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Science

Biological ChatGPT: Rewriting Life With Evo 2

May 4, 2025 by Jenna Lam

What makes life life? Is there underlying code that, when written or altered, can be used to replicate or even create life? On February 19th 2025, scientists from Arc Institute, NVIDIA, Stanford, Berkeley, and UC San Francisco released Evo 2, a generative machine learning model that may help answer these questions. Unlike its precursor Evo 1, which was released a year earlier, Evo 2 is trained on genomic data of eukaryotes as well as prokaryotes. In total, it is trained on 9.3 trillion nucleotides from over 130,000 genomes, making it the largest AI model in biology. You can think of it as ChatGPT for creating genetic code—only it “thinks” in the language of DNA rather than human language, and it is being used to solve the most pressing health and disease challenges (rather than calculus homework).

Computers, defined broadly, are devices that store, process, and display information. Digital computers, such as your laptop or phone, function based on binary code—the most basic form of computer data composed of 0s and 1s, representing a current that is on or off. Evo 2 centers around the idea that DNA functions as nature’s “code,” which, through protein expression and organismal development, creates “computers” of life. Rather than binary, organisms function according to genetic code, made up of A, T, C, G, and U–the five major nucleotide bases that constitute DNA and RNA.

Although Evo 2 can potentially design code for artificial life, it has not yet designed an entire genome and is not being used to create artificial organisms. Instead, Evo 2 is being used to (1) predict genetic abnormalities and (2) generate genetic code.

11 Functions of Evo 2 in biology at the cellular/organismal, protein, RNA, and epigenome levels.
Functions of Evo 2 at different levels. Adapted from https://www.biorxiv.org/content/10.1101/2025.02.18.638918v1.full

Accurate over 90% of the time, Evo 2 can predict which BRCA1 (a gene central to understanding breast cancer) mutations are benign versus potentially pathogenic. This is big, since each gene is composed of hundreds and thousands of nucleotides, and any mutation in a single nucleotide (termed a Single Nucleotide Variant, or SNV) could have drastic consequences for the protein structure and function. Thus, being able to computationally pinpoint dangerous mutations reduces the amount of time and money spent testing each mutation in a lab, and paves the way for developing more targeted drugs.

Secondly, Evo 2 can design genetic code for highly specialized and controlled proteins which provide many fruitful possibilities for synthetic biology (making synthetic molecules using biological systems), from pharmaceuticals to plastic-degrading enzymes. It can generate entire mitochondrial genomes, minimal bacterial genomes, and entire yeast chromosomes–a feat that had not been done yet.

A notable perplexity of eukaryotic genomes is their many-layered epigenomic interactions: the complex power of the environment in controlling gene expression. Evo 2 works around this by using models of epigenomic structures, made possible through inference-time scaling. Put simply, inference-time scaling is a technique developed by NVIDIA that allows AI models to take time to “think” by evaluating multiple solutions before selecting the best one.

How is Evo 2 so knowledgeable, despite only being one year old? The answer lies in deep learning.

Just as in Large Language Models, or LLMs (think: ChatGPT, Gemini, etc.), Evo 2 decides what genes should look like by “training” on massive amounts of previously known data. Where LLMs train on previous text, Evo 2 trains on entire genomes of over 130,000 organisms. This training—the processing of mass amounts of data—is central to deep learning. In training, individual pieces of data called tokens are fed into a “neural networks”—a fancy name for a collection of software functions that are communicate data to one another. As their name suggests, neural networks are modeled after the human nervous system, which is made up of individual neurons that are analogous to software functions. Just like brain cells, “neurons” in the network can both take in information and produce output by communicating with other neurons. Each neural network has multiple layers, each with a certain number of neurons. Within each layer, each neuron sends information to every neuron in the next layer, allowing the model to process and distill large amounts of data. The more neurons involved, the more fine-tuned the final output will be. 

This neural network then attempts to solve a problem. Since practice makes perfect, the network attempts the problem over and over; each time, it strengthens the successful neural connections while diminishing others. This is called adjusting parameters, which are variables within a model that can be adjusted, dictating how the model behaves and what it produces. This minimizes error and increases accuracy. Evo 2 was trained with 7b and 40b parameters to have a 1 million token context window, meaning the genomic data was fed through many neurons and fine-tuned many times.

Example neural network
Example neural network modeled using tensorflow adapted from playground.tensorflow.org

The idea of anyone being able to create genetic code may spark fear; however, Evo 2 developers have prevented the model from returning productive answers to inquiries about pathogens, and the data set was carefully chosen to not include pathogens that infect humans and complex organisms. Furthermore, the positive possibilities of Evo 2 usage are likely much more than we are currently aware of: scientists believe Evo 2 will advance our understanding of biological systems by generalizing across massive genomic data of known biology. This may reveal higher-level patterns and unearth more biological truths from a birds-eye view.

It’s important to note that Evo 2 is a foundational model, emphasizing generalist capabilities over task-specific optimization. It was intended to be a foundation for scientists to build upon and alter for their own projects. Being open source, anyone can access the model code and training data. Anyone (even you!) can even generate their own strings of genetic code with Evo Designer. 

Biotechnology is rapidly advancing. For example, DNA origami allows scientists to fold DNA into highly specialized nanostructures of any shape–including smiley faces and China–potentially allowing scientists to use DNA code to design biological robots much smaller than any robot we have today. These tiny robots can target highly specific areas of the body, such as receptors on cancer cells. Evo 2, with its designing abilities, opens up many possibilities for DNA origami design. From gene therapy, to mutation-predictions, to miniature smiley faces, it is clear that computation is becoming increasingly important in understanding the most obscure intricacies of life—and we are just at the start.

