Bowdoin Science Journal

Biology

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

 

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

Teplizumab: A New Breakthrough in the Treatment of Type 1 Diabetes

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     In Ancient Egypt, a diet of whole grains was prescribed to patients with frequent urination and emaciation (History of diabetes, 2020).  This condition, similarly documented by physicians in Ancient Greece, was likely first called “diabetes” by Apollonius of Memphis in the third century BCE. By the fifth century CE, type 1 diabetes had been differentiated from type 2, and in 1776, English physician Matthew Dobson confirmed the presence of excess glucose in the urine of diabetic patients. Canadian physician Frederick Banting and his colleagues successfully used insulin injections to treat a diabetic patient in 1922; this remains the predominant method of treatment today. Another milestone was reached this past November, when the drug Teplizumab (under the name Tzield) gained FDA approval. Teplizumab showed potential in delaying the onset of clinical type 1 diabetes in adults and pediatric patients 8 years and older who have not yet developed the condition (Commissioner of the FDA, 2022). 

     Type 1 diabetes, otherwise known as juvenile diabetes or insulin-dependent diabetes, is a form of diabetes mellitus in which a deficiency of insulin causes hyperglycemia (high blood sugar). It is referred to as “juvenile diabetes” because the symptoms of the condition typically appear in adolescence and is the result of an autoimmune disorder. The onset of type 1 diabetes depends on environmental factors that interact with predisposing genes to induce a long-term autoimmune attack against the pancreatic β cells, the insulin-producing cells of the pancreatic islets of Langerhans (de Beeck and Eizrik, 2018). 

     When left untreated, juvenile diabetes poses serious health risks. The buildup of sorbitol—a sugar alcohol that is manufactured from glucose—within the eye can result in cataracts and blindness (CDC, 2022).  Excess sorbitol is also associated with blood vessel lesions and gangrene. Other significant health risks for individuals with juvenile diabetes include ketoacidosis, the buildup of acidic ketones that can cause diabetic comas and diminished brain function, and hypoglycemia, otherwise known as “insulin shock,” resulting from an overdose of insulin or the failure to eat and potentially causing nerve damage and death (CDC, 2022). Approximately 1.6 million Americans live with type 1 diabetes, including 200,000 youth. Furthermore, despite significant developments in the treatment of type 1 diabetes, desired glycemic targets are rarely achieved in patients, who continue to face a higher risk of complications and death because of their condition (Herold et. al., 2019). 

     In those who are genetically susceptible to type 1 diabetes, there are two asymptomatic stages prior to the development of overt hyperglycemia, the clinical disease which requires insulin treatment. Stage 1 is characterized by the appearance of autoantibodies targeting pancreatic cells and stage 2 involves dysglycemia, an abnormality in blood sugar stability (Herold et. al., 2019). In this case, metabolic responses to high levels of glucose could be impaired, but other metabolic indexes, such as the level of glycosylated hemoglobin, are normal. During these stages, insulin treatment is not required. The goal of Teplizumab is to delay the development of clinical (stage 3) diabetes in those currently in stages 1 and 2 (Herold et. al., 2019). 

     Teplizumab is an Fc receptor–nonbinding anti-CD3 monoclonal antibody that modifies CD8+ T lymphocytes, which are part of the body’s adaptive immune response and thought to be important effector cells that kill β cells in the pancreas (Herold et. al., 2019). Evidence indicates that type 1 diabetes is initiated by both CD4+ and CD8+ T cells (Li and Qin, 2014). Autoreactive T cells differentiate into effector (CD4+) cells by engaging β-cell antigens on local antigen-presenting cells; these effector CD4+ T cells stimulate other immune cells to target β cells, whereas the cytotoxic CD8+ T cells can directly kill β cells via cell-to-cell contact (Gearty et. al., 2022). The CD3 protein complex is involved in activating both the cytotoxic and helper T-cells (Yang et. al., 2005); thus, the anti-CD3 properties of Teplizumab can inhibit the T cell–mediated damage to β-cells. 

