Bowdoin Science Journal

Science

The Contraceptive Brain Drain: How Birth Control Alters Women’s Brains

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There are millions of women taking steroids every day. But how is this possible? Are they just getting really buff? It feels like we always hear stories about how performance-enhancing drugs, namely steroids, are giving world-class athletes the boost they need to beat out their competition. But women across the globe are taking steroids every day as well, in the form of hormonal birth control. Despite their widespread use, side effects of hormonal contraceptives are largely unstudied, or have been until recently. In the last ten years, several studies have come out about the effect of taking a daily dose of steroids on women’s brains and mental health, which until now has been a severely neglected area where lack of knowledge affects millions of people worldwide. 

People take hormonal birth control, or hormonal contraceptives, for a myriad of reasons, from the obvious (preventing pregnancy) to the not-so-obvious (lessening iron deficiency) and everything in between. This type of medication simply refers to methods of pregnancy prevention that act on the endocrine system. The endocrine system controls growth, development, metabolism, and reproduction via signaling molecules called hormones. Two hormones in particular, estrogen and progesterone, control the menstrual cycle and are therefore the major components of hormonal birth control. Types of hormonal contraceptives come in many forms including the pill, the patch, the implant, injections, and hormonal intrauterine devices or IUDs, but despite the wide variety in the forms this medication takes, all of them contain one or both of these two hormones. As steroids, both estrogen and progesterone affect other body systems besides the reproductive system.

To study the impacts of taking a daily dose of steroids on other areas of the body, specifically the brain, Dr. Belinda Pletzer and her colleagues conducted a study in 2010. The brain is particularly susceptible to change due to an influx of synthetic hormones because it contains a very high quantity of hormone receptors. The brain needs to act as a “sponge” for these molecules since it plays an important role in creating the appropriate responses in the rest of the body. Pletzer’s study investigated how the sponginess of the brain would affect changes in its structure by comparing images of the brains of adult men, adult women during different stages of their menstrual cycle, and adult women taking hormonal contraceptives. To perform this comparison they used a technique called voxel-based morphology on MRIs of study participants (Pletzer et al., 2010). Voxel-based morphology measures differences in the concentration of tissue and the size and shape of different areas of the brain.

Overall, they found that women taking hormonal birth control had smaller areas of gray matter, or areas of the brain that have a high concentration of the cell bodies of nerve cells, when compared to “naturally cycling women” in both their follicular and luteal menstrual phases (Figure 1). Pletzer’s study also found interesting gendered differences in gray matter volume. While men had greater gray matter overall, the volume of gray matter in the prefrontal cortex, the pre-and postcentral gyri, and the supramarginal gyrus of both naturally cycling women and women taking hormonal contraceptives was higher than the volume of gray matter in these areas in men (Figure 2). These areas are involved in decision-making and problem-solving, controlling motor function, and emotional responses. However, the higher amount of gray matter in women in these areas was overshadowed by the larger volume of gray matter in men in the hippocampus, hypothalamus, parahippocampal and fusiform gyri, putamen, pallidum, amygdala, and temporal regions of the brain during the early follicular phase (A), mid-luteal phase (B), and in women taking hormonal birth control (C) (Figure 2). Many of these areas of reduced gray matter are ones of high importance for neurophysical ability and mental health.

Additionally, a study done by Rush University Medical Center showed an association between higher levels of gray matter and better cognitive function (“Everyday Activities Associated with More Gray Matter in Brains of Older Adults”). These findings suggest that taking birth control, and the associated decrease in gray matter, could be directly causing some of the symptoms women on hormonal contraceptives experience, such as brain fog, mood changes, and even anxiety and depression. For example, a smaller hypothalamus, one of the areas of decreased gray matter, is associated with heightened irritability and depression symptoms (“Study Finds Key Brain Region Smaller in Birth Control Pill Users”). Pletzer’s research and the work of others after her on the impact of birth control on structures of the brain represent important first steps in proving a causative relationship between birth control, symptoms associated with it, and structural changes in the brain.

Although this research has made some crucial preliminary steps into researching how taking a daily dose of steroids affects the brains of women taking hormonal contraceptives, the highly complex nature of the brain and its relationship with the regulation of the rest of the body means that further research is necessary. The sheer number of people that this issue affects means that it is essential to continue researching the impacts of this widely used drug. More importantly, knowing the potentially serious negative side effects enables millions of people to make more informed decisions concerning their health and their bodies.

 

Works Cited

Rush University Medical Center. (2018, February 14). Everyday activities associated with more gray matter in brains of older adults: Study measured amount of lifestyle physical activity such as house work, dog walking and gardening. ScienceDaily. Retrieved March 11, 2023 from www.sciencedaily.com/releases/2018/02/180214093828.htm.

Lewis, C. A., Kimmig, A. C. S., Zsido, R. G., Jank, A., Derntl, B., & Sacher, J. (2019). Effects of hormonal contraceptives on mood: a focus on emotion recognition and reactivity, reward processing, and stress response. Current psychiatry reports, vol. 21, no.11, 2019, p 115. PubMed Central, https://doi.org/10.1007/s11920-019-1095-z.

Meyer, Craig H., Kinsley, Elizabeth A. “Women’s Brains on Steroids.” Scientific American, https://www.scientificamerican.com/article/womens-brains-on-steroids/. Accessed 7 Mar. 2023.

Nemoto, Kiyotaka. “[Understanding Voxel-Based Morphometry].” Brain and Nerve = Shinkei Kenkyu No Shinpo, vol. 69, no. 5, May 2017, pp. 505–11. PubMed, https://doi.org/10.11477/mf.1416200776.

Pletzer, Belinda, et al. “Menstrual Cycle and Hormonal Contraceptive Use Modulate Human Brain Structure.” Brain Research, vol. 1348, Aug. 2010, pp. 55–62. ScienceDirect, https://doi.org/10.1016/j.brainres.2010.06.019.

Sharma, Rupali, et al. “Use of the Birth Control Pill Affects Stress Reactivity and Brain Structure and Function.” Hormones and Behavior, vol. 124, Aug. 2020, p. 104783. ScienceDirect, https://doi.org/10.1016/j.yhbeh.2020.104783.

“Study Finds Key Brain Region Smaller in Birth Control Pill Users.” ScienceDaily, https://www.sciencedaily.com/releases/2019/12/191204090819.htm. Accessed 7 Mar. 2023.

What Causes Aging? An Epigenetics Study From The Sinclair Lab May Have an Answer

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Dr. David Sinclair, A.O., Ph.D. Photo from the Sinclair Lab, Harvard Medical School (2023).

Aging, also known as “senescence,” is an inevitable process in all living things. Organisms small and large eventually break down, accumulating enough wear and tear in their cells that ultimately causes the body to stop functioning as a whole. While medicine and lifestyle improvements stave off aging, identifying its fundamental causes has been more challenging. In January 2023, scientists in Dr. David Sinclair’s lab at Harvard Medical School published a paper with experimental evidence supporting what Sinclair calls the “Information Theory of Aging,” where damage to the epigenome can cause aging.

After receiving his Ph.D. in molecular genetics from the University of New South Wales, Sinclair completed his postdoctorate at MIT where he co-discovered the role of sirtuin enzymes in limiting age-related cellular damage in yeast. In addition to teaching genetics and translational medicine at Harvard Medical School since 1999, Sinclair authored the popular book Lifespan: Why We Age – and Why We don’t Have To (2019). His breakthroughs in the science of aging have earned him a great deal of attention from the public eye, resulting in appearances on several popular media outlets, including CBS’s “60 Minutes” and TIME magazine (The Sinclair Lab, 2023).