 

Garyk Brixi, Matthew G. Durrant, Jerome Ku, Michael Poli, Greg Brockman, Daniel Chang, Gabriel A. Gonzalez, Samuel H. King, David B. Li, Aditi T. Merchant, Mohsen Naghipourfar, Eric Nguyen, Chiara Ricci-Tam, David W. Romero, Gwanggyu Sun, Ali Taghibakshi, Anton Vorontsov, Brandon Yang, Myra Deng, Liv Gorton, Nam Nguyen, Nicholas K. Wang, Etowah Adams, Stephen A. Baccus, Steven Dillmann, Stefano Ermon, Daniel Guo, Rajesh Ilango, Ken Janik, Amy X. Lu, Reshma Mehta, Mohammad R.K. Mofrad, Madelena Y. Ng, Jaspreet Pannu, Christopher Ré, Jonathan C. Schmok, John St. John, Jeremy Sullivan, Kevin Zhu, Greg Zynda, Daniel Balsam, Patrick Collison, Anthony B. Costa, Tina Hernandez-Boussard, Eric Ho, Ming-Yu Liu, Thomas McGrath, Kimberly Powell, Dave P. Burke, Hani Goodarzi, Patrick D. Hsu, Brian L. Hie (2025). Genome modeling and design across all domains of life with Evo 2. bioRxiv preprint doi: https://doi.org/10.1101/2025.02.18.638918.

 

Filed Under: Biology, Computer Science and Tech, Science Tagged With: AI, Computational biology

Motor Brain-Computer Interface Reanimates Paralyzed Hand

May 4, 2025 by Mauricio Cuba Almeida

Over five million people in the United States live with paralysis (Armour et al., 2016), representing a large portion of the US population. Though the extent of paralysis varies from person-to-person, most with paralysis experience unmet needs that subtract from their overall life satisfaction. A survey of those with paralysis revealed “peer support, support for family caregivers, [and] sports activities” as domains where individuals with paralysis experienced less fulfillment—with lower household income predicting a higher likelihood of unmet needs (Trezzini et al., 2019). Consequently, individuals with sufficient motor function have turned to video games as a means to meet some of these needs, as video games are sources of recreation, artistic expression, social connectedness, and enablement (Cairns et al., 2019). Oftentimes, however, these individuals are limited by what games they are able to engage with—as they often “avoid multiplayer games with able-bodied players” (Willsey et al., 2025). Thus, Willsey and colleagues (2025) explore brain-computer interfaces as a valuable potential solution for restoring more sophisticated motor control of not just video games, but of digital interfaces used for social networking or remote work.

Brain-computer interfaces (BCIs) are devices that read and analyze brain activity in order to produce commands that are then relayed to output devices, with the intent of restoring useful bodily function (Shih et al., 2012). Willsey et al. explain how current motor BCIs are unable to distinguish between the brain activity corresponding to the movement of different fingers, so BCIs have instead relied on detecting the more general movement of grasping a hand (where the fingers are treated as one group). This limits BCIs to controlling fewer dimensions of an instrument: just being able to control a computer’s point-and-click cursor control as compared to typing on a computer. Hence, Willsey et al. seek to expand BCIs to allow for greater object manipulation—implementing finger decoding that will differentiate the brain output signals for different fingers, allowing for “typing, playing a musical instrument or manipulating a multieffector digital interface such as a video game controller.” Improving BCIs would also involve continuous finger decoding, as finger decoding has mostly been done retrospectively, where finger signals are not classified and read until after the brain data is analyzed. 

Willsey et al. developed a BCI system that is capable of decoding three independent finger groups (with the thumb decoded into two dimensions), allowing for four total dimensions of control. By training on the participant’s brain over nine days as they attempt to move individual fingers, the BCI can learn to distinguish brain regions that correspond to finger movements. These four dimensions of control are well reflected in a quadcopter simulation, where a patient with an implemented BCI is able to manipulate a virtual hand to fly a quadcopter drone through various hoops of an obstacle course. Many applications, even beyond video games, are apparent. These finger controls can be extended to a robotic hand or could reanimate the paralyzed limb. 

Finger movement is decoded into three distinct groups (differentiated by color).
Finger movement is decoded into three distinct groups (differentiated by color; Willsey et al., 2025).
Participant navigates quadcopter through a hoop through decoded finger movements.
Participant navigates quadcopter through a hoop through decoded finger movements (Willsey et al., 2025).

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The patient’s feelings of social connectedness, enablement and recreation were greatly improved. Willsey et al. note how the patient often looked forward to the quadcopter sessions, frequently “[asking] when the next quadcopter session was.” Not only did the patient find enjoyment in controlling the quadcopter, but they found training not to be tedious and the controls intuitive. To date, this finger BCI proves to be the most capable kind of motor BCI, and will serve as a valuable model for non-motor BCIs, like Brain2Char, a system for decoding text from brain recordings.

However, BCIs raise significant ethical considerations that must be addressed alongside their development. Are users responsible for all outputs from a BCI, even with outputs unintended? Given that BCIs decode brain signaling and train on data from a very controlled setting, there is always the potential for natural “noise” that may upset a delicate BCI model. Ideally, BCIs are trained on a participant’s brain in a variety of different circumstances to mitigate these errors. Furthermore, BCIs may further stigmatize motor disabilities by encouraging individuals toward restoring “normal” abilities. I am particularly concerned about the cost of this technology. As with most new clinical technologies, implementation is expensive and ends up pricing out individuals with lower socioeconomic statuses. These are often the individuals that face the greatest need for technologies like BCI. As mentioned earlier, lower household income predicts more unmet needs for individuals with paralysis. Nonetheless, so long as they are developed responsibly and efforts are made to ensure their affordability, there is great promise in motor BCIs.