     In the Teplizumab trial, which was conducted over a 7-year period and led by Dr. Kevan Herold of Yale University, patients were randomly assigned to a single 14-day course of Teplizumab or placebo. Seventy-two percent of the participants were under the age of 18, and the majority had siblings with clinical type 1 diabetes, meaning they were at a high risk of developing the condition themselves (Herold et. al., 2019). Furthermore, of the 55 patients who were under 18, 47 had a confirmed dysglycemic oral glucose-tolerance test, one of the hallmarks of stage 2 type 1 diabetes, before undergoing randomization in the trial. Follow-up for progression to clinical type 1 diabetes was performed via oral glucose-tolerance tests every 6 months. The study indicated that a 2-week course of treatment with Teplizumab delayed the diagnosis of clinical type 1 diabetes in high-risk participants: following the completion of the trial, 57% of individuals in the Teplizumab trial group were diabetes-free compared to 28% in the placebo group, with a median delay in the diagnosis of clinical diabetes of 2 years (Figure 1). These results also reinforced prior findings that type 1 diabetes is a T-cell mediated condition and showed that immunomodulation before the onset of clinical type 1 diabetes is a promising development in the treatment of this disease (Herold et. al., 2019).

 

Figure 1. From the time of randomization until the clinical diagnosis of type 1 diabetes, the recipients of the Teplizumab infusion experienced a longer median time until diagnosis than those in the placebo group (adapted from K. C. Herold, et. al.). 

     Given the prevalence of patients with clinical type 1 diabetes, these results of this study are highly promising and a significant step forward in the mitigation of the harmful side effects of this condition. However, there are several areas which, in an effort to make the benefits of this trial widely applicable, require further research. Since the participants in the study were all relatives of patients with type 1 diabetes, it is currently unknown whether the findings can be applied to those who seem to be at risk for the type 1 diabetes and lack first-degree relatives with the condition (Evans-Molina and Oram, 2023). Furthermore, while patients can be carefully screened for the immunological or metabolic markers of preclinical type 1 diabetes in the research setting, a lack of infrastructure prevents a larger-scale screening of the general public and high-risk populations are typically the only groups surveyed for these symptoms (Evans-Molina and Oram, 2023). Finally, despite the promising results of the newly-approved drug, the current cost of treatment presents a significant barrier regarding access to care: one vial of Tzield costs $13,850, amounting to $193,000 over the 14-day infusion (Rodriguez, n.d.).  The exorbitant sum is not surprising, given the high cost of insulin medications and their widely-reported underuse (Herkert et. al., 2019). As a result, further efforts must be taken to ensure that those who are eligible for this new and potentially life-saving medication are able to access it. 

 

Sources: 

CDC. (2022, November 3). Prevent diabetes complications. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/managing/problems.html 

Commissioner, O. of the. (2022, November 18). FDA approves first drug that can delay onset of type 1 diabetes. FDA. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-can-delay-onset-type-1-diabetes 

de Beeck, A. O., & Eizirik, D. L. (2016). Viral infections in type 1 diabetes mellitus—Why the β cells? Nature Reviews. Endocrinology, 12(5), 263–273. https://doi.org/10.1038/nrendo.2016.30 

Dolgin, E. (2023). How a pioneering diabetes drug offers hope for preventing autoimmune disorders. Nature, 614(7948), 404–406. https://doi.org/10.1038/d41586-023-00400-x 

Evans-Molina, C., & Oram, R. A. (2023). Teplizumab approval for type 1 diabetes in the USA. The Lancet Diabetes & Endocrinology, 11(2), 76–77. https://doi.org/10.1016/S2213-8587(22)00390-4 

Gearty, S. V., Dündar, F., Zumbo, P., Espinosa-Carrasco, G., Shakiba, M., Sanchez-Rivera, F. J., Socci, N. D., Trivedi, P., Lowe, S. W., Lauer, P., Mohibullah, N., Viale, A., DiLorenzo, T. P., Betel, D., & Schietinger, A. (2022). An autoimmune stem-like CD8 T cell population drives type 1 diabetes. Nature, 602(7895), 156–161.  https://doi.org/10.1038/s41586-021-04248-x 

Herkert, D., Vijayakumar, P., Luo, J., Schwartz, J. I., Rabin, T. L., DeFilippo, E., & Lipska, K. J. (2019). Cost-related insulin underuse among patients with diabetes. JAMA Internal Medicine, 179(1), 112–114. https://doi.org/10.1001/jamainternmed.2018.5008 