Sinclair’s newest discovery, published as “Loss of epigenetic information as a cause of mammalian ageing” in January 2023, focused on the role of epigenetics in aging. The title specifies that epigenetic information loss, rather than genetic information loss, is a cause of aging. Genetics refers to the raw molecular information sequences stored in cells as deoxyribonucleic acid (DNA), which is physically condensed inside the nucleus into pairs of chromosomes. The material inside a chromosome is known as “chromatin.” The central dogma of molecular biology states that information in DNA sequences is read by the cell in the form of messenger RNA (mRNA) through transcription, and then ribosomes in the cell read this mRNA to make proteins through translation. DNA sequences that correspond to the production of a specific molecule are genes. The prefix epi- means “on top of,” so “epigenetics” refers to mechanisms that function “above” the molecules of DNA themselves, including reading DNA sequences, regulating gene transcription, and repairing mutated DNA. Like the DNA sequence, epigenetic changes are inheritable from parents to offspring.

The differences between genetics and epigenetics influence cellular reaction to damage. Damage to genes causes mutations, which are changes in the sequence of the DNA of that gene. Cells have mechanisms of repairing mutated DNA, but failure of these mechanisms can lead to cell death, or worse, cancer. Some DNA mutations, like those where a nucleotide is deleted, are irreversible.

By contrast, epigenetic mechanisms are more easily reversed. One epigenetic mechanism is DNA methylation, where a methyl group (-CH3) is added to a cytosine nucleotide by the DNA methyltransferase enzyme. This extra functional group blocks transcription factors from binding to promoter regions nearby the methylated cytosine, in effect “silencing” the gene as it cannot be transcribed into mRNA. DNA methylation is important for differentiating cells into specific cell types by enabling cells to only express the most pertinent genes while still containing the entire genome (Moore et al., 2012). DNA methylation is reversible with the help of TET dioxygenase enzymes (Wu and Zhang, 2014). Geneticists have found DNA methylation to be a way to assess molecular aging in cells as a sort of “epigenetic clock”. By analyzing methylation patterns of the genome (the “methylome”), scientists can find the biological age as well as the rate of aging in an organism’s cells (Hannum et al., 2012).

Figure 1: Methyl groups attached to cytosine bases in a gene block the enzyme RNA polymerase from binding to the promoter region of a gene, preventing transcription. Adapted from BOGOBiology (2017)

To investigate how changes to the epigenome affect aging in mice, Sinclair used a mouse system with induced changes to the epigenome (ICE). The genetically modified mice had a higher frequency of double-strand breaks (DSBs) in the DNA, which cause changes in the epigenome as cells are required to use their mechanisms of DNA repair more often . Sinclair’s method reduced the frequency of mutations by breaking the DNA strands in a way that left more whole unpaired nucleotides in the severed strand, making it more difficult for the cell to repair the DNA strand with a different sequence than before. While ICE mice had no significant difference in mutation frequencies versus control mice, DSBs in specific locations of the genome were observed as expected (Yang et al., 2023). Thus, any apparent changes in aging in the ICE mice of this study could be ascribed to the epigenetic DSB changes rather than mutations.

Figure 2: ICE treated mice after 10 months appear to have the physical hallmarks of aging, such as hair loss and reduced body mass, early compared to CRE control mice (Yang et. al. 2023).

The haggard appearance of the ICE 10 month old mice confirmed the early aging effects of the epigenetic changes (Figure 2). At the molecular level, analysis of DNA methylation at genome sites associated with age showed that ICE cells were approximately 1.5 times “older” than the control cells. With this artificially increased age came physiological consequences. ICE mice showed diminished short-term memory retention compared to Cre-control mice, as assessed by fear conditioning tests, and the ICE mice performed half as well in a Barnes Maze test as control, indicating decreased long-term memory. Additionally, ICE mice had decreased muscle mass and grip strength after 16 months. The authors attributed the cause of this accelerated aging to increased “faithful DNA repair” from the induced DSB breaks in the ICE mice, meaning that there were not significant mutations in the repair of DSBs.(Yang et al., 2023). During DSB repair, chromatin modifying factor proteins activate and move within a cell in a process known as “relocalization,” with repeated activation of this process known to cause epigenetic changes that silence genes normally expressed in young mice. Sinclair’s lab hypothesized that the relocalization of chromatin modifiers that occurs from repeated DSB repair associated with induced epigenetic changes lead to a gradual loss of cellular function associated with aging (Yang et al., 2023).

It may seem ironic that DNA strand break repair, a process meant to keep cells functioning when critical genes are damaged, is part of what ultimately causes the death of organisms. The fact that the mechanism implemented is epigenetic rather than genetic suggests that the effects of ageing may be reversible, like epigenetic mechanisms. In fact, Sinclair has shown that it is possible to partially undo the damaging effects of aging: after inducing OSK expression, which is a set of proteins known as “Yamanaka factors,” ICE mice exhibited some signs of rejuvenation in their eyes, kidneys, and muscles. Yamanaka factors like OSK are important in the fields of aging and regenerative medicine because they are keys to the synthesis of induced pluripotent stem cells, where somatic cells can become stem cells and potentially re-differentiate into other cell types (Takahashi and Yamanaka, 2006). The OSK treatment decreased the expression of age-associated markers in the kidney and muscle cells of the mice (Yang et al., 2023).

Sinclair’s experiments have shown the epigenome to be a key front in the investigation of aging, as the reversibility of changes to the epigenome can allow it to be a more accessible interface for scientists to interact with. The plasticity of the epigenome as demonstrated from the ability of Yamanaka factors to reverse the molecular indicators of aging mice show that there may be hope for science to bring this phenomenon to human epigenomes. Indeed, the news of reversing aging in mice made rounds in the media when Sinclair’s paper was published earlier this winter, and for good reason.

Works Cited

Al Aboud, N. M., Tupper, C., & Jialal, I. (2022). Genetics, Epigenetic Mechanism. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK532999/

Bannister, A. J., & Kouzarides, T. (2011). Regulation of chromatin by histone modifications. Cell Research, 21(3), Article 3. https://doi.org/10.1038/cr.2011.22

BOGObiology (Director). (2017, October 11). Epigenetics: Nature vs. Nurture. https://www.youtube.com/watch?v=Q8BMP6HDIco

CDC. (2022, August 15). What is Epigenetics? | CDC. Centers for Disease Control and Prevention. https://www.cdc.gov/genomics/disease/epigenetics.htm

David Sinclair | The Sinclair Lab. (n.d.-a). Retrieved March 5, 2023, from https://sinclair.hms.harvard.edu/people/david-sinclair

Fernandez, A., O’Leary, C., O’Byrne, K. J., Burgess, J., Richard, D. J., & Suraweera, A. (2021). Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review. Frontiers in Molecular Biosciences, 8, 685440. https://doi.org/10.3389/fmolb.2021.685440

Gilbert, S. F. (2000). Methylation Pattern and the Control of Transcription. Developmental Biology. 6th Edition. https://www.ncbi.nlm.nih.gov/books/NBK10038/

Hannum, G., Guinney, J., Zhao, L., Zhang, L., Hughes, G., Sadda, S., Klotzle, B., Bibikova, M., Fan, J.-B., Gao, Y., Deconde, R., Chen, M., Rajapakse, I., Friend, S., Ideker, T., & Zhang, K. (2013). Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates. Molecular Cell, 49(2), 359–367. https://doi.org/10.1016/j.molcel.2012.10.016

Jin, B., Li, Y., & Robertson, K. D. (2011). DNA Methylation. Genes & Cancer, 2(6), 607–617. https://doi.org/10.1177/1947601910393957

Kulis, M., & Esteller, M. (2010). 2—DNA Methylation and Cancer. In Z. Herceg & T. Ushijima (Eds.), Advances in Genetics (Vol. 70, pp. 27–56). Academic Press. https://doi.org/10.1016/B978-0-12-380866-0.60002-2

Molecules discovered that extend life in yeast, human cells. (n.d.). EurekAlert! Retrieved March 5, 2023, from https://www.eurekalert.org/news-releases/664233.