 

References

Armour, B. S., Courtney-Long, E. A., Fox, M. H., Fredine, H., & Cahill, A. (2016). Prevalence and Causes of Paralysis—United States, 2013. American Journal of Public Health, 106(10), 1855–1857. https://doi.org/10.2105/ajph.2016.303270

Cairns, P., Power, C., Barlet, M., Haynes, G., Kaufman, C., & Beeston, J. (2019). Enabled players: The value of accessible digital games. Games and Culture, 16(2), 262–282. https://doi.org/10.1177/1555412019893877

Shih, J. J., Krusienski, D. J., & Wolpaw, J. R. (2012). Brain-Computer interfaces in medicine. Mayo Clinic Proceedings, 87(3), 268–279. https://doi.org/10.1016/j.mayocp.2011.12.008

Trezzini, B., Brach, M., Post, M., & Gemperli, A. (2019). Prevalence of and factors associated with expressed and unmet service needs reported by persons with spinal cord injury living in the community. Spinal Cord, 57(6), 490–500. https://doi.org/10.1038/s41393-019-0243-y

Willsey, M. S., Shah, N. P., Avansino, D. T., Hahn, N. V., Jamiolkowski, R. M., Kamdar, F. B., Hochberg, L. R., Willett, F. R., & Henderson, J. M. (2025). A high-performance brain–computer interface for finger decoding and quadcopter game control in an individual with paralysis. Nature Medicine. https://doi.org/10.1038/s41591-024-03341-8

Filed Under: Computer Science and Tech, Psychology and Neuroscience, Science

Computer Vision Ethics

May 4, 2025 by Madina Sotvoldieva

Computer vision (CV) is a field of computer science that allows computers to “see” or, in more technical terms, recognize, analyze, and respond to visual data, such as videos and images. CV is widely used in our daily lives, from something as simple as recognizing handwritten text to something as complex as analyzing and interpreting MRI scans. With the advent of AI in the last few years, CV has also been improving rapidly. However, just like any subfield of AI nowadays, CV has its own set of ethical, social, and political implications, especially when used to analyze people’s visual data.

Although CV has been around for some time, there is limited work on its ethical limitations in the general AI field. Among the existing literature, authors categorized six ethical themes, which are espionage, identity theft, malicious attacks, copyright infringement, discrimination, and misinformation [1]. As seen in Figure 1, one of the main CV applications is face recognition, which could also lead to issues of error, function creep (the expansion of technology beyond its original purposes), and privacy. [2].

Computer Vision technologies related to Identity Theft
Figure 1: Specific applications of CV that could be used for Identity Theft.

To discuss CV’s ethics, the authors of the article take a critical approach to evaluating the implications through the framework of power dynamics. The three types of power that are analyzed are dispositional, episodic, and systemic powers [3]. 

Dispositional Power

Dispositional power is defined as the ability to bring out a significant outcome [4]. When people gain that power, they feel empowered to explore new opportunities, and their scope of agency increases (they become more independent in their actions) [5]. However, CV can threaten this dispositional power in several ways, ultimately reducing people’s autonomy. 

One way CV disempowers people is by limiting their information control. Since CV works with both pre-existing and real-time camera footage, people might be often unaware that they are being recorded and often cannot avoid that. This means that technology makes it hard for people to control the data that is being gathered about them, and protecting their personal information might get as extreme as hiding their faces. 

Apart from people being limited in controlling what data is being gathered about them, advanced technologies make it extremely difficult for an average person to know what specific information can be retrieved from visual data. Another way CV might disempower people of following their own judgment is through communicating who they are for them (automatically inferring people’s race, gender, and mood), creating a forced moral environment (where people act from fear of being watched rather than their own intentions), and potentially leading to over-dependence on computers (e.g., relying on face recognition for emotion interpretations). 

In all these and other ways, CV undermines the foundation of dispositional power by limiting people’s ability to control their information, make independent decisions, express themselves, and act freely.

Episodic Power

Episodic power, or as often referred to as power-over, defines the direct exercise of power by one individual or group over another. CV can both give new power or improve the efficiency of existing one [6]. While this isn’t always a bad thing (for example, parents watching over children), problems arise when CV makes that control too invasive or one-sided—especially in ways that limit people’s freedom to act independently.

 With CV taking security cameras to the next level, opportunities such as baby-room monitoring or fall detection for elderly people open up to us. However, it also leads to the issues of surveillance automation, which can lead to over-enforcement in scales as small as private individuals to bigger corporations (workplaces, insurance companies, etc.). Another power dynamic shifts that need to be considered, for example, when the smart doorbells show far beyond the person at the door and might violate a neighbor’s privacy by creating peer-to-peer surveillance. 

These examples show that while CV may offer convenience or safety, it can also tip power balances in ways that reduce personal freedom and undermine one’s autonomy.

Systemic Power

Systematic power is not viewed as an individual exercise of power, but rather a set of societal norms and practices that affect people’s autonomy by determining what opportunities people have, what values they hold, and what choices they make. CV can strengthen the systematic power by making law enforcement more efficient through smart cameras and increase businesses’ profit through business intelligence tools. 

However, CV can also reinforce the pre-existing systematic societal injustices. One example of that might be flawed facial recognition, when the algorithms are more likely to recognize White people and males [7], which led to a number of false arrests. This might lead to people receiving unequal opportunities (when biased systems are used for hiring process), or harm their self-worth (when falsely recognized as a criminal). 

Another matter of systematic power is the environmental cost of CV. AI systems rely on vast amounts of data, which requires intensive energy for processing and storage. As societies become increasingly dependent on AI technologies like CV, those trying to protect the environment have little ability to resist or reshape these damaging practices. The power lies with tech companies and industries, leaving citizens without the means to challenge the system. When the system becomes harder to challenge or change, that’s when the ethical concerns regarding CV arise.

Conclusion

Computer Vision is a powerful tool that keeps evolving each year. We already see numerous applications of it in our daily lives, starting from the self-checkouts in the stores and smart doorbells to autonomous vehicles and tumor detections. With the potential that CV holds in improving and making our lives safer, there are a number of ethical limitations that should be considered. We need to critically examine how CV affects people’s autonomy, might cause one-sided power dynamics, and reinforces societal prejudices. As we are rapidly transitioning into the AI-driven world, there is more to come in the field of computer vision. However, in the pursuit of innovation, we should ensure the progress does not come at the cost of our ethical values.

