspension feeders, grazers, and filter feeders. The plastic they retain in their systems will then be ingested by higher trophic levels like secondary and tertiary consumers that are omnivores,predators, and scavengers. Accordingly, the microplastic burdens would be highest in predators and omnivores, which matches the study’s findings.

In addition to the quantity of microplastics retained, feeding patterns were also found to influence the size and type of microplastics consumed were also different across groups. The most reported shape was fibers. The mean sizes of these fragments ranged from 0.2 micrometers to 17 centimeters, and herbivores in general retained the largest particles, but the precise mechanisms driving these patterns remain unclear.

These findings precisely highlight our gap in knowledge of microplastic distribution amongst marine communities. As Porter et al. highlights, a holistic consideration of subtle processes related to feeding patterns is essential in fine tuning our understanding of how our world is changing. Thus, although the study describes general trends on a global scale, future research focusing on regional subtleties is important. Subsequently, applying these findings as policy is crucial, as many marine organisms are frequently consumed commercial species. Being major consumers of seafood, the microplastic accumulation in marine animals can directly impact humans. This is particularly concerning in context of our status as the apex predator, and therefore the final stop in the chain of bioaccumulation. As the microplastic burden in marine organisms is rising at an alarming pace, the need for action is more urgent than ever.

Works Cited

Borrelle, S. B., Ringma, J., Law, K. L., Monnahan, C. C., Lebreton, L., McGivern, A., Murphy, E., Jambeck, J., Leonard, G. H., Hilleary, M. A., Eriksen, M., Possingham, H. P., De Frond, H., Gerber, L. R., Polidoro, B., Tahir, A., Bernard, M., Mallos, N., Barnes, M., & Rochman, C. M. (2020). Predicted growth in plastic waste exceeds efforts to mitigate plastic pollution. Science, 369(6510), 1515–1518. https://doi.org/10.1126/science.aba3656

Bour, Agathe, Carlo Giacomo Avio, Stefania Gorbi, Francesco Regoli, and Ketil Hylland. “Presence of Microplastics in Benthic and Epibenthic Organisms: Influence of Habitat, Feeding Mode and Trophic Level.” Environmental Pollution (Barking, Essex: 1987) 243, no. Pt B (December 2018): 1217–25. https://doi.org/10.1016/j.envpol.2018.09.115.

Foley, Carolyn J., Zachary S. Feiner, Timothy D. Malinich, and Tomas O. Höök. “A Meta-Analysis of the Effects of Exposure to Microplastics on Fish and Aquatic Invertebrates.” The Science of the Total Environment 631–632 (August 1, 2018): 550–59. https://doi.org/10.1016/j.scitotenv.2018.03.046.

Lindeque, P. K., Cole, M., Coppock, R. L., Lewis, C. N., Miller, R. Z., Watts, A. J. R., Wilson- McNeal, A., Wright, S. L., & Galloway, T. S. (2020). Arewe underestimating microplastic abundance in the marine environment? A comparison of microplastic capture with nets of different mesh-size. Environmental Pollution, 265, 114721. https://doi.org/10.1016/j.envpol.2020.114721

Pagter, Elena, Róisín Nash, João Frias, and Fiona Kavanagh. “Assessing Microplastic Distribution within Infaunal Benthic Communities in a Coastal Embayment.” Science of The Total Environment 791 (October 15, 2021): 148278. https://doi.org/10.1016/j.scitotenv.2021.148278.

Porter, A., Godbold, J. A., Lewis, C. N., Savage, G., Solan, M., & Galloway, T. S. (2023). Microplastic burden in marine benthic invertebrates depends on species traits and feeding ecology within biogeographical provinces. Nature Communications, 14(1), 8023. https://doi.org/10.1038/s41467-023-43788-w

Wang, W. -X. “Chapter 4 – Bioaccumulation and Biomonitoring.” In Marine Ecotoxicology, edited by Julián Blasco, Peter M. Chapman, Olivia Campana, and Miriam Hampel, 99–119. Academic Press, 2016. https://doi.org/10.1016/B978-0-12-803371-5.00004-7.

Engineered Nanoparticles Enable Selective Gene Therapy in Brain Tumors

May 8, 2024 by Sophie Nigrovic '24

Inborn protective mechanisms present challenges for therapies targeting cancers of the brain. Engineered nanoparticles permit the selective delivery of CRISPR-Cas9 to glioblastoma tumors.

Glioblastoma accounts for almost half of all cancerous tumors originating in the brain.¹ Even with maximum safe treatment, the median survival period for patients is less than 1.5 years.² However, survival varies widely by age, from a 0.9% 5-year survival rate for patients over 75 years old to an 18.2% 5-year survival rate for patient 0-19 years old.³ Nevertheless, the overall 5-year survival rate remains low at 5%² and novel therapies are urgently needed for glioblastoma treatment. Zou et al. present a highly specific CRISPR-Cas9-based gene therapy for glioblastoma.⁴

Gene therapies offer an attractive treatment for cancers. The goal of gene therapy is to mutate or remove deleterious DNA sequences such that they are unable to be transcribed and translated into functioning proteins. In the most prevalent technique, CRISPR-Cas9, single guide RNA (sgRNA) identifies and binds to the target DNA sequence. It then recruits Cas9 proteins to excise parts of the target DNA sequence. Mutations are generated as the cell tries to repair the damaged DNA.⁵

While a powerful tool, researchers have struggled to effectively deliver CRISPR-Cas9 to their cellular target. Delivery is particularly complex in brain tumors such as glioblastoma. Traditionally medications are trafficked through the body and delivered to their target through the bloodstream. However, the brain is a more complex and protected system. Primarily, selective delivery of therapeutics to tumor cells is necessary to protect neuronal function. Moreover, the brain is separated from the blood stream by a thin layer of cells termed the blood-brain barrier (BBB). The BBB allows for selective permeation of compounds into the brain, shielding neurons from toxins while permitting the passage of essential nutrients.⁶ Previous studies have sought to transport CRISPR-Cas9 therapies across the BBB using viruses as delivery capsules⁷ or circumvent the BBB altogether via intercranial injection of therapeutics.⁸ Yet these methods carry risk, either an immune response to the viral vector or complications from the invasive injection.

Zou et al. sought to resolve the issues of specific cell targeting and BBB permeability in CRISPR-Cas9 delivery by encapsulating the gene editing complex within a nanoparticle. The researchers chose to target Polo-like kinase 1 (PLK1) using CRISPR-Cas9 gene therapy. PLK1 is an attractive for selective gene therapy due to its higher overexpression by glioblastoma cells and by the proliferative glioblastoma subtype in particular.⁹ Moreover, inhibition of PLK1 has been shown to reduce tumor growth and induce cell death.⁹

The researchers encapsulated Cas9 and sgPLK1 in a neutrally charged nanoparticle for delivery. The small size of nanoparticles, which are measured in nanometers, allow for easy transport through the bloodstream and uptake by cells. Taking advantage of the high expression of lipoprotein receptor-related protein-1 (LRP-1) on both BBB endothelial cells and glioblastoma tumor cells, they decorated the nanocapsule surface with LRP-1 ligand angiopep-2 peptide to facilitate selective uptake by BBB and glioblastoma cells (Figure 1). Zou and her colleagues bound the nanoparticle together with disulfide bonds as an added layer of selectivity for glioblastoma cell delivery. In the high glutathione environment of a glioblastoma cell, the nanoparticle dissolves, releasing its contents. However, glutathione concentrations are lower in BBB endothelial cells and healthy neurons, reducing the dissolution of the nanoparticles and leaving healthy DNA alone.