Moore, L. D., Le, T., & Fan, G. (2013). DNA Methylation and Its Basic Function. Neuropsychopharmacology, 38(1), 23–38. https://doi.org/10.1038/npp.2012.112

Offord, Catherine. Two research teams reverse signs of aging in mice. (n.d.). Retrieved March 14, 2023, from https://www.science.org/content/article/two-research-teams-reverse-signs-aging-mice.

Takahashi, K., & Yamanaka, S. (2006). Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell, 126(4), 663–676. https://doi.org/10.1016/j.cell.2006.07.024

What is Epigenetics? The Answer to the Nature vs. Nurture Debate. (n.d.). Center on the Developing Child at Harvard University. Retrieved March 5, 2023, from https://developingchild.harvard.edu/resources/what-is-epigenetics-and-how-does-it-relate-to-child-development/

Wu, H., & Sun, Y. E. (2009). Reversing DNA Methylation: New Insights from Neuronal Activity–Induced Gadd45b in Adult Neurogenesis. Science Signaling, 2(64), pe17–pe17. https://doi.org/10.1126/scisignal.264pe17

Wu, H., & Zhang, Y. (2014a). Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions. Cell, 156(0), 45–68. https://doi.org/10.1016/j.cell.2013.12.019

Yang, J.-H., Hayano, M., Griffin, P. T., Amorim, J. A., Bonkowski, M. S., Apostolides, J. K., Salfati, E. L., Blanchette, M., Munding, E. M., Bhakta, M., Chew, Y. C., Guo, W., Yang, X., Maybury-Lewis, S., Tian, X., Ross, J. M., Coppotelli, G., Meer, M. V., Rogers-Hammond, R., … Sinclair, D. A. (2023). Loss of epigenetic information as a cause of mammalian aging. Cell, 186(2), 305-326.e27. https://doi.org/10.1016/j.cell.2022.12.027

 

Ecology, Policy, and Science Communication: The Story of Biologist and Activist Erika Zavaleta

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Erika Zavaleta is an interdisciplinary scientist that has worked her career to make her research accessible, has broken down barriers for biologists of color, and is seen by many to be a trailblazer in her field. Zavaleta is a community and ecosystem biologist at the University of California Santa Cruz (UCSC) that focuses on global and regional environmental change, ecosystem functioning, and effective stewardship. She uses environmental policy, economics, anthropology, and outreach as tools to communicate her research to a larger audience as a scientist that aims to make the field accessible. She received her bachelor’s and master’s in anthropology and Ph.D. in biological sciences at Stanford University. Dr. Zavaleta is a Howard Hughes Medical Institute Professor in the Ecology and Evolutionary Biology department at UCSC. She is an appointed California Fish and Game Commission science advisor, an Ecological Society of America (ESA) “Excellence in Ecology Scholar,” ESA fellow, and a fellow of the California Academy of Sciences. Dr. Zavaleta has also co-authored over 75 papers and book chapters in the fields of conservation, ecology, and social sciences. In 2021, she received the Commitment to Human Diversity in Ecology Award from ESA due to her devotion to highlighting the voices of low-income, Indigenous, Black, and Latino backgrounds in the ecology and conservation field.

Dr. Zavaleta’s Conservation Science and Solutions Lab is interested in questions related to ecological responses to climate change, changes in biodiversity due to environmental variability, and conservation-based approaches to mediate these impacts. Some research projects currently taking place by her lab members are the impacts of land and water use changes on bat ecological communities, the impacts of community-led forestry conservation efforts in Brazil and Nepal, and the effectiveness of current conservation efforts in response to climate change. Through this research, Zavaleta’s group works to act as a link between ecology theory and research to develop and recommend effective conservation and management practices. The lab places an emphasis on collaborating with community partners, approaching research through a multidisciplinary lens, and furthering initiatives that promote inclusivity in the field of conservation and biology.

Zavaleta’s lab has supported initiatives that she founded at UCSC that provide mentorship and support for historically excluded scientists including the Doris Duke Conservation Scholars Program and the Center to Advance Mentored, Inquiry-Based Opportunities (CAMINO) in 2013 and 2017 respectively. The Doris Duke Conservation Scholars Program (DDCSP) is a national fellowship that aims to increase accessibility to the conservation field, mainly focusing on providing training and research experience for underrepresented students in science. DDCSP is carried out by five partners including the DDCSP Collaborative, the University of California at Santa Cruz, the University of Michigan, the University of Washington, and the Yale School of the Environment. CAMINO works directly with students at UCSC and provides academic and professional assistance from graduate and faculty mentors. The center pairs CAMINO scholars with funded internships where they can gain research experience regardless of their previous internships in the ecology and conservation field. Dr. Zavaleta currently serves as a faculty director for both of these programs.

Most recently, Zavaleta established a training called FieldFutures with biologist Dr. Melissa Cronin that emphasizes the importance of field-based education and research that prevent sexual harassment for scientists in the ecology and conservation field. As said on their website, “studies have shown that 64% of surveyed field researchers experienced harassment—and one in five experienced assault— while conducting fieldwork. Women, people of color, LGBTQIA+ people, and people with other marginalized identities are more likely to experience these problems.” Since fieldwork directly places scientists of all genders at greater risk of sexual violence, FieldFutures works to provide workshops that identify ways to increase prevention, provides a space for scientists to get hands-on experience in dealing with these situations, and offers protocols that can be used in the field. The “Futures” component of their name symbolizes their vision of a future for fieldwork free of sexual assault and harassment—and they are working towards getting closer to this prospect with each training.

I write about Dr. Zavaleta as a fellow Latina and future conservation biologist who not only admires her research and intellectual contributions to the field but also her dedication to making the field one that welcomes people like me. During my first and second summers as an undergraduate, I spent them as a Doris Duke Conservation Scholar at the University of California Santa Cruz (UCSC). I have heard first-hand Dr. Zavaleta’s passion for finding climate solutions, diversifying the field, and using public policy to enact impactful environmental legislation. She has not only shown her commitment to increasing diversity in the field, but she has also asserted her support for social movements around the country and pledged to incorporate their missions in her own work. In 2020 in a letter as director of DDCSP, she contended that

Science and conservation have long marginalized Black and brown voices, faces, and talents. The demographics of our country tell us that there should be five times as many scientists and professionals of color in ecology, evolution, and conservation as there are. The absence of diverse leadership in our field sustains this gap unless all of us work for change. We all have to speak up and act when we see racial inequities affect our peers, colleagues, students, and communities.

As a beneficiary of the initiatives she has passionately poured time and energy into, I can attest that programs like DDSCP have helped me and my peers realize that scientists like us—first-generation college students and people of color— can thrive in this field and use our experiences to connect to a greater audience in the scientific field. I wish to be as intentional and inclusive as Dr. Zavaleta moving forward as a scientist, educator, and science communicator and I hope that more people in this career follow her lead.

The Battle of the Medications: The Connection Between Antidepressants and Antibiotic Resistance in Bacteria

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         The consumption of antidepressant medications has skyrocketed in recent decades, reaching more than 337 million prescriptions written in 2016 in the United States alone (Wang et. al. 2019). For many individuals, these drugs are critical to maintaining everyday health as they treat many life-threatening psychiatric disorders. While their exact mechanisms differ, these medications travel in the bloodstream to the brain where they are able to influence the release of chemicals known as neurotransmitters that generate emotional states. However, while their intended target is the brain, these drugs continue to circulate throughout the body, thereby interacting with other organs and structures (Wang et. al. 2019).