References:

[1] Lauronen, M.: Ethical issues in topical computer vision applications. Information Systems, Master’s Thesis. University of Jyväskylä. (2017). https://jyx.jyu.fi/bitstream/handle/123456789/55806/URN%3aNBN%3afi%3ajyu-201711084167.pdf?sequence=1&isAllowed=y

[2] Brey, P.: Ethical aspects of facial recognition systems in public places. J. Inf. Commun. Ethics Soc. 2(2), 97–109 (2004). https:// doi.org/10.1108/14779960480000246

[3] Haugaard, M.: Power: a “family resemblance concept.” Eur. J. Cult. Stud. 13(4), 419–438 (2010)

[4] Morriss, P.: Power: a philosophical analysis. Manchester University Press, Manchester, New York (2002)

[5] Morriss, P.: Power: a philosophical analysis. Manchester University Press, Manchester, New York (2002)

[6] Brey, P.: Ethical aspects of facial recognition systems in public places. J. Inf. Commun. Ethics Soc. 2(2), 97–109 (2004). https://doi.org/10.1108/14779960480000246

[7] Buolamwini, J., Gebru, T.: Gender shades: intersectional accuracy disparities in commercial gender classification. Conference on Fairness, Accountability, and Transparency, pp. 77–91 (2018) Coeckelbergh, M.: AI ethics. MIT Press (2020)

Filed Under: Computer Science and Tech, Science Tagged With: AI, AI ethics, artificial intelligence, Computer Science and Tech, Computer Vision, Ethics, Technology

Identification of Underlying Apoptotic Pathways in MCF-7 Breast Cancer Cells via CRISPRa Upregulation of HtrA2/Omi

December 20, 2024 by Avery Park

This experiment investigated a possible candidate for cancer treatment utilizing a cell’s own function for programmed cell death. The purpose of this study was to determine if upregulation of the apoptotic gene HtrA2/Omi in breast cancer cells would lead to increased apoptosis in the cells. Previous literature had described upregulation of apoptotic pathways as a possible viable mechanism for cancer treatment. However, this study did not find significant results to support these claims. 

Breast cancer, one of the most prevalent forms of cancer in the world, disproportionately affects women in the United States. On average, 13 percent of women in the United States will be diagnosed with breast cancer at some point during their lifetime (Breast Cancer Facts and Statistics 2023). Every year, 42,000 women die from breast cancer in the United States, with 240,000 more diagnosed with breast cancer (Basic Information About Breast Cancer 2023). 

Cells undergo a highly regulated process of programmed cell death called apoptosis that allows for natural development and growth of the organism. Through apoptosis, organisms are able to destroy surplus, infected, and damaged cells. Cancerous tumors develop when the apoptosis function of a cell is not working properly, resulting in a malignant cell that can grow and divide uncontrollably into a tumor. As apoptosis pathways can be induced non-surgically, it is a highly effective method used to control or terminate malignant cancer cells. By utilizing the cell’s own mechanism for death, research for cancer treatment has identified apoptosis as a way to target malignant tumors (Pfeffer et al., 2018). 

Research has shown that apoptosis is induced by overexpressing certain genes. HtrA2/Omi is a gene that induces apoptosis when overexpressed in the cell. When released from the mitochondria, HtrA2 inhibits the function of an apoptosis inhibitor, effectively inducing cell death (Suzuki et al., 2001). These data suggest that modulating and upregulating HtrA2 expression shows promising findings in enhancing apoptosis in breast cancer. 

CRISPR-Cas9 is a type of cellular biotechnology which can be used to study the manipulation of genomes by either adding, deleting, or altering genetic material in specific locations. This tool can be used to overexpress the HtrA2 gene in order to induce cell death. The process of CRISPR-Cas9 involves using sgRNA (a single guide RNA) with an enzyme to act as a gene-editing tool and introduce mutations into a desired target sequence in the genome. In order to modulate the HtrA2 gene, this experiment will require CRISPRa, a variant of CRISPR that uses a protein (dCas9) and transcriptional effector. The sgRNA navigates to the genome locus, guiding the dCas9. The dCas9 is unable to make a cut, so the effector instead activates the desired downstream gene expression (“Chapter 2: CRISPRa,” n.d.). This experiment will use CRISPRa technology to upregulate the HtrA2/Omi gene, which will inhibit the X chromosome-linked inhibitor of apoptosis, inducing either caspase-dependent cell death or Caspase-3 independent cell death in MCF-7 cells.

The pilot study for this experiment was conducted to determine the optimal level of Lipofectamine – which is a reagent that can be used for an efficient transfection without causing the cells to undergo apoptosis. The Lipofectamine concentration was varied to identify the fold change it would create in the expression of the target gene, HtrA2/Omi. After statistical analyses, researchers found no statistically significant correlation between the HtrA2/Omi gene expression and the Lipofectamine concentration in this experiment.

Fig. 1. After the transfection, qPCR was conducted on the control, 100% Lipofectamine, 75% Lipofectamine with sgRNA, and 75% Lipofectamine without sgRNA. The average Ct values were calculated and graphed.

Overall, the results from conducting quantitative PCR (qPCR), which shows how much of the HtrA2 was transfected, demonstrated extreme variance, indicating that there may have been errors that significantly affected these results. One possible error was that qPCR was conducted as cells were undergoing apoptosis, which would skew the results as mRNA is destroyed in cells as they die, leaving fragments behind. Another error observed throughout this experiment was high cell confluence (number of cells covering the adherent surface). Much of this experiment was conducted with cells at 100% or almost 100% confluence, which means it is possible that the concentrations of Lipofectamine that were predicted to cause efficient transfection did not work because the reagent could not enter the cells. Ultimately, it was found that a cell seeding concentration of 1*104 cells/mL worked best with regard to transformation, but the experiment still did not yield statistically significant results.