Figure 1. Nanoparticles enable permeation of the blood brain barrier (BBB) and selective delivery of the CRISPR/Cas9 system to glioblastoma (GBM) cells. Angiopep-2 peptides, which decorate the nanoparticle’s surface, bind with lipoprotein receptor-related protein-1 (LRP-1) overexpressed on BBB and GBM cells. Following uptake into GBM cells, the nanoparticles dissolve in the high glutathione environment, releasing the Cas9 nuclease and single guide RNA (sgRNA) targeting Polo-like kinase 1 (PLK-1) genes. Zou et al. demonstrated the selective mutation of PLK-1 induced apoptosis in GBM cells with minimal off-target effects.

Through Cas9/sgPLK1 delivery by nanoparticle, Zou et al. demonstrated a 53% reduction in expression of the targeted gene in vitro. PLK1 gene editing was cell selective, with negligible genetic mutation in the healthy surrounding brain tissue. While nanoparticles with and without disulfide cross-linking were capable of gene editing, the disulfide cross-linked nanoparticle induced almost 400% more mutations. Glioblastoma cells treated with disulfide cross-linked nanoparticles were also over 3 times more likely to undergo apoptosis cell death. Mice grafted with patient glioblastoma tumors treated with Cas9/sgPLK1 nanocapsules experienced an almost 3-fold extension in life expectancy, suggesting this treatment as a viable anti-glioblastoma therapy.⁵

Yet in order to be effectively applied as a cancer therapy, the efficiency of this nanoparticle delivery system must be increased. In mouse glioblastoma models, Zou et al. only achieved a maximum accumulation of 12% and effected a 38% knockdown of PLK1.⁵ Despite their low magnitude, these values are far greater than similar gene therapy treatments currently studied, suggesting nanoparticles present an innovation in the delivery of CRISPR-Cas9 to difficult to access tumors.

In addition to the improved efficacy over existing systems, the work of Zou et al. opens the door for less invasive administration of treatment. In contrast to previous gene therapies administered directly to the tumor through intercranial injection, the BBB penetration and tumor-specific accumulation of the nanoparticles may permit systemic administration. Zou et al. injected the nanoparticles intravenously, but treatment may even be given as a pill taken orally, eliminating any surgical intervention. Moreover, due to their modular design, the engineered nanoparticles may be adapted as targeted treatments for other tumors. Exchanging the angiopep-2 peptides for another ligand would facilitate uptake by cells expressing the corresponding receptor. The load carried within the nanoparticle could be altered to contain a different sgRNA targeting a new gene or another therapeutic entirely as a complementary treatment. Nanoparticle delivery systems like that studied by Zou et al. contains many layers of selectivity, offering hope for effective delivery of treatment to previously inaccessible tumors.

Works Cited:

Wirsching, H.-G. & Weller, M. Glioblastoma. in Malignant Brain Tumors : State-of-the-Art Treatment (eds. Moliterno Gunel, J., Piepmeier, J. M. & Baehring, J. M.) 265–288 (Springer International Publishing, Cham, 2017). doi:10.1007/978-3-319-49864-5_18.
Delgado-López, P. D. & Corrales-García, E. M. Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol 18, 1062–1071 (2016).
Ostrom, Q. T. et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011. Neuro Oncol 16, iv1–iv63 (2014).
Lino, C. A., Harper, J. C., Carney, J. P. & Timlin, J. A. Delivering CRISPR: a review of the challenges and approaches. Drug Delivery 25, 1234–1257 (2018).
Zou, Y. et al. Blood-brain barrier–penetrating single CRISPR-Cas9 nanocapsules for effective and safe glioblastoma gene therapy. Sci Adv 8, eabm8011.
Dotiwala, A. K., McCausland, C. & Samra, N. S. Anatomy, Head and Neck: Blood Brain Barrier. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2024).
Song, R. et al. Selection of rAAV vectors that cross the human blood-brain barrier and target the central nervous system using a transwell model. Molecular Therapy Methods & Clinical Development 27, 73–88 (2022).
Lee, B. et al. Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. Nat Biomed Eng 2, 497–507 (2018).
Lee, C. et al. Polo-Like Kinase 1 Inhibition Kills Glioblastoma Multiforme Brain Tumor Cells in Part Through Loss of SOX2 and Delays Tumor Progression in Mice. Stem Cells 30, 1064–1075 (2012).

Atlantic on the Brink: Climate Change Impacts to a Critical Ocean Circulation System

April 25, 2024 by Christian Sullivan '26

Global warming due to anthropogenic greenhouse gas emissions poses an immense threat to Earth’s oceans, which serve as a vital climate regulation system. The influx of large quantities of freshwater from melting Arctic sea ice has the potential to critically alter ocean circulation in the North Atlantic. Changes to the physical properties of seawater in the North Atlantic could eventually lead to the collapse of the Atlantic Meridional Overturning Circulation (AMOC), an event that would result in potentially catastrophic changes to climate in the Northern Hemisphere. Predictive climate models have noted that this shift could occur in the future, developing a series of warnings that could help understand more accurately when this major climate shift could occur. Writing in Science Advances, Van Westen and colleagues report the findings of the Community Earth System Model (CESM) and their predictions regarding the impacts of the AMOC’s collapse.

Figure 1: A visualization of the Atlantic Meridional Overturning Circulation (Adapted from “The Ocean Conveyor – Woods Hole Oceanographic Institution,” n.d.).

The AMOC is a “tipping element” of Earth’s climate, meaning that it is very sensitive to changes in salinity and temperature and could have substantial, reverberating climate impacts if disrupted (Armstrong et al., 2022). Since 1950, oceanographic and climate data have displayed that AMOC strength has significantly decreased and is potentially in its weakest state over the past thousand years (Caesar et al., 2021). These changes largely result from an increased freshwater flux into the North Atlantic due to high rates of Arctic sea ice melting as a product of anthropogenic climate warming. This methodical increase in freshwater flux into the North Atlantic could eventually lead to the collapse of this critical ocean circulation system, an event that would have severe impacts on temperature and weather patterns, especially in the Northern Hemisphere. Prior predictive climate models, which fail to encapsulate Earth climate systems as accurately as the model used by Van Westen and colleagues, have not yet modeled an AMOC collapse. Van Westen et al.’s 2024 study is the first to definitively model this crucial climate tipping point.

Van Westen and colleagues performed their study in CESM version 1.0.5, a complex climate model that simulates earth systems (Danabasoglu et al., 2020). The research team set a preindustrial control simulation with corresponding earth and ocean system conditions at model year 0. To model sea ice melt, they added a methodical, yet variable freshwater flux from the Arctic into the North Atlantic which was increased linearly through model year 2200. This gradual increase in freshwater flux into the North Atlantic corresponded to a gradual decrease in AMOC strength, consistent with predictions made by the research team. AMOC strength began diminishing in model year 800 and abruptly collapsed in model year 1758. This collapse represented a five-fold decrease in AMOC strength over the course of a century from model years 1750 to 1850, a shockingly abrupt change given the slow, consistent freshwater flux into the North Atlantic. By model year 2000, northward heat transport by the AMOC in the Atlantic decreased to nearly zero.