         In their 2019 study, researchers led by Iva Lukic used data indicating the presence of antidepressants in the digestive tract to investigate the effect of these medications on the gut microbiome. After treating mice with different types of antidepressants, the team noticed a change in the types of bacteria present within the gut when compared to controls (Lukic et. al. 2019). This discovery that antidepressants could impact the types of bacteria present within the body ultimately led researcher Jianhua Guo to question the additional effects that these medications could have on bacteria. As antibiotics have also been shown to affect the composition of the gut microbiome, Guo began by investigating if the antidepressant fluoxetine could help Escherichia coli cells survive in the presence of various antibiotics. After finding that exposure to this medication did increase E. coli’s resistance to antibiotic treatments, Guo decided to expand his hypothesis to examine the overall connection of antidepressant usage with antibiotic resistance in bacteria.

        Collaborating with researchers Zue Wang and Zhigang Yue, Guo’s lab began by choosing five major types of antidepressant medications: sertraline, escitalopram, bupropion, duloxetine, and agomelatine. These medications differ in the ways that they prevent the reuptake of serotonin and norepinephrine in the brain, thereby allowing the researchers to examine the effects of various types of antidepressants that may be prescribed to patients. Then, E. coli bacteria were added to media containing varying concentrations of these five antidepressants. Once these cells were treated with antidepressants, the researchers began to test the cells’ resistance against antibiotics. In order to accurately reflect antibiotic use in the real world, the tested antibiotics covered the six main categories of antibiotic medications available on the market. The antidepressant-treated bacteria were then swabbed onto plates containing one of the tested antibiotics to observe cell growth. Based on the growth present on these plates, the researchers were able to estimate the incidence rate of bacterial resistance of E. coli bacteria treated with different antidepressants.

         Through this experiment, the lab observed that E. coli cells grown in sertraline and duloxetine, two antidepressants that inhibit the reuptake of serotonin, exhibited the greatest number of resistant cells across all the tested antibiotics (fig. 1). They also noted that E. coli cells exhibiting resistance to one antibiotic often demonstrate some level of resistance to other antibiotics as well. After detecting a correlation between antibiotic-resistance development and exposure to antidepressants, the lab tested the concentration dependence of this effect. While lowering the concentration of antidepressants seemed to decrease the amount of resistant E. coli cells, resistant cells continued to appear on the plates over time, suggesting that lowering antidepressant dosages only prolongs the process of developing antibiotic resistance.

Figure 1: These graphs showcase the change in the number of antibiotic-resistant E. coli cells after exposure to antidepressants over sixty days. The title of each graph indicates the tested antibiotic while the colored trend lines on the graph represent one of the five, tested antidepressants. On the y-axis of each graph, the fold change measurement is used to describe the change in the number of resistant cells that develop over time. As demonstrated by the purple and yellow trend lines, duloxetine and sertraline are associated with the greatest development of resistant cells to each of the four represented antibiotics. (Adapted from Wang et. al. 2019)

         After analyzing this data, the researchers were confronted with a question: what about anti-depressants led to the development of antibiotic resistance in bacteria? To examine this question, the lab used flow cytometry to examine what was happening within the bacterial cells. This lab technique uses a fluorescent dye that binds to specific intercellular target molecules, thereby allowing these components to be visualized. After applying this dye to resistant cells grown on the antibiotic agar plates, the researchers noticed the presence of specific oxygen compounds known as reactive oxygen species (ROS). Unstable ROS bind to other molecules within a cell, disrupting normal functioning and causing stress. Elevated cellular stress levels have been shown to induce the transcription of specific genes in bacteria that produce proteins to help return the cell to normal functioning (Wang et. al. 2019).

         ROS molecules have been shown to induce the production of efflux pumps in bacteria, leading the lab to investigate if these structures were involved in the antibiotic resistance of E. coli cells. Efflux pumps are structures in the cell membrane of a protein that pump harmful substances out of the cell. The lab mapped the genome to look for activated genes associated with the production of this protein. According to the computer model, more DNA regions in resistance bacteria coding for efflux pumps were active than in the Wild Type. The researchers then concluded that efflux pumps were being produced in response to antidepressant exposure. These additional efflux pumps removed antibiotic molecules in resistant E. coli, thereby allowing them to survive in the presence of lethal drugs.

         The antibiotic resistance uncovered in this study was significant and persistent. Even one day of exposure to antidepressants like sertraline and duloxetine led to the presence of resistant cells. Furthermore, the team demonstrated that these antibiotic-resistant capabilities often do not disappear over time; rather, they are inherited between generations of bacteria, leading to the proliferation of dangerous cells unsusceptible to available treatments. The next logical step towards validating the connection between antidepressants and antibiotic resistance would include studying the gut microbiomes of patients taking anti-depressants to look for antibiotic-resistant bacteria.

         This study reveals a novel issue that must be attended to.  In 2019, 1.27 million deaths worldwide could be directly attributed to antibiotic-resistant microbes, a number expected to grow to 10 million by the year 2050 (O’Neill 2023). These “superbugs” present a dangerously growing reality. If the correlation between antidepressant use and antibiotic resistance is left uninvestigated, superbugs will likely continue to develop even as antibiotic use is regulated and monitored to battle them. Only by taking this connection seriously will researchers be able to fully grapple with and battle the growing antibiotic resistance trends, thereby preventing common infections from becoming death sentences. 

 Sources:

CDC. (2022, July 15). The biggest antibiotic-resistant threats in the U.S. Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/biggest-threats.html

Drew, L. (2023). How antidepressants help bacteria resist antibiotics. Nature. https://doi.org/10.1038/d41586-023-00186-y

Jin, M., Lu, J., Chen, Z., Nguyen, S. H., Mao, L., Li, J., Yuan, Z., & Guo, J. (2018). Antidepressant fluoxetine induces multiple antibiotics resistance in Escherichia coli via ROS-mediated mutagenesis. Environment International, 120, 421–430. https://doi.org/10.1016/j.envint.2018.07.046 

Lukić, I., Getselter, D., Ziv, O., Oron, O., Reuveni, E., Koren, O., & Elliott, E. (2019). Antidepressants affect gut microbiota and Ruminococcus flavefaciens is able to abolish their effects on depressive-like behavior. Translational Psychiatry, 9(1), 1–16. https://doi.org/10.1038/s41398-019-0466-x

O’Neill, J. (Ed.). (2016). Tackling Drug-Resistant Infections Globally: Final Report and Recommendations. The Review on Antimicrobial Resistance. https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf

Thompson, T. (2022). The staggering death toll of drug-resistant bacteria. Nature. https://doi.org/10.1038/d41586-022-00228-x

Wang, Y., Yu, Z., Ding, P., Lu, J., Mao, L., Ngiam, L., Yuan, Z., Engelstädter, J., Schembri, M. A., & Guo, J. (2023). Antidepressants can induce mutation and enhance persistence toward multiple antibiotics. Proceedings of the National Academy of Sciences, 120(5), e2208344120. https://doi.org/10.1073/pnas.2208344120

The Anti-cancer and Antimicrobial Activity Associated with Sea Sponge Extracts

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Toxic Negombata magnifica sponge at Shaab el Erg reef (Red Sea, Egypt) (Alexander Vasenin, 2010)

With an ever-increasing demand for novel drug therapies, scientists are turning to marine organisms as a source of bioactive chemicals, whose properties can be harnessed for medical development. One such organism is a rather unlikely candidate: the sea sponge (phylum Porifera). Lacking a brain and a central nervous system, sea sponges rely upon specialized cells to perform their required functions. As result of their structural simplicity and sedentary existence, these ancient creatures have evolved to protect themselves against predation by means of toxic chemicals, which can prove similarly lethal to cancer cells and microbes in humans (El-Naggar et. al., 2022). A study published in Applied Sciences examined the properties of two sponge species, Negombata magnifica (finger sponge) and Callyspongia siphonella (tube sponge). This drew from the scientists’ previous study, which had indicated that all eight extracts of finger-sponge and tube-sponge studied promoted the death and inhibited the growth of cells associated with liver, breast, and colorectal cancer (El-Naggar et.al., 2022).