Herold, K. C., Bundy, B. N., Long, S. A., Bluestone, J. A., DiMeglio, L. A., Dufort, M. J., Gitelman, S. E., Gottlieb, P. A., Krischer, J. P., Linsley, P. S., Marks, J. B., Moore, W., Moran, A., Rodriguez, H., Russell, W. E., Schatz, D., Skyler, J. S., Tsalikian, E., Wherrett, D. K., … Greenbaum, C. J. (2019). An anti-cd3 antibody, teplizumab, in relatives at risk for type 1 diabetes. New England Journal of Medicine, 381(7), 603–613. https://doi.org/10.1056/NEJMoa1902226 

History of diabetes: Early science, early treatment, insulin. (2020, June 17). https://www.medicalnewstoday.com/articles/317484 

Li, M., Song, L.-J., & Qin, X.-Y. (2014). Advances in the cellular immunological pathogenesis of type 1 diabetes. Journal of Cellular and Molecular Medicine, 18(5), 749–758. https://doi.org/10.1111/jcmm.12270 

Masharani, U. B., & Becker, J. (2010). Teplizumab therapy for type 1 diabetes. Expert Opinion on Biological Therapy, 10(3), 459–465. https://doi.org/10.1517/14712591003598843 

Rodriguez, A. (n.d.). FDA approves first treatment that delays Type 1 diabetes. Why it could be “game changing.” USA TODAY. Retrieved April 2, 2023, from https://www.usatoday.com/story/news/health/2022/11/18/fda-approves-teplizumab-delays-onset-diabetes/10721707002/ 

Yang, H., Parkhouse, R. M. E., & Wileman, T. (2005). Monoclonal antibodies that identify the CD3 molecules expressed specifically at the surface of porcine γδ-T cells. Immunology, 115(2), 189–196. https://doi.org/10.1111/j.1365-2567.2005.02137.x 



Ferroptosis-Related LncRNAs Found in Colon Cancer

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Colon cancer is the malignant growth of tumor cells in the large intestine. It is the third most common cancer and has the fourth highest death rate out of all types of cancer. Current treatments are limited, as they can be painful for the patient by killing healthy cells alongside cancer cells, and there is no guarantee that the treatments will completely eliminate all cancer cells.

Ferroptosis is a type of programmed cell death caused by high intracellular iron levels, which in turn activates cell death pathways. It differs from traditional cell death, apoptosis, since it is triggered by high iron intracellular concentrations. Rather than affecting the cell’s genetic material or plasma membrane, ferroptosis causes cell death through shrinking mitochondria and increasing mitochondrial membrane density. 

Long noncoding RNAs (lncRNAs) are a type of RNA that does not code for protein synthesis. While they don’t code for protein, lncRNAs have other functions, such as controlling gene regulation through unwinding chromatin for transcription and consequent translation and RNA processing. In regards to cancer, lncRNAs have been proven to contribute to proliferation, metastasis, and reproduction of malignant cells, and can therefore be indicators of the disease and its prognosis. Ferroptosis-related lncRNAs (FRLs), which influence the titular cellular process, in particular have been identified as possible indicators of cancer prognosis, yet not much is known.

The purpose of Wu et al (2022)’s study was to determine the molecular functions of FRLs in colon cancer. In this experiment, RNA sequencing data and genes related to ferroptosis were obtained from databases. In addition, human intestinal epithelial cells and various human colon cancer cell lines and colon cancer cell samples taken from patients at the Gastrointestinal Surgery Department of Xiangya 3rd Hospital were tested for cell composition via CIBERSORT, and had their RNA extracted for qRT-PCR and analysis. Malondialdehyde (MDA), Fe2+, reactive oxygen species (ROS), and IC50 levels of various drugs were also tested in these cells, as they all have a role in controlling ferroptosis and the consequent cell death. It was found that 26 different FRLs had some relationship to colon cancer, most of them being risk genes, genes specifically associated with the onset of cancer. Two lncRNAs, AP003555.1 and AC005841.1, had a significant relationship to colon cancer, as seen by the increased MDA, Fe2+, and ROS levels in cells with those two lncRNAs silenced and their knockout inhibiting cell proliferation.

 

Figure 1: Construction and validation of the ferroptosis-related lncRNA signature model in the training cohort, validation and overall groups. (A–C) The distribution of the risk scores and the distributions of overall survival status and risk score in the training, validation and overall groups. (D–F) The Kaplan–Meier curves for survival status and survival time in the training, validation and overall groups. (G–I) The receiver operating characteristic (ROC) curve shows the potential of the prognostic ferroptosis-related lncRNAs signature in predicting 1-, 2-, and 3-year overall survival (OS) in the training, validation and overall groups. (J–L) AUC of ROC curves comparing the prognostic accuracy of the risk score and other prognostic factors in the training, validation and overall groups.