Fig. 2. For the pilot experiment, mCherry plasmid was transfected in MCF-7 cells. The following ZOE images showed the images of MCF-7 before transfection under different fluorescence as well as the merged image of both green and red fluorescence.

 

References

ATCC. (n.d.). MCF-7. ATCC. Retrieved November 17, 2021, from https://www.atcc.org/products/htb-22

Breast cancer facts and statistics, 2023. (n.d.). https://www.breastcancer.org/facts-statistics

Siegel, R. L., Miller, K. D., Fuchs, H., & Jemal, A. (2021). Cancer Statistics, 2021. CA: A Cancer Journal for Clinicians, 71(1), 7–33. https://doi.org/10.3322/caac.21654

Basic Information About Breast Cancer, 2023. https://www.cdc.gov/cancer/breast/basic_info

Pfeffer, C. M., & Singh, A. T. K. (2018). Apoptosis: A Target for Anticancer Therapy. International Journal of Molecular Sciences, 19(2), 448. https://doi.org/10.3390/ijms19020448

Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell. 2001 Sep;8(3):613-21. doi: 10.1016/s1097-2765(01)00341-0. PMID: 11583623.

Hu, Q., Myers, M., Fang, W., Yao, M., Brummer, G., Hawj, J., Smart, C., Berkland, C., & Cheng, N. (2019). Role of ALDH1A1 and HTRA2 expression in CCL2/CCR2-mediated breast cancer cell growth and invasion. Biology open, 8(7), bio040873. https://doi.org/10.1242/bio.040873

Camarillo, Ignacio G., et al. “4 – Low and High Voltage Electrochemotherapy for Breast Cancer:

An in Vitro Model Study.” ScienceDirect, Woodhead Publishing, 1 Jan. 2014. www.sciencedirect.com/science/article/abs/pii/B9781907568152500042.

Rouhimoghadam M, Safarian S, Carroll JS, Sheibani N, Bidkhori G. Tamoxifen-Induced Apoptosis of MCF-7 Cells via GPR30/PI3K/MAPKs Interactions: Verification by ODE Modeling and RNA Sequencing. Front Physiol. 2018 Jul 11;9:907. doi: 10.3389/fphys.2018.00907. PMID: 30050469; PMCID: PMC6050429.

Mooney, L. M., Al-Sakkaf, K. A., Brown, B. L., & Dobson, P. R. (2002). Apoptotic mechanisms in T47D and MCF-7 human breast cancer cells. British journal of cancer, 87(8), 909–917. https://doi.org/10.1038/sj.bjc.6600541

Suzuki, Y., Takahashi-Niki, K., Akagi, T. et al. Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways. Cell Death Differ 11, 208–216 (2004). https://doi.org/10.1038/sj.cdd.440134

Chapter 2: CRISPRa and CRISPRi. (n.d.). In A Comprehensive Guide on CRISPR Methods. https://www.synthego.com/guide/crispr-methods/crispri-

Filed Under: Biology, Chemistry and Biochemistry, Science

Uncovering Our Inner Overlord: How DEADbox ATPases Built Their Empire Off Regulating RNA Maturation

December 9, 2024 by Lia Scharnau

Do you remember the simple days? Recall your fond memories of learning about organelles in introductory biology. This is where we learned our favorite biology fact, that the mitochondria is the powerhouse of the cell. Sigh, those were the days. Well, recently the field of biology has discovered a new type of organelles in the cell; membraneless organelles! They are formed through liquid-liquid phase separation (LLPS). If you imagine the droplets formed when you combined oil and water, that’s a form of LLPS. Membraneless organelles rely on LLPS for rapid and reversible cell compartmentalization.

In 2019, researcher Maria Hondele and her team took particular interest in investigating membraneless organelles, focusing specifically on DEAD-box ATPases (DDX) and their role in regulating them. DEAD-box ATPases keep ribonucleoprotein complexes from misfolding or building up over time. The role of DDX-mediated phase separation in compartmentalizing RNA processing is a rare cellular organization conserved across prokaryotes and eukaryotes over time (Hondele 2022). Highly conserved proteins have withstood the test of evolution and have continued to be passed down through generations without significant mutation. Hondele looked specifically at RNA-dependent DEAD-box ATPases because they regulate the RNA movement in and out of the membraneless organelles.

This investigation focused on  Dhh1, which is a DEAD-box ATPase specific to Saccharomyces cerevisiae (yeast). A wide range of assays were run to systematically determine the conditions required for the in vitro formation of Dhh1 liquid droplets. Liquid droplets are formed through LLPs and are indicators of membraneless organelles. Hondele found that liquid droplet formation is a fickle process that requires specific amounts of RNA and ATP to be added to the system and the cell environment to be at a low pH and salt concentration (Hondele 2019). Additionally from a DNA standpoint, the DDX itself must have low-complexity domain tails which means the ends of the proteins do not consist of a large variety of amino acids (Hondele 2019). 

After the initial investigation of the DDX ATPase and how it runs controls Dhh1 droplet formation, Hondele, and her team investigated DDX ATPase’s role in the regulation of RNA. Through a series of experiments, they found that DDX ATPases have played an extensive role in RNA regulation. The DDX ATPases can actually control the RNA maturation steps so they become spatially and temporally separated in distinct membraneless organelles (Hondele 2019). This means that each membraneless organelle may specialize in one step of the RNA maturation process so that the RNA must move between different organelles throughout the process. Of course, the release and transfer of RNA is regulated by ATPase activity, confirming DDX ATPase’s role as the omnipotent overlord of RNA. The DDXs derive their power from the low-complexity domains. These domains give DDXs the intrinsic ability to set up distinct compartments and when teamed up with the ATPases, they can influence the partitioning of RNA molecules between compartments (Hondele 2019).

Hondele and her team managed to uncover a complex and extensive dictatorship that has been operating for years under our very noses and in our very cells. The well-established and conserved cellular network of DEAD-box ATPases allows the RNA processing steps to be regulated, leading to DEAD-box ATPase control over maturation state, RNP composition, and ultimately RNA fate.