Whereas the earlier study had used four different solvents in the production of sponge extracts, this newerstudy examined only the methanolic extracts of Negombata magnifica (NmE) and Callyspongia siphonella (CsE). Sponge specimens were collected from the Dahab region on the Sinai Peninsula and soaked with methanol to obtain NmE and CsE. One microliter of each extract was examined for its contents of bioactive compounds via a Gas Chromatography–Mass Spectrometer (GC–MS analysis). Out of the 117 chemical compounds revealed by GC­–MS analysis, 37 were determined to be bioactive. These compounds were tested against cultured liver, breast, and colorectal cancer cell lines and ten test microorganisms representing filamentous fungi, yeasts, and Gram-positive and Gram-negative bacteria (El-Naggar et.al., 2022).

While CsE showed no antiproliferative action against the cancer cells, NmE dose-dependently impeded their growth: it induced cell cycle arrest in the liver cancer lines by inhibiting the cell division protein CDK6. It also halted mitotic progress in all three cell types by inhibiting D1 and E1 cyclins, which regulate progression through the cell cycle (Alao, 2007). Furthermore, NmE activated reactive oxygen species (ROS) production in liver cancer cells and induced apoptosis in all cell lines, via Bax (a pro-apoptotic regulatory protein) and caspase-3 (a death protease that cleaves cellular proteins) increase and BCL2 (an anti-apoptotic regulatory protein) decrease (Blanco and García-Sáez, 2018) (Ponder and Boise, 2019; Youle and Strasser, 2002). Regarding antimicrobial activity, CsE was shown to be a superior antimicrobial agent by acting against six microbial strains, whereas NmE reacted favorably to only two strains (El Naggar et. al., 2022).

Looking forward, the anti-cancer properties of NmE indicate its potential for development as an anti-cancer drug, while CsE is a promising source for antimicrobial drug discovery. Additionally, several of the compounds’ bioactivity is neither anti-cancer nor antimicrobial—for instance, both fenretinide and ethyl iso-allocholate have been attributed to anti-COVID-19 activity (Orienti, et. al., 2020; Poochi et. al., 2020). Ultimately, given that approximately eighty of the compounds have yet to be attributed to anti-cancer or anti-microbial mechanisms, the study emphasizes the importance of looking to Earth’s oceans as potential sources of bioactive compounds and harnessing the biological potential of marine organisms in the development of novel drug therapies.

References:

Alao, J.P. The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention. Mol Cancer 6, 24 (2007). https://doi.org/10.1186/1476-4598-6-24

El-Naggar, H. A., Bashar, M. A. E., Rady, I., El-Wetidy, M. S., Suleiman, W. B., Al-Otibi, F. O., Al-Rashed, S. A., et al. (2022). Two Red Sea Sponge Extracts (Negombata magnifica and Callyspongia siphonella) Induced Anticancer and Antimicrobial Activity. Applied Sciences, 12(3), 1400. MDPI AG. Retrieved from http://dx.doi.org/10.3390/app12031400

Orienti, I.; Gentilomi, G.A.; Farruggia, G. Pulmonary Delivery of Fenretinide: A Possible Adjuvant Treatment in COVID-19. Int. J. Mol. Sci. 2020, 21, 3812.

Peña-Blanco, A., & García-Sáez, A. J. (2018). Bax, Bak and beyond – mitochondrial performance in apoptosis. The FEBS journal, 285(3), 416–431. https://doi.org/10.1111/febs.14186

Ponder, K.G., Boise, L.H. (2019). The prodomain of caspase-3 regulates its own removal and caspase activation. Cell Death Discovery 5, 56. https://doi.org/10.1038/s41420-019-0142-1

Poochi, S.P.; Easwaran, M.; Balasubramanian, B.; Anbuselvam, M.; Meyyazhagan, A.; Park, S.; Bhotla, H.K.; Anbuselvam, J.; Arumugam, V.A.; Keshavarao, S.; et al. Employing bioactive compounds derived from Ipomoea obscura (L.) to evaluate potential inhibitor for SARS-CoV-2 main protease and ACE2 protein. Food Front. 2020, 1, 168–179.

Youle, R., Strasser, A. (2008). The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9, 47–59. https://doi.org/10.1038/nrm2308

 

Examining the work of 2022 Nobel Prize in Physiology or Medicine Laureate Svante Pääbo

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Svante Pääbo. Max Planck Institute for Evolutionary Anthropology. Retrieved November 6, 2022. https://www.eva.mpg.de/genetics/staff/paabo/#c28042

 

 

            Have you ever wondered how humans lived on Earth before the first major civilizations formed? It turns out that we were not the only hominid species on Earth in those times: other relatives of humans, such as Neanderthals, lived and intermingled with humans. The genetic relationship between humans and these hominids is a subject of great interest to the scientific community, since the traits of our species’s distant relatives can explain genetic phenomena in modern humans. On October 3rd, 2022, the Nobel Prize Committee announced they would be awarding Swedish geneticist Svante Pääbo the prize in Physiology or Medicine “for his discoveries concerning the genomes of extinct hominins and human evolution” (NobelPrize.org, 2022). One of Dr. Pääbo’s most significant achievements leading to his prize was sequencing the Neanderthal genome. A closer look at Dr. Paabo’s work in the field of genetics elucidates how his work led to the foundation of the field of paleogenetics.

            Originally a student of Egyptology, Dr. Pääbo received a Ph.D. in molecular immunology from the University of Uppsala in 1986, but his interest in the former remained: his first Nature publication was about cloning ancient DNA from ancient Egyptian mummies (Gruber Foundation, 2022; Pääbo, 1985). Despite the possibility of degradation or contamination from the mummification process itself and from the millenia that passed since, he found that surface-level tissue samples in a one-year old boy yielded DNA that could be cloned using DNA recombination techniques (Pääbo, 1985). Since publishing this, Dr. Pääbo has made a career of refining techniques that allow the sequencing of genomes from many other types of ancient humans or hominins.
            Dr. Pääbo’s discoveries have advanced the field of paleogenomics, the study of genomes belonging to extinct species. Of primary concern is recovering ancient DNA (aDNA) from specimens in ideal physical conditions, as in dry and high-salinity environments, since in those environments long DNA molecules will not degrade as fast (Lan, 2019). Then, with techniques such as polymerase chain reaction (PCR) and Sanger sequencing, the aDNA molecules can be cloned and amplified to allow scientists to study copies of genes without needing more of the original sample (Lan, 2019). Storing individual genes from these recovered genomes in bacteria allows scientists to form “libraries” of specimen genomes. The contents of these genomic libraries can then be analyzed to fully sequence the genome of the specimen. After sequencing the genome of one species, scientists can then compare the genome to a related species to identify the differences (Genome.gov, 2020).
            In 2010, Dr. Pääbo and colleagues published “A Draft Sequence of the Neandertal Genome,” where they collected and analyzed aDNA from three individual Neanderthal specimens in Europe using the techniques described above (Green, 2010). Using data from this draft genome of the Neanderthal, they identified key genetic differences between modern humans and ancestral species. In particular, there were mutations in certain genes associated with disorders in modern humans, such as in RUNX2. Mutations of the RUNX2 gene can lead to cleidocranial dysplasia, a disorder that causes protruded frontal bones on the cranium and bell-shaped rib cages. These symptoms resemble the known skeletal morphologies of Neanderthals, which gives researchers a clue as to how humans and Neanderthals diverged genetically from each other (Green, 2010).
            The discoveries that Dr. Pääbo made in the field of paleogenomics have brought to light how molecular differences between Neanderthals and humans translate to their defining features as species. With the techniques that he developed, scientists can now examine the genomes of specimens thousands of years old without fear of contamination. Future developments in the field of paleogenomics could be expanding upon the links between Neanderthal DNA in human genomes and risk factors for diseases like COVID-19, which Dr. Pääbo himself has contributed to (Zeberg & Pääbo, 2021). Svante Pääbo’s work will help scientists uncover further links between our distant ancestors and modern humans for decades to come.