Figure 2: AMOC strength at 1000m depth and 26° N latitude. Yellow band shows the range of previously observed AMOC strength (Adapted from Van Westen et al., 2024).

Researchers found influential and dynamic changes to physical properties in oceans across the globe with AMOC collapse. Sea surface temperatures (SST) in the Northern Hemisphere after AMOC collapse significantly cooled, with differences as large as 10℃ observed off the coast of western Europe. SSTs increased slightly in the Southern Hemisphere due to the near absence of northward heat transport by the AMOC. Dramatic shifts in salinity in the upper 100 meters of the ocean were observed in addition to the complete interruption of deep ocean convection in the North Atlantic. Sea-level also rose nearly 70 cm in some regions of the coastal Atlantic due to AMOC collapse.

Researchers also investigated potential effects of AMOC collapse on climate and sea-ice extent in both the Northern and Southern Hemispheres. Significant changes to Hadley Cell air circulation and the subtropical jet stream were observed. Sea ice coverage in the Arctic extended to 50°N in the Arctic (current sea ice rarely forms below 60°N), while Antarctic sea-ice retreated. Model outputs showed atmospheric temperature decreases by around 3℃ per decade in the Northern Hemisphere, a rate at which human adaptation efforts would be largely impossible (current rates of temperature increase due to anthropogenic climate warming are ~0.2℃). These temperature shifts were amplified by ice-albedo feedback, where increased ice coverage in the Northern Hemisphere after AMOC collapse reflects a larger amount of solar radiation back into space, reducing atmospheric temperatures further. Additionally, precipitation patterns in tropical regions shifted with a slight increase in atmospheric temperature in the Southern Hemisphere after AMOC tipping. These results explicitly demonstrate that AMOC tipping would have dramatic, cascading climate impacts across the globe.

Van Westen and colleagues’ study was also the first of its kind to develop a comprehensive warning system for AMOC collapse based on historical climate and oceanographic data and model predictions. Observation of freshwater transport at 34°S, an important proxy for AMOC strength, and the identification of a minimum value for freshwater transport at which AMOC collapse could occur are essential characteristics of AMOC tipping that Van Westen and colleagues identified. These markers of AMOC strength provide an observable set of characteristics that could help predict AMOC collapse in real life.

This research is especially unique because it provides a definitive, model-based answer to the question of whether AMOC collapse can occur in climate models. Prior researchers assumed that AMOC tipping was highly theoretical and would not be predicted in a model that accurately accounts for complicated elements of climate systems. Van Westen and colleagues’ findings clearly demonstrate that AMOC tipping is not only possible, but highly likely under sufficient freshwater influx due to melting Arctic ice.

While the simulation performed by Van Westen et al. (2024) represents an effective predictor of major changes in Atlantic circulation, more data is needed to optimize predictive climate models and apply findings to real climate systems. Van Westen’s research team was unable to provide a meaningful estimate of when an actual AMOC tipping event could occur due to uncertainties in the rate and effects of future climate change. In a paper examining crucial climate tipping points, another European research team estimated that AMOC collapse could occur anywhere from 15-300 years from now, with researchers agreeing that collapse may most likely occur 50 years from now (Armstrong et al., 2022). Another study by researchers from the University of Copenhagen predicted with 95% confidence that tipping may occur from 2025-2095 (Ditlevsen & Ditlevsen, 2023). Precise monitoring of the physical changes in the North Atlantic and stringent data collection are essential to develop more accurate predictions of when AMOC collapse could occur in real life.

This research by Van Westen and colleagues shows evidence that the AMOC could reach a tipping point due to freshwater transport, temperature changes, and salinity changes in the Atlantic, leading to catastrophic climate impacts across the globe, especially in the Northern Hemisphere. Predictive models of major climate events are instrumental in helping communicate the severity of anthropogenic climate change and should be utilized by scientists, policymakers, and advocates throughout the transition away from our reliance on high emission fossil fuel combustion.

References:

Armstrong McKay, D. I., Staal, A., Abrams, J. F., Winkelmann, R., Sakschewski, B., Loriani, S., Fetzer, I., Cornell, S. E., Rockström, J., & Lenton, T. M. (2022). Exceeding 1.5°C global warming could trigger multiple climate tipping points. Science, 377(6611), eabn7950. https://doi.org/10.1126/science.abn7950

Caesar, L., McCarthy, G. D., Thornalley, D. J. R., Cahill, N., & Rahmstorf, S. (2021). Current Atlantic Meridional Overturning Circulation weakest in last millennium. Nature Geoscience, 14(3), 118–120. https://doi.org/10.1038/s41561-021-00699-z

Danabasoglu, G., Lamarque, J.-F., Bacmeister, J., Bailey, D. A., DuVivier, A. K., Edwards, J., Emmons, L. K., Fasullo, J., Garcia, R., Gettelman, A., Hannay, C., Holland, M. M., Large, G., Lauritzen, P. H., Lawrence, D. M., Lenaerts, J. T. M., Lindsay, K., Lipscomb, W. H., Mills, M. J., … Strand, W. G. (2020). The Community Earth System Model Version 2 (CESM2). Journal of Advances in Modeling Earth Systems, 12(2), e2019MS001916. https://doi.org/10.1029/2019MS001916

Ditlevsen, P., & Ditlevsen, S. (2023). Warning of a forthcoming collapse of the Atlantic meridional overturning circulation. Nature Communications, 14(1), 4254. https://doi.org/10.1038/s41467-023-39810-w

The Ocean Conveyor—Woods Hole Oceanographic Institution. (n.d.). https://www.whoi.edu/. Retrieved April 21, 2024, from https://www.whoi.edu/knowyourocean/oceantopics/how-the-ocean-works/ocean-circulation/the-ocean-conveyor/

Van Westen, R. M., Kliphuis, M., & Dijkstra, H. A. (2024). Physics-based early warning signal shows that AMOC is on tipping course. Science Advances, 10(6), eadk1189. https://doi.org/10.1126/sciadv.adk1189

The Solution to Alzheimer’s May Lie in Depression

April 21, 2024 by Nicholas Enbar-Salo '27

Despite being discovered by Alois Alzheimer almost 120 years ago, Alzheimer’s Disease (AD) still remains incurable (Hippius & Neundörfer, 2003). AD causes the brain to break down over time, which is also known as neurodegeneration. AD begins by deterioration of the hippocampus, which is the part of the brain responsible for memory and emotion. It then slowly spreads to other parts of the brain, eventually breaking apart the brain stem, which is responsible for involuntary movements such as breathing and swallowing (Lee et al., 2015). Given that around 39 million people have Alzheimer’s worldwide and that this disease has a 100% fatality rate, scientists across the world have tried to find a cure to this ravaging disease (World Health Organization, 2023). While there is yet to be a cure, recent developments by Stephanie Langella could help with mitigating one of the earliest signs of Alzheimer’s: depressive symptoms.

In this study, Langella and her team studied Presenilin-1 (PSEN1) gene mutations, a major cause of early-onset Alzheimer’s Disease. The PSEN1 gene provides instructions for making the presenilin-1 protein. This protein is an essential part of a protein complex known as gamma-secretase. This complex cleaves toxic proteins such as the amyloid precursor protein (APP) to create nontoxic proteins. When the PSEN1 gene mutates, gamma-secretase struggles to form and break down these toxic proteins, causing APP molecules to join together to create amyloid-beta (also known as amyloid-ꞵ or A-ꞵ), the protein responsible for the neurodegeneration seen in Alzheimer’s Disease (Bagaria et al., 2022).