Unfortunately, we are still in the investigation phase and are yet to decide on how best to manipulate this dictatorship to benefit us. Current intelligence indicates that the dysregulation of DDXs could have pathological consequences that could contribute to the development of aggregation diseases, such as Parkinson’s, Alzheimer’s, Amyotrophic lateral sclerosis, and Frontotemporal Dementia (Gomes 2018). Luckily liquid-liquid phase separation has provided a mechanistic link between normal cellular function and disease phenotypes. Over time, these liquid droplets become more static and aggregated, likely leading these protein aggregates to be an end-stage phenotype after aberrant phase separation has overwhelmed cellular machinery that ordinarily reverses these altered phases (Gomes 2018). Through further study and comprehension of how DDXs contribute to these diseases, new treatments could be developed.

 

Literature Cited:

Gomes, E,. Shorter, J. The molecular language of membraneless organelles. J. Biol Chem. 2018; 294(18):7115-7127. 10.1074/jbc.TM118.001192

Hondele, M.,  Sachdev, R., Heinrich, S., Wang, J., Vallotton, P., Fontoura, B.M.A., Weis, K. DEAD-box ATPases are global regulators of phase-separated organelles. Nature. 2019; 573(7772):144-148. 10.1038/s41586-019-1502-y.

Hondele, M., Weis, K. The Role of DEAD-Box ATPases in Gene Expression and the Regulation of RNA-Protein Condensates. Annu Rev Biochem. 2022;  91:197-219. 10.1146/annurev-biochem-032620-105429. 

Filed Under: Biology, Science Tagged With: Biology, Cell Biology, Proteins

Sex-Specific Brain Responses: How Chronic Stress Reshapes Astrocytes Differently in Males and Females

December 9, 2024 by Hailey Ryan '26

Chronic stress is one of the major precursors to numerous neuropsychiatric disorders, such as depression. Women are twice as likely to be affected by mood disorders and respond differently than men to current available treatments. Nonetheless, many preclinical studies are conducted only in male rodents. Investigating the sex-specific responses to stress is critical to identifying mechanisms underlying mood disorders and moving towards developing treatments suitable for sex differences (Zhang et al. 2024). 

Chronic stress is associated with increased inflammation in the brain. The astrocyte is a type of cell in the nervous system that regulates inflammation in the brain. Astrocytes are important for keeping neurons alive, maintaining homeostasis, and secreting cytokines that regulate proinflammatory factors in the brain. The morphological changes of reactive astrocytes can tell us about the inflammation in the brain. These changes include the number of branches the astrocyte has; the more branches it has, the more reactive the astrocyte is, which is a sign of increased stress and inflammation in the brain. Chronic stress can lead to hyperactivation of astrocytes, impairing their ability to control and limit the spread of inflammation. Remodeling of astrocytes through changes in their cellular branching (more cellular branching) has been observed in suicide victims and preclinical chronic stress models. A recent study at Rowan University investigated sex-specific astrocyte responses to chronic stress in brain regions associated with mood disorders. 

Figure 1. Non-reactive vs. Reactive astrocytes. Reactive astrocytes have thicker cell bodies and processes. Astrocytes become reactive in response to injury, as well as to chronic stress. Adapted from: Pekny M, Wilhelmsson U, Pekna M. 2014. The dual role of astrocyte activation and reactive gliosis. Neuroscience Letters. 565:30–38. 

The study used the unpredictable chronic mild stress (UCMS) model to model chronic stress or a lipopolysaccharide (LPS) injection to model systemic inflammation. The UCMS model in rodents induces behavioral symptoms commonly associated with clinical depression as well as physiological and neurological changes that are associated with depression, such as hypertension and learned helplessness. The protocol involves randomized, daily exposures to different stressors, such as removal or bedding, social stresses, or predator sounds/smells. This model allows for an in-depth investigation of changes associated with chronic-stress induced depression (Frisbee et al. 2015). The LPS injection leads to neuroinflammation, sickness behavior, and cognitive impairment; it is a model often used to study neuroinflammation-associated diseases in mice. LPS causes inflammation because it activates microglia, which are the immune cells in the nervous system and play a large role in neuroinflammation (Zhao et al. 2019). 

Male and female mice were randomly assigned to the control group (saline), a 4 hour LPS injection (4LPS), a 24 LPS injection (24LPS), no stress (NS), or stress (UCMS). They measured GFAP (a biological marker of astrocyte reactivity) fluorescent intensity for astrocyte expression and quantified branch points to assess astrocyte complexity in different brain regions. 

The astrocyte complexity was investigated in the hippocampus, amygdala, and hypothalamus. The hippocampus and amygdala are critical brain regions in regulating physiological and behavioral stress processes, which can be useful in the short-term but detrimental in the long-term. In the short term, they help the body respond to stressors in order to maintain homeostasis. However, these stress mechanisms can lead to long-term dysregulation of this process as they promote maladaptive damage on the body and brain under chronically stressful conditions, which compromises resiliency and health. The amygdala is involved in detecting and responding to threats in the environment; the hippocampus is important for memory. These regions work together to make emotional and salient memories strong and long-lasting. Inflammation may hinder learning and memory through structural remodeling of the hippocampus (McEwen and Gianaros 2010). The hypothalamus, which is part of the hypothalamic-pituitary-adrenal (HPA) axis, is essential for mediating the stress response, primarily through the release of stress hormones (Bao et al. 2008). 

Figure 2.  The hypothalamus, hippocampus, and amygdala. Adapted from: https://www.brainframe-kids.com/emotions/facts-brain.htm.

The study found that chronic stress-induced morphological changes in astrocytes occurred in all brain regions that were looked at, and that the effects of chronic stress were both region and sex specific. Females had greater stress or inflammation-induced astrocyte activation in the hypothalamus, hippocampus, and amygdala than males. This indicates that chronic stress induces astrocyte activation that could drive sex-specific differences, which may contribute to the sex differences of mood disorders and disease. 