Works Cited:

Callaway, E., & Ledford, H. (2022). Geneticist who unmasked lives of ancient humans wins medicine Nobel. Nature, 610(7930), 16–17. https://doi.org/10.1038/d41586-022-03086-9


DNA Sequencing Fact Sheet. (n.d.). Genome.Gov. Retrieved November 6, 2022, from https://www.genome.gov/about-genomics/fact-sheets/DNA-Sequencing-Fact-Sheet


Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H.-Y., Hansen, N. F., Durand, E. Y., Malaspinas, A.-S., Jensen, J. D., Marques-Bonet, T., Alkan, C., Prüfer, K., Meyer, M., Burbano, H. A., … Pääbo, S. (2010b). A Draft Sequence of the Neandertal Genome. Science, 328(5979), 710–722. https://doi.org/10.1126/science.1188021


Lan, T., & Lindqvist, C. (2019). Paleogenomics: Genome-Scale Analysis of Ancient DNA and Population and Evolutionary Genomic Inferences. In O. P. Rajora (Ed.), Population Genomics: Concepts, Approaches and Applications (pp. 323–360). Springer International Publishing. https://doi.org/10.1007/13836_2017_7


Pääbo, S. (1985). Molecular cloning of Ancient Egyptian mummy DNA. Nature, 314(6012), Article 6012. https://doi.org/10.1038/314644a0

The Nobel Prize in Physiology or Medicine 2022. (n.d.-a). NobelPrize.Org. Retrieved October 16, 2022, from https://www.nobelprize.org/prizes/medicine/2022/advanced-information/


The Nobel Prize in Physiology or Medicine 2022. (n.d.-b). NobelPrize.Org. Retrieved October 16, 2022, from https://www.nobelprize.org/prizes/medicine/2022/press-release/

 

The Nobel Prize in Physiology or Medicine 2022. (n.d.-c). NobelPrize.Org. Retrieved October 16, 2022, from https://www.nobelprize.org/prizes/medicine/2022/paabo/facts/

Svante Pääbo | Gruber Foundation. (n.d.). Retrieved October 16, 2022, from https://gruber.yale.edu/genetics/svante-p-bo


Svante Pääbo—Max Planck Institute for Evolutionary Anthropology. (n.d.). Retrieved October 22, 2022, from https://www.eva.mpg.de/genetics/staff/paabo/#c28042


Warren, M. (2018). Mum’s a Neanderthal, Dad’s a Denisovan: First discovery of an ancient-human hybrid. Nature, 560(7719), 417–418. https://doi.org/10.1038/d41586-018-06004-0
Zeberg, H., & Pääbo, S. (2021). A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. Proceedings of the National Academy of Sciences, 118(9), e2026309118. https://doi.org/10.1073/pnas.2026309118

Zeberg, H., & Pääbo, S. (2021). A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. Proceedings of the National Academy of Sciences, 118(9), e2026309118. https://doi.org/10.1073/pnas.2026309118

From Crystal Balls to Blue Flies: Death Prediction in the Modern Scientific World

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To most people, the phrase “death prediction” conjures distant images of glowing crystal balls, vibrant tarot cards, or the mystical fortune tellers in popular movies like Big and Ghost. Despite the terrifying implications of a finite and predictable death, a societal obsession with it pervades our media, culture, and everyday life. Though death prediction has historically been confined to fiction and spirituality, scientific advances are transforming it into an imminent next step.

Until the early 2010s, death prediction in the scientific sphere was limited to chronological age. The basic understanding that humans are more likely to die as they reach the end of their average life span was, and still is in many ways, the foundation to any scientific attempts to predict mortality (Gaille et al.). However, more recently, researchers have discovered observable markers of “physiological age”, or traits independent of chronological age that indicate when an individual organism is near the end of its life. In a 2012 experiment, scientists Rera et al. found a reliable predictor in the model organism Drosophila melanogaster, otherwise known as the common fruit fly. According to the study, the flies enter an identifiable “pre-death stage” marked by an increase in intestinal permeability, which can accurately predict when they are near the end of their life. Increases in intestinal permeability were tracked by injecting the drosophila flies with a non-digestible blue dye and observing if their intestinal walls allowed the dye to pass through, causing them to externally turn blue (in drosophila with normal levels of intestinal permeability the dye remained confined to the digestive tract). The high intestinal permeability associated with the blue flies and pre-death stage was appropriately dubbed the “Smurf phenotype”.

Drosophila with the Smurf phenotype were observed to have significantly lower remaining life spans than their age-matched non-Smurf counterparts. While the link between intestinal dysfunction and approaching death is still not fully understood, recent data point to changes in immunity-related gene expression and the aging fly’s microbiome as potential causes. These changes can be caused by old age or other afflictions; in the Smurf flies who were significantly below the average lifespan of the species, other morbidities were often observed, such as mitochondrial dysfunction, increased internal bacterial load, and insulin resistance syndrome. Evidently, the flies’ transition to their “pre-death stage”, or the Smurf phenotype, is a more accurate and comprehensive predictor of death than chronological age (Rera et al.). This biological phenomenon was later observed in other animals too, notably zebrafish and nematodes (Gaille et al.). The prevalence of this observable transition in multiple organisms coupled with its accuracy is slowly but surely turning mortality prediction into a reality.

Surprisingly, death prediction in humans is not far off from the developments seen in Drosophila and other model organisms. In a 2019 UCLA clinical trial, scientists tentatively proved that intestinal permeability is linked to approaching mortality in humans. While the trial was small and needs to be replicated, it provided significant evidence that the efficacy of intestinal permeability decline in death prediction has significant potential for human mortality prediction (Angarita et al.).

Outside of intestinal permeability, scientists have discovered alternative ways to predict a pre-death stage in humans. In a 2014 study, Pinto et al. theorized that olfaction could serve as another indicator as it relies heavily on peripheral and central cell regeneration, which tend to degrade near the end of an individual’s life due to old age or other morbidities. In the study, roughly 3,000 adults in the age range of 57-85 were asked to identify five different common odorants via forced choice. After 5 years, scientists collected data on which subjects were still alive, and analyzed the connection between their olfactory capability and mortality within the 5 year span. The findings were startling: the mortality rate was four times higher for adults with complete loss of smell than adults with fully intact senses of smell (Pinto et al.).

  A: Olfactory dysfunction versus 5 year mortality separated by age group

B: Progression of errors in scent identification versus 5 year mortality (Pinto et al.)

While other methods of death prediction such as biomarkers, genetic screenings, and
demographic studies exist, the discovery of pre-death indicators like intestinal permeability and olfactory decline grant us a unique and improved perspective on mortality. As research continues to grow on this subject, we must question the implications these developments have on our society: how will we reckon with the seemingly impossible ability to predict the future? Is it possible to enjoy life with an exact knowledge of its end? How will both health and wealth inequalities affect the commercialization of testing for death prediction? The moral and ethical dilemmas arising from this development are boundless.

Though these questions do not have finite answers, they must remain present in our discussions of death prediction. While scientific innovations like mortality predictors hold great promise in advancing society, they also have the capacity to exacerbate inequity and other social ills. As rapid development continues to occur in the scientific world, we must maintain both an open mind and an understanding of the complex challenges change poses to our world.

Works Cited

Angarita, Stephanie A. K., et al. “Quantitative Measure of Intestinal Permeability Using Blue Food Coloring.” Journal of Surgical Research, vol. 233, Jan. 2019, pp. 20–25. DOI.org (Crossref), https://doi.org/10.1016/j.jss.2018.07.005.

Gaille, Marie, et al. “Ethical and Social Implications of Approaching Death Prediction in Humans – When the Biology of Ageing Meets Existential Issues.” BMC Medical Ethics, vol. 21, no. 1, Dec. 2020, p. 64. DOI.org (Crossref), https://doi.org/10.1186/s12910-020-00502-5.