A figure of gamma-secretase, APP processing, and generation of Amyloid-β (Aβ). Cleavages of C99 by gamma secretase (ε/ζ/γ) release sAPPβ, a type of APP which is beneficial to cells. When the PSEN1 gene mutates, gamma secretase (γ) produces AICD, a harmful type of APP, into a cell’s liquid (cytosol) and amyloid-β 37-43 into cell organelles. Aβ42 is the form of amyloid-β responsible for neurodegeneration in AD patients. (Steiner et al., 2018).

In particular, they studied its relationship to the neurodegeneration of the hippocampus and depressive symptoms (Langella et al., 2023). They began by creating two groups: the first group consisted of carriers of the PSEN1 mutation but that had not yet been diagnosed with AD, and the second group consisted of the family members of the respective PSEN1 carriers that did not have the mutation and were not diagnosed with Alzheimer’s. Then, two structural MRIs – a method of neuroimaging which models the brain structures of a patient– with a one-year gap in between the two images were taken of the participants’ hippocampuses to measure the change in the volume of the hippocampus over a year. Participants also took the Geriatric Depression Scale, a 15-item survey that measures depressive symptoms, such as the subjects’ feelings of hopelessness and rating their interest in hobbies, to measure depressive symptoms over one year.

Once the study was concluded, Langella found that there was no significant difference in the severity of the depressive symptoms between those carrying the PSEN1 mutation and those that did not. However, within the group carrying the PSEN1 mutation, those with smaller hippocampal volumes experienced more depressive symptoms. This association remained even after accounting for the age differences in the participants. This same association was not present in the non-PSEN1 carriers (Langella et al., 2023). Since the volume of the hippocampus did not have any relationship with depressive symptoms with non-PSEN1 carriers, there is likely some relationship between Alzheimer’s and depressive symptoms caused by hippocampal neurodegeneration.

A). Structural MRI of the hippocampus from the back of the head (shown in yellow)

C). Top-down structural MRI of the hippocampus (shown in yellow) (Sato et al., 2021)

There are several important implications of this research. To start, if there is indeed a relationship between the severity of depressive symptoms and the size of the hippocampus in someone with AD, there is a chance that trying to mitigate these depressive symptoms through therapy and antidepressant medication could slow down the deterioration of the hippocampus. By keeping the hippocampus intact for a longer time, people with AD could have better emotional control and memory later in life, which would greatly improve their quality-of-life (Langella et al., 2023). Also, since AD first deteriorates the hippocampus, it is possible that the onset of depressive symptoms in people with the PSEN1 mutation could be used as an indicator to doctors on the severity of the neurodegeneration. For instance, if someone with the PSEN1 gene mutation suddenly begins displaying depressive symptoms, it is possible that AD has just recently started decaying the hippocampus. Doctors can then try to intervene and slow the decay of the hippocampus through administering antidepressants and therapy, but also through encouraging lifestyle changes such as increased exercise. This way, those with Alzheimer’s can live a longer time before their hippocampus fully degrades, letting them keep their memories for a longer time.

Since this is one of the first studies relating depression and hippocampal decay in people with PSEN1 mutations, there is no theorized mechanism behind why this relationship exists in people with the PSEN1 mutation but not in those without. However, Langella et al. did find a particularly strong association between hippocampal decay in those with the PSEN1 mutation and displaying apathy, one of the measured depressive symptoms in the study (2023). More research should be done on the potential role of certain depressive symptoms on hippocampal decay, along with more research on the neural underpinnings relating the PSEN1 mutation, depression symptoms, and hippocampal decay. There is some evidence linking the formation of amyloid-ꞵ to depression in late-life major depression, but further research into the mechanism underlying this relationship is required (Pomara et al., 2022).

However, there is a pressing issue with this study; it had a fairly small sample size, with the PSEN1 carrier group having 27 participants and the non-PSEN1 group having 26. Since AD is a disease that affects everyone slightly differently, having such a small sample size makes the results unreliable and hard to generalize to everyone with AD. Regardless of the issues in the study, developments such as the ones created by this study serve to improve the quality of life and life expectancy of people with AD, which promises to improve the lives of almost 39 million people and their families. With every passing discovery into Alzheimer’s, scientists are also getting more information on the mechanisms behind the disease, which could eventually lead humanity to curing the disease altogether.

Citations

Bagaria, J., Bagyinszky, E., & An, S. S. A. (2022). Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene. International journal of molecular sciences, 23(18), 10970. https://doi.org/10.3390/ijms231810970

Hippius, H., & Neundörfer, G. (2003). The discovery of Alzheimer’s disease. Dialogues in clinical neuroscience, 5(1), 101–108. https://doi.org/10.31887/DCNS.2003.5.1/hhippius

Langella S, Lopera F, Baena A, et al. Depressive symptoms and hippocampal volume in autosomal dominant Alzheimer’s disease. Alzheimer’s Dement. 14 Oct. 2023, 986–994. https://doi.org/10.1002/alz.13501

Lee, J. H., Ryan, J., Andreescu, C., Aizenstein, H., & Lim, H. K. (2015). Brainstem morphological changes in Alzheimer’s disease. Neuroreport, 26(7), 411–415. https://doi.org/10.1097/WNR.0000000000000362

Pomara, N., Bruno, D., Plaska, C.R. et al. Plasma Amyloid-β dynamics in late-life major depression: a longitudinal study. Transl Psychiatry 12, 301 (2022). https://doi.org/10.1038/s41398-022-02077-8

Sato, Jinya, et al. “Lower Hippocampal Volume in Patients with Schizophrenia and Bipolar Disorder: A Quantitative MRI Study.” Journal of Personalized Medicine, vol. 11, no. 2, 13 Feb. 2021, p. 121, https://doi.org/10.3390/jpm11020121.

Steiner, H., Fukumori, A., Tagami, S., & Okochi, M. (2018, October 28). Making the final cut: Pathogenic amyloid-β peptide generation by γ-secretase. The Journal of Cellular Pathology. https://www.cell-stress.com/researcharticles/making-the-final-cut-pathogenic-amyloid-%ce%b2-peptide-generation-by-%ce%b3-secretase

World Health Organization. “Dementia.” Dementia, 2023, www.who.int/news-room/fact-sheets/detail/dementia.

S. glomerata show resistance to the negative effects of ocean acidification on marine microbes

April 21, 2024 by Layla Silva '27

As more CO2 enters the ocean, the water’s pH and temperature change in processes called ocean warming and acidification. Both processes pose a risk to marine microbes, as they are unaccustomed to their new, more acidic environment. Several marine species depend on the microbes that dwell in the ocean, and if the change in pH negatively impacts the oceanic microbiome, there would be negative implications for a large number of organisms.

Microbes are essential to the development of many species in the world’s oceans. They are able to activate genes, sculpt the bodies of multicellular organisms, and provide vital life information to juvenile species (Yong 2016). But these abilities may be disrupted if the ocean’s change in pH negatively affects the microbiomes both in the water and living within ocean creatures.