To better assess astrocyte reactivity, they used the ramification index, which is the ratio between the total number of primary branches and the branch maximum. It indicates how ramified the astrocytes are, as more branches (more ramified) indicates more reactive astrocytes. The ramification index indicated that astrocytes were significantly ramified due to chronic stress or LPS injection. They also conducted analysis of morphological changes, which provides the strongest evidence of astrocyte reactivity. The following results demonstrate the sex differences due to stress in branch point and terminal point morphology measurements. 

In the chronic-stress induced inflammatory environment (UCMS), there was higher astrocyte activation in the female hippocampus and hypothalamus, as demonstrated by increased branch points (Figure 3). 

Figure 3. UCMS and LPS activate astrocytes in the hypothalamus by inducing morphological changes. A. Representative images of female astrocytes in the hypothalamus in each condition (saline, no stress, 4 hours post-LPS, 24 hours post-LPS, and UCMS). D. Branching points in the hypothalamus. There were significant differences between treatment and between sex. There were significantly more branch points for females in the UCMS condition than for males. Adapted from: Zhang AY, Elias E, Manners MT. 2024. Sex-dependent astrocyte reactivity: Unveiling chronic stress-induced morphological changes across multiple brain regions. Neurobiology of Disease. 200:106610.

In the amygdala and hippocampus in the 24LPS condition, there was increased astrocyte reactivity in females compared to males. This indicates that females are more susceptible to chronic systemic inflammation than males in these brain regions (Figure 4). 

Figure 4. UCMS and LPS activate astrocytes in the amygdala by inducing morphological changes. A. Representative images of female astrocytes in the amygdala in the saline, no stress, 4LPS, 24LPS, and UCMS groups. D. Analysis of branch points in the amygdala. There were significant differences between treatment and between sex. Females had significantly more branching points in the 24LPS condition than males. Adapted from: Zhang AY, Elias E, Manners MT. 2024. Sex-dependent astrocyte reactivity: Unveiling chronic stress-induced morphological changes across multiple brain regions. Neurobiology of Disease. 200:106610.

Astrocytes work in tandem with other cells in the nervous system, including microglia, to regulate various processes. Microglia, the cells in the nervous system important for immune response, are also important in the inflammatory response in the brain. Reactive microglia can activate astrocytes by secreting cytokines. Blocking microglia may be able to decrease the number of reactive astrocytes and apply a protective effect against inflammation in the brain. Future studies can look at the activation of microglia and how microglia and astrocytes interact in the chronic stress model. 

Overall, it is important that this study looked at sex differences since there is such a disparity among mental health disorders and treatment in women and men. Understanding the mechanisms behind the sex differences can improve the development of new medications for stress-related disorders so that both men and women can be correctly treated. 

Moreover, female susceptibility to chronic stress may mediate the increased risk for Alzheimer’s Disease. The different biochemical responses to stress, such as activity of the hypothalamic-pituitary-adrenal (HPA) axis and female-biased increases in molecules associated with AD, between females and males could be a sex-dependent risk factor for AD. Female-specific alterations in inflammation and microglial function are proposed to be one reason, but this needs more investigation (Yan et al. 2018). Understanding sex-specific disease mechanisms is essential for the development of personalized medicine, which is the use of an individual’s genetic profile to prevent, diagnose, and treat disease. Differences in mechanisms of disease between sexes will likely require different drugs for men and women to treat a variety of psychiatric and neurological disorders (Bangasser and Wicks 2017). 

 

References. 

Bangasser DA, Wicks B. 2017. Sex-specific mechanisms for responding to stress. Journal of Neuroscience Research. 95(1–2):75–82. 

Bao A-M, Meynen G, Swaab DF. 2008. The stress system in depression and neurodegeneration: Focus on the human hypothalamus. Brain Research Reviews. 57(2):531–553. 

Emotion Facts: Emotions in the Brain. [accessed 2024 Oct 29]. https://www.brainframe-kids.com/emotions/facts-brain.htm.

Frisbee JC, Brooks SD, Stanley SC, d’Audiffret AC. 2015. An Unpredictable Chronic Mild Stress Protocol for Instigating Depressive Symptoms, Behavioral Changes and Negative Health Outcomes in Rodents. J Vis Exp.(106):53109. 

McEwen BS, Gianaros PJ. 2010. Central role of the brain in stress and adaptation: Links to socioeconomic status, health, and disease. Annals of the New York Academy of Sciences. 1186:190. 

Pekny M, Wilhelmsson U, Pekna M. 2014. The dual role of astrocyte activation and reactive gliosis. Neuroscience Letters. 565:30–38. 

Tynan RJ, Naicker S, Hinwood M, Nalivaiko E, Buller KM, Pow DV, Day TA, Walker FR. 2010. Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain, Behavior, and Immunity. 24(7):1058–1068. 

Yan Y, Dominguez S, Fisher DW, Dong H. 2018. Sex differences in chronic stress responses and Alzheimer’s disease. Neurobiology of Stress. 8:120–126. 

Zhang AY, Elias E, Manners MT. 2024. Sex-dependent astrocyte reactivity: Unveiling chronic stress-induced morphological changes across multiple brain regions. Neurobiology of Disease. 200:106610. 

Zhao J, Bi W, Xiao S, Lan X, Cheng X, Zhang J, Lu D, Wei W, Wang Y, Li H, et al. 2019. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep. 9(1):5790. 

Filed Under: Psychology and Neuroscience, Science Tagged With: astrocytes, chronic stress, sex differences

Unlikely Weapon: Marburg Virus

December 8, 2024 by Basant Kaur

                  From the Tartar army catapulting bubonic plague victims to their enemies in the 14th century (Hale, n.d.) to the 2001 Anthrax attacks, bioterrorism has a long, but often understated, history. When thinking of terrorism, the general population generally focuses on the prospect of nuclear weapons. However, given the increasing issue of microbial resistance and rapid mutation of viruses, we must not ignore the potential of bioterrorism. In particular, Marburg Virus, a viral hemorrhagic fever closely related to Ebola, is one of the most promising potential biological weapons that should be further studied for prevention measures.