Pinto, Jayant M., et al. “Olfactory Dysfunction Predicts 5-Year Mortality in Older Adults.” PLoS ONE, edited by Thomas Hummel, vol. 9, no. 10, Oct. 2014, p. e107541. DOI.org (Crossref), https://doi.org/10.1371/journal.pone.0107541.

Rera, Michael, et al. “Intestinal Barrier Dysfunction Links Metabolic and Inflammatory Markers of Aging to Death in Drosophila.” Proceedings of the National Academy of Sciences, vol. 109, no. 52, Dec. 2012, pp. 21528–33. DOI.org (Crossref), https://doi.org/10.1073/pnas.1215849110.

Cover Image Credit: https://www.npr.org/2019/07/26/745361267/hello-brave-new-world

Immortality: a biological possibility

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Immortality is biologically possible. It has been biologically possible ever since the discovery of the ‘immortal’ jellyfish Turritopsis. dohrnii in the Mediterranean Sea in 1883. This cnidarian is an exception to the normal cycle of life and death; they have an extra stage in their life cycle known as ‘rejuvenation’ where the mature medusa can metamorphose back into its juvenile form – as polyps. This is usually in response to damage or natural deterioration with age. If they are not eaten or killed by predators, they can rejuvenate and live forever. Therefore there could actually be an existing Turritopsis. dohrnii jellyfish that has lived since the time when dinosaurs roamed the Earth, as this species of jellyfish have been floating in the oceans since 66 million years ago. 

Fig 1: The immortal jellyfish: Turritopsis. dohrnii (American Museum of Natural History, 2015)

The diagram on the left of Figure 2 shows what the life cycle of a jellyfish normally is. The fertilized egg first grows into a small larva, known as a planula (Pascual-Torner, 2021). The planula the proceeds to ground itself into a solid surface and form a polyp where it develops a digestive system and reproduces asexually to form a colony (Pascual-Torner, 2021). A section of the polyp within the colony develops a new set of nerves and muscle, which can swim, grow and feed independently; eventually growing into a medusa, a full grown adult jellyfish which can reproduce sexually (Pascual-Torner, 2021). If not by being eaten or injured by a predator, old age is usually what kills these jellyfish (Pascual-Torner, 2021). 

Fig 2: The life cycles of Turritopsis. rubra (‘normal’ lifecycle) and Turritopsis. dohrnii  (Pascual-Torner, 2021)

Aging is generally governed by cellular senescence – formally defined as a state of cell cycle arrest where proliferating cells stop responding towards growth-promoting stimuli (Osterloff). This is usually in response to stresses such as telomere dysfunction and persistent DNA damage (Cell Signaling Technology). The number of senescent cells normally increases with age, negatively impacting other biological processes and impairs any potential for pluripotency – ability of a cell to differentiate into any type of specialized cell – and the possibility of regeneration. But this cnidarian species is able to challenge this trait and reverse their life cycle even after reaching sexual maturity, through a process called ontogeny reversal.

Comparative genomic studies have been conducted in hopes to find the genes involved in ontogeny reversal. In the study conducted by Pascual-Torner et al. (2021), the genes involved in aging and DNA repair were compared between Turritopsis. dohrnii and Turritopsis. rubra, which can’t rejuvenate at mature stages. Some of their findings suggested that Turritopsis. dohrnii may have “more efficient replicative mechanisms and repair systems” (Pascual-Torner et al., 2021). This includes the amplification of the genes POLD1 and POLA2, which encode for the enzyme DNA polymerase. This enzyme is involved in DNA replication, therefore its respective genes being amplified suggest enhanced replication in this cnidarian species. Furthermore, duplications to certain DNA repair genes such as XRCC5, GEN1, RAD51C, and MSH2 suggest more efficient DNA repair mechanisms (Pascual-Torner et al., 2021). A more efficient DNA repair mechanism reduces DNA damage and the triggers for cellular senescence, resulting in the slowing down of aging. In addition, there are also many other genomic differences noted by the study that also contribute to reducing the stressors for senescence that are not mentioned in this article. 

However, the ability Turritopsis. dohrnii has for ontogeny reversal implies that this jellyfish species additionally possesses some sort of cell reprogramming mechanism. To promote dedifferentiation, where cells grow in reverse from a differentiated stage to a less differentiated stage, there should be pathways that target the enzyme PRC2 (polycomb repression complex 2) and pluripotency related genes (Pascual-Torner et al., 2021). PRC2 catalyzes methylation of a specific set of histones to silence specific genes that enhance and maintain pluripotency in embryonic stem cells (Pascual-Torner et al., 2021). According to the same study, the silencing of PCR2 targets and activation of pluripotency targets was observed in Turritopsis. dohrnii (Pascual-Torner et al., 2021). Through these mechanisms, pluripotency is enhanced, leading the jellyfish to be able to form undifferentiated cells and thereby reversing back into its cyst stage, which is similar to its planula stage, as shown in Figure 2. 

It is mind-blowing that a mere floating sea creature is able to reverse its lifecycle and biologically be immortal. There is still a lot unknown about its process to being able to be immortal; scientists have only just started to uncover the basics from their genomic analysis. Maybe as scientists go deeper into uncovering Turritopsis. dohrnii’s strange immortality, we can start to think about whether we can transfer this ability to other creatures, even humans – or if we even want to? Now that immortality is actually a reality, do we want it to be a biological possibility for other creatures, for us? 

References

“Cellular Senescence.” Cell Signaling Technology, https://www.cellsignal.com/science-resources/overview-of-cellular-senescence. 

Matsumoto, Yui, and Maria Pia Miglietta. “Cellular Reprogramming and Immortality: Expression Profiling Reveals Putative Genes Involved in Turritopsis Dohrnii’s Life Cycle Reversal.” Genome Biology and Evolution, edited by Dennis Lavrov, vol. 13, no. 7, July 2021, p. evab136. DOI.org (Crossref), https://doi.org/10.1093/gbe/evab136.

Osterloff, Emily. “Immortal Jellyfish: The Secret to Cheating Death.” Natural History Museum, https://www.nhm.ac.uk/discover/immortal-jellyfish-secret-to-cheating-death.html. 

Pascual-Torner, Maria, et al. “Comparative Genomics of Mortal and Immortal Cnidarians Unveils Novel Keys behind Rejuvenation.” Proceedings of the National Academy of Sciences, vol. 119, no. 36, Sept. 2022, p. e2118763119. DOI.org (Crossref), https://doi.org/10.1073/pnas.2118763119.

“The ‘Immortal’ Jellyfish That Resets When Damaged: AMNH.” American Museum of Natural History, 2015, https://www.amnh.org/explore/news-blogs/on-exhibit-posts/the-immortal-jellyfish.

 

Recently Discovered Fossil Sheds Light on Paired Limb Evolution

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         Evolutionary biologists consistently work with limited information to untangle the complicated web of life’s origin and evolution. However, new evidence constantly emerges and fills gaps in scientific understanding. A well-preserved new species of galeaspid, a clade of extinct jawless fishes, called Tujiaaspis vividus provides novel insight into the evolutionary history of paired appendages. The researchers modeled water flow around the specimen’s paired fin flaps to analyze the function of the non-muscularized fins in improving the mobility of T. vividus (Gai et al., 2022).

The evolution of a jaw is a key development in the history of vertebrates as it marks when paired appendages started to develop and is a shared trait in most living vertebrates. Thus, modern-day jawless fish like hagfish and lampreys are classified into a different clade from all other vertebrates to indicate the divergence. While galeaspids like T. vividus lacked jaws, they were a stepping stone on the evolutionary path to jawed vertebrates and thus can help understand the evolutionary connection between jawless vertebrates and jawed vertebrates (gnathostomes). T. vividus has paired ventrolateral fins that are not muscularized like the fins of a modern bony fish or the appendages of land animals. However, these paired fins flaps are a necessary intermediary in the development of paired fins. Therefore, T. vividus morphology provides insight into how evolution through natural selection can occur gradually (Gai et al., 2022).