Dr. Elliot Scanes and his colleagues at the University of Technology Sydney evaluated the effects of ocean acidification on the Sydney rock oysters’ (S. glomerata) ability to transfer its microbiome down to its offspring during reproduction. Oysters reproduce via broadcast spawning, a process in which sedentary organisms release all of their eggs and sperm into the surrounding water in hopes that a portion of the gonads will be fertilized (Bondar, 2018). Because these broadcasted embryos are now exposing their microbiomes to warmer, more acidic environments than the microbiomes of previous generations have been accustomed to, the microbes living within these embryos are not well adapted to the new conditions. This poorly equipped microbiome is causing fewer and fewer embryos to develop properly. An oyster’s microbiome is a necessary part of its body, and without it, a juvenile oyster may not be able to develop and function as effectively (Scanes et al. 2023).

Scanes set out to examine whether exposure to ocean warming and acidification during both broadcast spawning and early reproduction would alter an oyster’s microbiome strength.

The lab team acclimated these oysters to the lab tanks and then harvested their eggs and sperm, later fertilizing them (Figure 1.) (Scanes et al. 2023). Half of the oyster embryos were raised in tanks with a normal pH, and the other half were raised in tanks with decreased pH to mimic ocean acidification. The team conditioned both sets of S. glomerata for reproduction, then used eggs and sperm from each set to breed the next generation of oysters. The next generation was divided into four groups: first, the oyster embryos collected in tanks with a normal pH were split into two groups, with one group being raised in another tank with a normal pH and the other being raised in a tank with a low pH that mimics ocean acidification. Then, the oyster embryos collected in tanks with a low pH were also split into two groups, with one group being raised in another tank with a low pH

Figure 1. Scanes et al. depicts their experimental design. The PCO2 that appears in several of the diagram labels means partial pressure of carbon dioxide, which is a term used to describe how much carbon dioxide exists within a system (Messina 2022). Ambient PCO2 means normal pH. Elevated PCO2 means acidic water.

and the other being raised in a tank with a normal pH.

The embryos produced from these four sets of oysters informed Scanes et al. of the physiological differences that occur between oyster microbiomes that are exposed to ocean acidification at different steps in the reproductive process. The team found significant alteration of the microbiome in the parent oysters exposed to ocean acidification and concluded that when oyster parents were exposed, more oyster embryo microbiomes were prepared for the new conditions, and so the more protected oyster embryos survived (Scanes et al. 2023). This information is of much consequence because it provides a baseline for studying other microbe–sea creature relationships in the future. The marine microbiome plays a critical role in the development and wellbeing of animals like the Hawaiian bobtail squid and the Hydroides elegans, otherwise known as the “squiggly worm,” who depend on them for gene activation and information on safe places to live, respectively (Yong 2016). Now that there is evidence that the changing conditions of ocean water harms microbes, and therefore harms the creatures that depend on them, as well as evidence that exposure to these conditions protects the microbes in future generations, scientists are better informed about how to protect marine species moving forward.

Literature Cited

Bondar C. Wild Moms. 2018.

Messina Z et al. Partial Pressure of Carbon Dioxide. National Library of Medicine. 2022.

Scanes E et al. Transgenerational transfer of the microbiome is altered by ocean acidification in oyster larvae. Aquaculture. 2023.

Yong E. Body Builders. I Contain Multitudes: The Microbes Within Us and a Grander View of Life. 2016. 49-59.

SMART Conservation Software aids wildlife management teams in conservation efforts

April 21, 2024 by Layla Silva '27

Those who work in the field of wildlife management aim to protect the biodiversity of ecosystems, which is critical in maintaining the health of the environment. But wildlife management workers around the world frequently experience serious challenges such as poaching, logging, illegal farming, forest fires, and insufficient resources. For example, poachers use snare loops (wire traps that tighten around the necks of animals) to catch protected species. In 2014, tiger poachers in the Sundarbans Reserved Forest of Bangladesh placed thousands of these snare loops across the entire reserve, in locations too far from guard posts to be monitored full time (Abdul Aziz et al., 2017). In most conservation groups, there are not enough funds, employees, or volunteers to efficiently manage wildlife and simultaneously prevent poachers from killing protected animals. Thus, wildlife management teams are calling for improved tools that will better protect endangered animals from further harm.

Figure 1. Snare loop around a lion’s neck. Loops can tighten around any part of the body, holding the animal in place until poachers arrive or weakening it until it dies of its injuries.

Companies such as SMART, Re:Wild, and the World Wildlife Fund developed SMART Conservation Software in 2011 to better support wildlife conservation groups. SMART is short for Spatial Monitoring and Reporting Tool, and it is a digital platform capable of collecting and evaluating data on wildlife management sites. Workers within the same management system can input data as they come across new information, allowing the platform to record what they find in real time like where animals are mating, as well as where and when poacher traps are found (https://smartconservationtools.org/). Using these inputs, SMART plots a management team’s efforts, impacts, and shortcomings over time, highlighting areas that need improvement. Once those improvements are made, management groups are better able to conserve biodiversity, enforce the law, encourage and oversee tourism, and use natural resources properly.

Figure 2. Wildlife management employees use SMART device to log important conservation information.

SMART is used by conservation organizations around the world, one example being the Chirripó National Park in the Talamanca Mountain Range of Costa Rica. For years, the Chirripó management team had been struggling to precisely locate and record the illegal activities taking place on protected land, making it impossible to remove offenders or convince authorities that their ongoing complaints were valid (Madrigal). But SMART software can be downloaded on personal devices, so when the park introduced SMART to their employees and surrounding members of the community, citizens who were not involved in full-time park conservation were still able to contribute (Madrigal). This added many more eyes, ears, and hands to the conservation effort, and within one year, Chirripó was able to report the exact dates and locations of 44 cases of illegal activity across the park to law enforcement (Madrigal). Once law enforcement gained access to this concrete information, they were able to operate efficiently, driving down the crime rate. More importantly to Chirripó National Park, the added coverage helped protected species such as the Baird’s tapir, the spider monkey, the puma, the agouti, and the jaguar (Madrigal). Chirripó’s experience with SMART demonstrates how useful this technology is for organizing and communicating the issues conservationists face on a daily basis.

Figure 3. SMART conservation software helps Chirripó National Park to protect animals like the Baird’s tapir pictured above.

Like most technology, SMART software is exciting, innovative, and solves modern day problems – but it also comes with some challenges. The Zimbabwe Parks and Wildlife Management Authority (ZPWMA), an organization that works to protect lions, elephants, leopards, and buffalo across all of Zimbabwe, points out that implementing SMART conservation technology can present capacity and resource issues for conservation management employees (Kavhu et al, 2021). Many workers were unfamiliar and uncomfortable with the technology, there were not enough electronic devices such as computers to collect all field data, and many of the patrol routes were without internet access (Kavhu et al, 2021). While it is possible that technological innovation is not a priority for Zimbabwe, it is also important to remember that Zimbabwe’s history is one marred by British colonialism, and the country only gained its independence in the late 1970’s (Ingham et al., 2023). These setbacks help to explain why Zimbabwe has been unable to progress as in the world of electronic technology, even if the progress is desired. These issues of technological access can be applied to other countries that do not yet have a strong electronic infrastructure, meaning that SMART works best in more electronically informed countries and falls short in countries that have not expanded their electronic bandwidth.

Figure 4. Parks in Zimbabwe aim to protect their buffalo populations.