 

Sources

Li, Jie, Feng Cao, He-liang Yin, Zi-jian Huang, Zhi-tao Lin, Ning Mao, Bei Sun & Gang Wang (2020), Ferroptosis: past, present and future, Cell Death and Disease, Volume 11, Issue 2, Page 88

 

Mármol, Inés, Cristina Sánchez-de-Diego, Alberto Pradilla Dieste, Elena Cerrada, and María Jesús Rodriguez Yoldi (2017) Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer, International Journal of Molecular Sciences, Volume 18, Issue 1, Pages 197. 

 

Qian, Yuchen, Lei Shi, and Zhong Luo (2020) Long Non-coding RNAs in Cancer: Implications for Diagnosis, Prognosis, and Therapy, Frontiers in Medicine

 

Wu, Zhiwei, Zhixing Lu1, Liang Li, Min Ma, Fei Long, Runliu Wu, Lihua Huang, Jing Chou, Kaiyan Yang, Yi Zhang, Xiaorong Li, Gui Hu, Yi Zhang, and Changwei Lin (2022) Identification and Validation of Ferroptosis-Related LncRNA Signatures as a Novel Prognostic Model for Colon Cancer, Sec. Cancer Immunity and Immunotherapy, Volume 12

 

Yao, Run-Wen, Yang Wang & Ling-Ling Chen (2019) Cellular functions of long noncoding RNAs, Nature Cell Biology, Volume 21, Issue 5, Pages 542-551

 

Yu, Haitao, Pengyi Guo, Xiaozai Xie, Yi Wang, and Gang Chen (2017) Ferroptosis, a new form of cell death, and its relationships with tumourous diseases, Journal of Cellular and Molecular Medicine, Volume 21, Issue 4, Pages 648–657

 

Zhang, Kaiming, Liqin Ping, Tian Du, Gehao Liang, Yun Huang, Zhiling Li, Rong Deng, and Jun Tang (2021) A Ferroptosis-Related lncRNAs Signature Predicts Prognosis and Immune Microenvironment for Breast Cancer, Frontiers in Molecular Bioscience

Targeting the MYC Proto-Oncogene, BHLH Transcription Factor (MYC) interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

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According to the World Health Organization (WHO), in 2020, cancer was responsible for the deaths of almost ten million people worldwide. Such statistics place cancer as a leading cause of death worldwide, second to heart disease. Cancer is when a series of mutations occurs in a cell, resulting in uncontrollable cellular division that eventually leads to interference in the function of vital organs. One of the more common types of cancer is lymphoma, the malignant growth of tumor cells of the lymphatic system. Current treatments for lymphoma include radiation therapy and chemotherapy, but these treatments can have drawbacks: they can be painful for the patient by killing healthy cells alongside cancer cells, and there is no guarantee that the treatments will completely eliminate all cancer cells. With a treatment that specifically targets the malignant cells, we can better treat lymphoma as well as other types of cancers.

MYC is a gene that when expressed in moderation, is responsible for maintaining cellular functions such as the cell cycle, apoptosis (programmed cell death), and protein production. It does so through “recruiting” enzymes such as histone acetyltransferases p300/CBP or the histone deacetylases (HDACs) to regulate expression of other genes. However, dysregulation of MYC expression can cause these cell functions to lose control as HDACs will have no means of regulation, genes to aid in the increase in cellular processes and pathways that would lead to the cell to become cancerous. MYC has also been found to be overexpressed in other types of cancers, such as uterine leiomyosarcoma.

The purpose of this project was to determine the effect of HDAC6 inhibitor Marbostat-100 (M-100) on oncogenic MYC expression levels in mice with MYC-induced aggressive B-cell lymphoma. In this experiment, mice with B-cell lymphoma as well as human B cell lymphoma cells were treated with various concentrations of M-100. It was found that all experimental concentrations of M-100 caused HDAC inhibition and reduction of MYC expression and protein levels, consequently inducing apoptosis in the murine and human cancer cells and statistically significantly increasing the mice’s survival rates. Therefore, MYC inhibition could be a possible therapeutic treatment for cancers like B-cell lymphoma.

Sources

https://www.nature.com/articles/s41388-022-02450-3

https://www.who.int/news-room/fact-sheets/detail/cancer

https://www.cancer.gov/about-cancer/treatment/types

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