The researchers investigated how the development of primitive paired limbs could have improved mobility for galeaspids. This allowed them to hypothesize about the original reasons paired limbs were useful. To do so, they simulated water flow over models of T. vividus with and without paired fins at many angles of attack. Varying the attack angle means that the researchers varied the direction of water flow in their model to gain a more complete understanding of the hydrodynamics of T. vividus. The authors found that ventrolateral fins generated passive lift and improved movability in the water. The surviving ancestors of T. vividus are not sessile, meaning they are not confined to the sea floor like a clam. However, hagfishes and lampreys are mostly benthic, spending their time on the seafloor. Improved lift in galeaspids provides insight into how bony and cartilaginous fishes could move towards being true nekton, which implies total mobility in the water column (Gai et al., 2022).

This analysis is relevant to the understanding of current evolutionary theories. The new-head hypothesis postulates that the mobility of jawed vertebrates enabled by the development of paired appendages allowed them to develop more active feeding practices (Gai et al., 2022). The paired appendages of ancestral gnathostomes that generated lift underwater supports the hypothesis that increased mobility coincided with more active predation practices (Gai et al., 2022). Additionally, the lateral fin fold hypothesis argues that distinct fins emerged from a long fold around the body of early vertebrates (Diogo, 2020). This theory has always been challenging to test, as the remains of many relevant species lack bone structure around the possible fin fold (Gai et al., 2022). The findings of this study suggest a more complex fin evolution where paired fins groups evolved separately, although still in the same chronological order as the fin-fold hypothesis postulates, pectoral fins before pelvic fins (Gai et al., 2022). Overall, this study suggests that paired fins played an important role in creating more mobile life. 

Illustrator: Isabelle Lee ’25 (https://news.wisc.edu/jawless-fish-take-a-bite-out-of-the-blood-brain-barrier/)

Works Cited

Diogo, R. (2020). Cranial or postcranial—Dual origin of the pectoral appendage of vertebrates combining the fin-fold and gill-arch theories? Developmental Dynamics, 249(10), 1182–1200. https://doi.org/10.1002/dvdy.192

Gai, Z., Li, Q., Ferrón, H. G., Keating, J. N., Wang, J., Donoghue, P. C. J., & Zhu, M. (2022). Galeaspid anatomy and the origin of vertebrate paired appendages. Nature, 609(7929), 959–963. https://doi.org/10.1038/s41586-022-04897-6

Beware the Blob!

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“Beware of the Blob! It creeps, and leaps, and glides and slides across the floor! Indescribable…Indestructible! Nothing Can Stop It! The indestructible creature! Bloated with the blood of its victims!” (The Blob, 1958). Physarum polycephalum, nicknamed the “The Blob” after the 1958 classic from Irvin Yeaworth and Russel Doughten, has taken the scientific community by storm. Its impressive repertoire includes spending a summer in space, modeling the early evolutionary history of eukaryotes, and of course, navigating the reproductive scene with over 720 sexes in one organism. Traveling without legs and healing injuries in just under two minutes, this slime mold “belongs to one of nature’s mysteries” according to Bruno David, director of the Paris Museum of Natural History (The Guardian, 2019). 

Such a creature shrouded in mystery can commonly be located growing within rotting logs searching for food via a long network of thin tendrils. When the organism encounters food it grows over the object, secreting digestive enzymes to “consume” the decaying vegetation or microorganism. Its intricate structure allows for nutrients to be passed around within the network of the organism. 

Toshiyuki Nakagaki,  a mathematical biologist, and colleagues observed Physarum polycephalum’s networking capabilities to predict effective city planning. The laboratory placed the mold into a culture mirroring Tokyo’s infrastructure. Upon placing food in the city’s population centers, the organism’s tendrils uncovered pathways nearly identical to Tokyo’s railway system (Wogan, 2012). The research demonstrated Physarum polycephalum’s incredible ability to solve complex problems, such as uncovering the fastest pathway through a maze, despite having no “brain-like” center (Kramar, 2021).   

The single-celled slime mold’s ability to make intelligent decisions without a central nervous system, “a memory without a brain,” has sparked intrigue into its real-world applications. Within a medical context, the mold’s early growth could be essential to understanding how tumors supply themselves with blood. Slime molds in their early stages of growth begin as a collection of isolated spores that grow in an outwards direction. Next, the spores gather in smaller groupings which release tendrils that connect with other gatherings nearby. This eventually forms a larger single celled organism that can transport nutrients, fluid, etc within itself. This process is called “percolation transition”, when separate networks become interconnected to form a transport system. Tumors subscribe to a similar process.They produce factors that stimulate the creation of blood vessels that supply the components necessary for their growth (NCI, 2018). This process is a highly active subject of research within the field of oncology. “The Blob” may aid in furthering the field’s understanding of tumors. 

Further research on Physarum polycephalum may provide insight into not only understanding but preventing tumor growth. Hans-Gunther Dobereiner, Adrian Fessel, and colleagues from the University of Bremen and Mechanobiology Institute focus their studies on slime mold percolation transition. They observed how the mold’s tendrils grew and joined with one another similar to a subway map system, as seen earlier by Nakagaki. Researchers recorded the connections and discovered that percolation transition always happened when the collection “nodes” of the mold and the tendril lines observed a specific pattern. Regardless of the number of collection “nodes,” there was a constant ratio of tendrils to nodes. Dobereiner hopes that further research into the vascular network formation of the slime mold can lead to techniques of preventing tumor growth using their slime mold-derived mathematical model (Wogan, 2012).

Whether a Mathematician, Puzzle-enthusiast, or Urban planner Physarum polycephalum’s many talents merits many real-world applications. While it may not make a cinema debut quite like its chilling movie-star counterpart, this slime mold is ready for the big screen of the scientific community. What will Physarum polycephalum accomplish next? Certainly something, “Indescribable…indestructible…insatiable” (The Blob, 1958). 

Image Credit: https://www.imdb.com/title/tt0051418/

Works Cited

The Blob. (1958). Movie Quote. Retrieved November 6, 2022, from https://www.moviequotedb.com/movies/blob-the-1958.html.

The Guardian Staff. (2019, October 17). The ‘blob’: Zoo showcases slime mold with 720 sexes that can heal itself in minutes. The Guardian. Retrieved November 6, 2022, from https://www.theguardian.com/world/2019/oct/17/the-blob-zoo-unveils-baffling-new-organism-with-720 sexes#:~:text=The%20slime%20mold%2C%20Physarum%20polycephalum,minutes%20if%20cut%20in%20half.&text=%E2%80%9CThe%20blob%20is%20a%20living,the%20Zoological%20Park%20is%20part.

Mirna Kramar, Karen Alim. Encoding memory in tube diameter hierarchy of living flow network. Proceedings of the National Academy of Sciences, 2021; 118 (10): e2007815118 DOI: 10.1073/pnas.2007815118

National Cancer Institute. (2018). Angiogenesis inhibitors. National Cancer Institute. Retrieved November 6, 2022, from https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet#:~:text=have%20side%20effects%3F-,What%20is%20angiogenesis%3F,chemical%20signals%20in%20the%20body.

Technical University of Munich (TUM). “A memory without a brain: How a single cell slime mold makes smart decisions without a central nervous system.” ScienceDaily. ScienceDaily, 23 February 2021. <www.sciencedaily.com/releases/2021/02/210223121643.htm>.

Wogan , T. (2012). A slimy insight into treating cancer. Science. Retrieved November 6, 2022, from https://www.science.org/content/article/slimy-insight-treating-cancer.