There are some solutions to these technological problems. For example, building a strong implementation plan, motivating the discouraged workers, following the example of other institutions that have implemented SMART technology, and, most importantly, raising funds to buy more computers would make the use of SMART technology easier in Zimbabwe parks (Kavhu et al, 2021). Adding more volunteers to the conservation effort is also a great solution. If ZPWMA advertised volunteer opportunities in their communities using layperson terms, supporters of the conservation effort would be more likely to help manage the wildlife in Zimbabwe’s parks. Of course, volunteers would need to be trained so that they are able to properly identify notable occurrences in the parks, but their contributions have the potential to greatly strengthen the conservation effort.

SMART Conservation Software is off to a great start in helping to better manage parks around the world. Though SMART does find its faults in countries unaccustomed to the devices needed for software implementation, this problem will only grow smaller as the world continues to progress in the realm of personal electronic devices (given that countries like Zimbabwe want to prioritize electronic familiarity moving forward). Its ability to collect, organize, and present data across long distances and multiple devices allows wildlife management teams to care for protected species much more efficiently, making SMART a tool that revolutionizes the realm of conservation.

Works Cited

Abdul Aziz, M. et al. Investigating patterns of tiger and prey poaching in the Bangladesh Sundarbans: Implications for improved management. ScienceDirect, vol. 9, 2017, pp. 70-81.

Barrantes Madrigal, Jimmy. “Community-based SMART patrolling in one of the Great Five Forests of Mesoamerica: the Talamanca Highlands.” SMART, https://smartconservationtools.org/en-us/SMART-Community/Your-stories/Case-Study?CaseStudyID=27.

Ingham, Kenneth, et al. “History of Zimbabwe”. Encyclopedia Britannica, 12 Dec. 2023, https://www.britannica.com/topic/history-of-Zimbabwe.

Jones, J.J.. “Snared Lioness in Kruger National Park.” Wildestofficial.com, 20 September 2019, https://wildestofficial.com/news/snare-poaching-increasing-in-kruger-national-park/.

Kavhu, Blessing, et al. Spatial Monitoring and Reporting Tool (SMART) in Mid‐Zambezi Valley, Zimbabwe: Implementation challenges and practices. ProQuest, vol. 3, 2021.

San Diego Zoo. Baby Baird’s Tapir. animals.SandiegoZoo.com, https://animals.sandiegozoo.org/animals/tapir.

Slade, James. Conservationists operating SMART device. Smartconservationtools.com, https://smartconservationtools.org/en-us/SMART-in-Practice/How-we-use-SMART.

SMART. “About Us.” SMART, https://smartconservationtools.org/en-us/About/About-us. The Great Projects. Buffalo in Zimbabwe. thegreatprojects.com, https://www.thegreatprojects.com/volunteer-in-zimbabwe.

It’s in the Cards: A Dive into Tarot Card Psychology, Interpretation and Therapeutic Applications

April 21, 2024 by Gabe O'Brien '26

With a long history dating back nearly 700 years, Tarot cards have maintained a presence in society as a tool that is considered to predict the future and understand one’s inner issues, desires, and motivations. There are many conflicting theories regarding the origin of Tarot cards, with the predominant notion pointing to 14th century northern Italy (Tarot Heritage). Researchers claim that the major arcana of Tarot is based on the Egyptian hieroglyphic book of Thoth (the Egyptian god of wisdom), which is also known as the book of Tarot (Willis 1988). But why do people still use Tarot cards, and what do we get out of using them? The phenomenon surrounding the use and interpretation of Tarot cards can be broken down into two juxtaposing explanations: paranormal and nonparanormal. The paranormal explanation claims that Tarot cards reveal hidden motives, portray opportunities, and offer a reflection of a person’s inner processes, allowing the cards to provide clarity regarding a person’s questions or conflicts. Meanwhile, the nonparanormal explanation claims that the entire phenomenon of Tarot cards can be explained by examining two simple psychological effects: The Barnum effect and “cold reading” (Ivtzan 2007). Additionally, several modern therapeutic approaches have employed the use of Tarot cards as a tool for self-reflection, with Tarot card readings offering clients a sense of order and control in their own lives (Hofer 2009). There are several different reasons for why people use Tarot cards, and the associated applications of the cards can help to improve a person’s mental health when the cards are utilized in a therapeutic context (Hofer 2009).

Many standard Tarot decks follow the same 78-card structure, which is divided into the minor arcana (56 cards), and the major arcana (22 cards). The cards in the major arcana represent the main themes of human life, such as love, death, spirituality, acceptance, etc. The cards in the minor arcana represent subtle mysteries of life, and are considered to be lesser compared to the major arcana (Ivtzan 2007). Additionally, there are several different techniques for choosing the cards in a reading, with the most popular option being for the reader to ask the client to shuffle the cards while focusing on a question, spread the deck, and choose the cards that they feel the most drawn to (Ivtzan 2007). The use of Tarot cards has continued to flourish, even in western societies, and the popularity of Tarot cards is not an indication of reliability or validity, but rather a look into how using the cards can influence our thought processes and mental state.

Figure 1: The major arcana of Tarot (Medium).

The paranormal explanation surrounding the phenomenon of Tarot cards is the approach that is acclaimed by occultists who believe that the cards reveal information about the quality of a moment for an individual (Ivtzan 2007). They do not believe that the cards predict the future as if it is fixed, but rather reveal information and potential circumstances about changeable events. By creating more awareness about the meaning of a specific moment for a client, this can help to provide the client with important insights, as well as a drive to take control of their own life and make changes that will be beneficial to them in the long run. Comparatively, the nonparanormal explanation examines the use of Tarot cards through the lens of psychological effects, with the Barnum effect being the most emphasized. The Barnum effect is the tendency to believe that vague predictions or general personality descriptions, such as those offered by Tarot or astrology, have specific applications to one’s unique circumstances (American Psychological Association). A Tarot reader may make general, trivial statements that could apply to anyone, and a client, eager to seek guiding information about their life, will accept these statements as truth. The major arcana of Tarot deals with themes that concern every individual’s life, so it is not difficult to come up with general statements about these themes that any person could be susceptible to (Ivtzan 2007). The other psychological effect that the nonparanormal explanation examines is “cold reading,” which is a set of deceptive psychological techniques that give a client the impression that a reader has paranormal abilities. The Barnum effect falls under the umbrella of “cold reading,” and the techniques behind “cold reading” involve the use of sharp observational skills and a good memory when examining a client. Cues such as a client’s clothing, physical characteristics, and manner of speech can reveal a lot of valuable information to a reader, that a reader can then use to inform the statements that they make to a client regarding the topic of their reading (Ivtzan 2007).

Although there are underlying psychological influences behind the use of Tarot cards, Tarot card readings can still have beneficial effects on a person’s mental health when used in a therapeutic context. A 2009 study investigated how regular users of Tarot cards employed the cards as a tool for self-reflection (rather than for divination). The study involved conducting interviews with several co-researchers who used Tarot cards regularly and in a self-reflective manner, and the interviews from the study were transcribed, with the common themes and qualities that existed between the interviews being extracted (Hofer 2009). Overall, the results of the study found that the co-researchers used Tarot cards as a way to gain insight into their current life situations. The cards were found to be used the most often during difficult times where they could offer a source of comfort. This source of comfort involved providing confirmation that everything was okay and that life had a sense of order.

On top of this, Tarot cards were also used as a tool for positive reinforcement, where cards were drawn both intentionally and randomly to provide insights about what the co-researchers were seeking in their own lives. With a goal in mind, some of the co-researchers drew a card and then kept it with them until what they were working on or towards had been resolved. They claim that Tarot does not reveal new information to them, but that the use of Tarot cards can help to provide a new perspective on an issue that can influence a plan for a possible course of action (Hofer 2009).

By examining how therapeutic techniques involving Tarot have been successful for co-researchers who have consistently employed these techniques in their own lives, this study outlines how Tarot has the potential to be used as an effective therapeutic tool. Despite the foundational psychological effects behind the mainstream use of Tarot, Tarot cards can still have beneficial impacts on a person’s mental health and inner psychological processes. Further research surrounding the beneficial impacts of Tarot in a therapeutic setting would involve examining a greater number of participants from a wider variety of backgrounds, so that this research could be generalized to a larger audience. Regardless of the reasoning behind why a person may use Tarot cards, there is no doubt that Tarot cards have maintained a strong presence in society, and these cards have the potential to do more than just “predict the future.”

Literature Cited

APA Dictionary of Psychology. “APA Dictionary of Psychology.” Apa.org, 2014, dictionary.apa.org/barnum-effect.
“History.” Tarot Heritage, 24 July 2011, tarot-heritage.com/history-4/. Accessed 13 Apr. 2024.
Hofer, Gigi Michelle. “Tarot cards: an investigation of their benefit as a tool for self reflection.” University of Victoria PhD diss (2009).
Ivtzan, Itai. “Tarot cards: a literature review and evaluation of psychic versus psychological explanations.” Journal of Parapsychology 71 (2007).
Macsparrow, Mark. “Many Major Arcana Cards in a Reading Means Many Changes Ahead.” Medium, 12 May 2021, tarotreadings.medium.com/many-major-arcana-cards-in-a-reading-means-many-changes-ahead-516becf2faf5. Accessed 13 Apr. 2024.
Willis, T. Magick and the tarot. Wellingborough, UK: Aquarian (1988).

New Cancer Vaccine Harnesses the Human Immune System

April 21, 2024 by Olivia Miller '27

Right now, cancer is the second most common cause of death in the world, and it’s set to become the leading cause within the next several decades (Drexler) (Figure 1). Unlike many other diseases that have plagued humans throughout our history, even revolutionary advancements in medicine have not been able to fully prevent or cure it. To understand why, it’s important to recognize that cancer comes not from the outside, but from within ourselves, when our own cells begin to divide uncontrollably and spread throughout our bodies. Because cancer arises in our bodies, we can’t treat it using antibiotics or vaccines that target a particular pathogen. However, a 2023 study has proposed a new vaccine treatment that fights pancreatic cancer (which has a five-year survival rate of only 12%) using our own immune system.

Figure 1. Cancer deaths are expected to surpass deaths due to heart disease in the United States. Source: CDC

To understand this discovery, it’s important to learn a little about how the immune system works. One important component of our body’s defense system are our T cells, which fight invaders by identifying and killing body cells infected with pathogens such as viruses. A T cell only knows what to attack after it’s activated by a foreign particle called an antigen. Antigens are often tiny pieces of invading viruses or bacteria, like “keys” which unlock a T cell immune response. Now, what does all this have to do with cancer? The idea behind this proposed treatment is to use neoantigens (a type of antigen) to help the body recognize cancer cells. Neoantigens are mutant proteins which only form on tumor cells, so helping T cells recognize them could help the body learn to attack cancerous cells.

This study’s major discovery was a new way to prompt the immune system to recognize neoantigens. The researchers took genetic material (such as DNA and RNA) from the surgically removed tumors of sixteen people with pancreatic cancer. Then they gave each patient a kind of treatment called an immune-checkpoint inhibitor (ICI). Immune checkpoints are proteins on the surfaces of healthy cells which usually tell our T cells not to attack them. The problem is that sometimes, immune checkpoints on cancerous cells prevent T cells from attacking them too. ICIs can treat some kinds of cancers by blocking these interactions between T cells and cancerous cells, allowing T cells to kill them, but they often do not work well on pancreatic cancer. To solve this problem, the researchers used the genetic information collected from the tumors to create a personalized vaccine containing mRNA (a type of RNA) that codes for the exact neoantigen formed on an individual’s cancer cells. After receiving this vaccine, a person’s cells would be able to use the mRNA to produce this neoantigen in abundance. Then, their T cells could theoretically recognize it, become activated, and know to go after the cancer cells with the neoantigen on their surfaces (Figure 2). To maximize the chances of triggering this T cell response, the vaccines included mRNA coding for as many as twenty neoantigens.

Now for the big question: did it work? Well, cancer unfortunately came back an average of 13.4 months after treatment for half of the study’s participants. The other eight, however, all had T cells which recognized the artificial neoantigens in their bodies after vaccine treatment and also remained cancer-free after ~18 months (Huff & Zaidi, 2023). This vaccine is clearly not perfect, and future research is still needed to understand why half the patients’ immune systems did not respond to the treatment. However, it is still an incredible breakthrough that could shift the direction of cancer treatment. A clinical trial, the second phase of this study, is already well underway and includes over 250 patients (Stallard, 2024). Given the small sample size of this first study, the new clinical trial will help clarify how effective this vaccine treatment really is. Immunotherapy is emerging as a leading factor in the fight against cancer, and this study gives reason to believe that new treatment possibilities could be on the horizon for cancer patients, even those with aggressive tumors.

References

Drexler, M. (n.d.). The Cancer Miracle Isn’t a Cure. It’s Prevention. Harvard Public Health. https://www.hsph.harvard.edu/magazine/magazine_article/the-cancer-miracle-isnt-a-cure-its-prevention/.

Heron, M. & Anderson, R.N. (2016). Changes in the leading cause of death: Recent patterns in heart disease and cancer mortality. CDC: NCHS data brief, 254. https://www.cdc.gov/nchs/products/databriefs/db254.htm.

Huff, A.L. & Zaidi, N. (2023, May 10). Vaccine boosts T cells that target pancreatic tumours. Nature. https://www.nature.com/articles/d41586-023-01526-8.

Rojas, L.A., Sethna, Z., Soares, K.C. et al. (2023). Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150. https://doi.org/10.1038/s41586-023-06063-y.

Stallard, J. (2024, April 7). Investigational mRNA Vaccine Induced Persistent Immune Response in Phase 1 Trial of Patients With Pancreatic Cancer. Memorial Sloan Kettering Cancer Center. https://www.mskcc.org/news/can-mrna-vaccines-fight-pancreatic-cancer-msk-clinical-researchers-are-trying-find-out.

Unveiling the True Potential of Telomeres in Cellular Health

April 21, 2024 by Jared Lynch

Telomeres have long been known as repetitive DNA elements protecting the ends of chromosomes, but recently, reports of their transcription and translation have revealed an emerging pathological role upon abnormal expression.

When studying the nuclear genome of eukaryotes, one of the most basic characteristics is the organization of DNA into chromosomes that condense and duplicate during mitosis and meiosis. Within each chromosome, a critical protective feature is a string of repeated sequences at each end known as telomeres. These repeat sequences exist as (TTAGGG)n in mammals, which serve to prevent chromosome fusing and shortening. In fact, the shortening of telomeres throughout one’s lifetime is linked closely to aging, reflecting one of the many important health implications of telomeres [1].

More recently, these implications have grown with the discovery that telomeres are both transcribed and translated into repeat sequences (Figure 1, top) [2]. Transcription creates what is known as telomeric repeat-containing RNA (TERRA), and while most of these molecules never leave the nucleus, some escape to the cytoplasm [3]. Initially, TERRA was believed to have no substantial effect on cell functioning due to the absence of AUG start codons. However, its unique 3D structure is able to bypass this roadblock and initiate AUG-independent translation [4]. The result is one of two repeated protein sequences, depending on which reading frame translation begins at: valine-arginine (VR) and glycine-leucine (GL) [4]. In appreciable quantities, these are expected to impact cell functioning, but in what way is largely unknown, particularly in humans.

Al-Turki and Griffith sought to fill this knowledge gap by assessing the properties of VR repeats and GL repeats in vitro and in human cells [5]. To start, the researchers hypothesized that VR would bind nucleic acids, which are negative charged, due to its positively-charged arginines. By contrast, GL was predicted to form large aggregates known as amyloids due to its hydrophobic properties. In both cases, these molecules could severely impact cell functioning, so determining the exact behavior of VR and GL was an essential start.

For their first experiment, Al-Turki and Griffith synthesized VR and GL, then added them to a salt buffer to mimic how they would self-interact in the cytoplasm. Visualization revealed that VR was unable to aggregate due to the repulsion of repeated arginines. However, GL demonstrated mild aggregation with the potential to form amyloids and induce inflammatory responses in extreme cases (Figure 1).

Next, the binding of VR to nucleic acids was tested by adding the peptide to a solution of RNA or DNA. In support of their hypothesis, the authors found that VR bound to both with a high affinity. They then took this a step further and added DNA plasmids containing a replication fork (i.e., the structure that forms during DNA replication) to test the interaction with VR. Intriguingly, VR bound with high preference to the replication fork itself which altered its geometry, possessing the ability to disrupt the replication process (Figure 1).

Finally, an antibody for VR was developed which allowed the authors to visualize its presence in human cells. VR levels were found to positively correlate with the abundance of TERRA, and in osteosarcoma (“U2OS”) cells specifically, these were both at unusually high levels. Moreover, VR was often found in the nucleus as discrete clumps or “foci,” contrary to the in vitro experiment, due to stabilization by the negatively-charged DNA. The authors then attempted to alter VR levels by either knocking down TERRA or promoting its transcription. Intriguingly, VR aggregates increased in size for both cases, which may result in a cytotoxic effect that has yet to be explored.

Telomeres were initially viewed as protective elements with no function beyond the DNA level. Yet, the discovery of TERRA and its translated peptide sequences have completely flipped this narrative. Al-Turki and Griffith expand on this by showing that VR and GL peptides generated by translation could have significant physiological effects on cells including altered DNA replication, inflammation, and cytotoxicity. In particular, VR can not only bind DNA but also aggregate in the nucleus. These aggregates increased in size when altering TERRA levels, indicating that dysfunctional telomeres capable of promoting TERRA could have negative consequences for cell functioning.

In spite of these discoveries, future work remains in order to understand the full picture of VR and GL. For one, GL was unable to be assessed in live cells as the authors were unable to create an antibody for it. Additionally, these peptides are likely to have other functions beyond aggregating and killing cells. Understanding these abilities is crucial for not only characterizing its pathological potential but also for developing treatments down the line. Nevertheless, the present study creates a strong foundation for exploring this underappreciated chromosomal feature.

References

1. Ren F et al. (2009). Estimation of human age according to telomere shortening in peripheral blood leukocytes of Tibetan. Am J Forensic Med Pathol, 30(3):252-5. https://doi.org/10.1097/PAF.0b013e318187df8e.

2. Azzalin CM et al. (2007). Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science, 318(5851):798-801. https://doi.org/10.1126/science.1147182.

3. Schoeftner S, Blasco MA (2008). Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol, 10(2):228-36. https://doi.org/10.1038/ncb1685.

4. Zu T et al. (2010). Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A, 108(1):260-5. https://doi.org/10.1073/pnas.1013343108.

5. Al-Turki TM, Griffith JD (2023). Mammalian telomeric RNA (TERRA) can be translated to produce valine-arginine and glycine-leucine dipeptide repeat proteins. Proc Natl Acad SciU S A, 120(9): e2221529120. https://doi.org/10.1073/pnas.2221529120.

The Melting Arctic’s Impact on the Gulf of Maine

December 6, 2023 by Zoe Peterson '25

Recent observation and nutrient analysis in the Gulf of Maine has found that within the past 50 years nutrient sources have become more limited, impacting the entire ecosystem. The Gulf of Maine receives nutrient-rich waters from the continental slope that enters through the Northeast Channel, north of Georges Bank (figure 1). These continental slope waters originate off southern Newfoundland and travel into the Gulf of Maine passing by Labrador and the Scotian Shelf, all the while accumulating and retaining its high concentration of nutrients. Nutrients from this water source, such as nitrate and silicate that exist in excess within continental slope water, make the Gulf of Maine a highly productive area. Nitrate is of particular interest as it is often the limiting nutrient. In other words, nitrate is often scarce in an ecosystem and therefore is the nutrient that puts a cap on the accumulation of biomass such as phytoplankton. However, recent observation and nutrient analysis in the Gulf of Maine has found that within the past 50 years nutrient sources have become more limited, impacting the entire ecosystem.

Since the 1970s, studies have shown a notable decrease in the abundance of nitrate in the Gulf of Maine. Along with this change, the deep waters in the Gulf of Maine have become cooler and less salty. In 2010, Townsend et al suggested that these changes all originate from the accelerating melting of ice in the Arctic. Since salt does not freeze, when water freezes in the Arctic, the ice it forms is made of freshwater. As this freshwater melts at a faster rate than the Earth has previously seen, it changes the salinity of the water, making it fresher and therefore less dense. Deep ocean circulation is based on density and so with this change in density, comes a change in the way water circulates the planet.

Given the changes in densities of water in the Arctic, a new source of water from the bottom of the Atlantic ocean carrying far less nutrients now supplies the Gulf of Maine. With the changes in deep ocean circulation patterns, now water entering the Gulf of Maine passes closer to the bottom of the ocean. As this water passes the ocean floor, microbes in the sediment remove nitrogen from the water (for use as a nutrient), a process called denitrification. While this benefits ecosystems at the bottom of the deep ocean, by the time the water reaches the Gulf of Maine, much of the nitrate in the water has already been used.

The Gulf of Maine will become less productive as ecosystems are supplied with low concentrations of nitrate for long periods of time. Phytoplankton, the first step of the food web, absorb these nutrients and use them for growth. Once phytoplankton are less abundant, animals that rely on them for food will begin to struggle. As nitrogen deficiency continues up the food chain, it will eventually reach the larger fish upon which we in Maine rely on for our food. The gradual loss of nitrogen rich waters to the Gulf of Maine is not only a sad reminder of climate change’s far reaching consequences, but also presents a growing issue for the fishing industry in Maine which relies on the productivity of the water.

Work Cited

Townsend, D. W., Pettigrew, N. R., Thomas, M. A., Neary, M. G., McGillicuddy, D. J., & O’Donnell, J. (2015). Water masses and nutrient sources to the Gulf of Maine. Journal of Marine Research, 73(3), 93–122. doi:10.1357/002224015815848811

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