Background

                    Marburg Virus (MARV) was first discovered through simultaneous outbreaks of the virus in German and Yugoslavian laboratories in 1967, which is believed to have been caused by exposure to Ugandan African green monkeys. 31 people fell ill, and 7 deaths were recorded (Centers of Disease Control and Prevention, n.d.). Since the initial outbreak, there have been irregular outbreaks in Africa throughout the years, ranging from 1 to over 250 reported human cases (Centers of Disease Control and Prevention, n.d.).

                  MARV is categorized as a filovirus, which is the same virus classification as Ebola. MARV is a severe hemorrhagic fever, defined by its high mortality rate of up to 90% (Centers of Disease Control and Prevention, n.d.; Leroy et al., 2011). A MARV infection starts off with common symptoms such as a fever, nausea, headaches, and muscle pain, but quickly escalates to gastrointestinal problems (stomach pain and vomiting), respiratory problems (chest pains and coughing), neurological issues (delirium), and hemorrhagic manifestations (skin rashes, nosebleeds, and vomiting blood) (Leroy et al., 2011). Unfortunately, the severity of a MARV infection has made it a contender as a biological weapon.

Potential for Bioterrorism

                  MARV is often considered to be an effective agent of bioterrorism. According to the Centers for Disease Control and Prevention, MARV is a Category A (high-priority) pathogen based on the following criteria: a high transmission rate, high mortality rate and potential for major public health impact, potential for public panic, and requires special action for public health preparation (Centers for Disease Control and Prevention, 2024). MARV can also be aerosolized (turning infected body fluids or excrements into a fine mist) for higher transmission through the air, produced in large industrial quantities, and is spread from person to person (Filoviridae, n.d., Texas Department of State Health Services). In the Soviet Union’s Biological Weapons program, MARV was one of the strategic-operational weapons (meant for long-distance and short-distance targets) that would have been used in future wars (Tucker, 1999). The Soviet Union actually preferred MARV over Ebola because MARV’s weaponized form was more stable than Ebola’s (Filoviridae, n.d.). Considering MARV’s potential for bioterrorism, it is essential to develop prevention methods.

Vaccines in Development

                  While MARV is widely regarded as a high-priority pathogen with likely devastating consequences, there is still no known treatment or vaccine. However, within the last 5 years, two vaccine trials show great potential. One of the trials was tested on nonhuman primates, while the other trial was tested on humans. Both trials were successful in developing antibodies against MARV and didn’t have any severe side effects on the participants (O’donnell et al., 2023; Hamer et al., 2023).  These trials display promising results that can potentially mark a significant advancement in reducing the spread of MARV.

                  Initially only causing irregular outbreaks, MARV now has the potential to become a huge public health issue due to its potential for bioterrorism and high mortality rate. Therefore, the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services awarded $21.8 million to the Sabin Vaccine Institute to continue developing a vaccine for MARV (Sabin Receives, 2022). Current vaccines in development show great potential to lessen MARV outbreak, though future studies need to continue monitoring the efficacy and safety of these vaccines. These measures highlight the importance of MARV vaccine research to protect global health from potential bioterrorism.

 

References

Centers of Disease Control and Prevention. (n.d.). About Marburg Virus Disease. Centers for Disease Control and Prevention. Retrieved July 15, 2023, from https://www.cdc.gov/vhf/marburg/about.html#:~:text=Marburg%20virus%20disease%20(MVD)%20is,within%20the%20virus%20family%20Filoviridae

Centers for Disease Control and Prevention. (n.d.). Marburg Virus Disease Outbreaks. Centers for Disease Control and Prevention. Retrieved July 15, 2023, from https://www.cdc.gov/vhf/marburg/outbreaks/chronology.html

Centers for Disease Control and Prevention. (2024, November 21). Emergency Preparedness and Response. Emergency Preparedness and Response. https://www.cdc.gov/emergency/index.html

Filoviridae. (n.d.). Federation of American Scientists. Retrieved December 7, 2024, from https://programs.fas.org/bio/factsheets/ebolamarburgfs.html

Hale, Kristina. (n.d.) Yersinia pestis as a Biological Weapon—Insects, Disease, and History | Montana State University. (n.d.). Retrieved December 7, 2024, from https://www.montana.edu/historybug/yersiniaessays/hale.html

Hamer, M. J., Houser, K. V., Hofstetter, A. R., Ortega-villa, A. M., Lee, C., Preston, A., Augustine, B., Andrews, C., Yamshchikov, G. V., Hickman, S., Schech, S., Hutter, J. N., Scott, P. T., Waterman, P. E., Amare, M. F., Kioko, V., Storme, C., Modjarrad, K., Mccauley, M. D., . . . Stanley, D. A. (2023). Safety, tolerability, and immunogenicity of the chimpanzee adenovirus type 3-vectored marburg virus (cAd3-Marburg) vaccine in healthy adults in the usa: A first-in-human, phase 1, open-label, dose-escalation trial. The Lancet, 401(10373), 294-302. https://doi.org/10.1016/s0140-6736(22)02400-x

Leroy, E.m., Gonzalez, J.-P., & Baize, S. (2011). Ebola and marburg haemorrhagic fever viruses: Major scientific advances, but a relatively minor public health threat for africa. Clinical Microbiology and Infection, 17(7), 964-976. https://doi.org/10.1111/j.1469-0691.2011.03535.x

O’donnell, K. L., Feldmann, F., Kaza, B., Clancy, C. S., Hanley, P. W., Fletcher, P., & Marzi, A. (2023). Rapid protection of nonhuman primates against marburg virus disease using a single low-dose vsv-based vaccine. EBioMedicine, 89, 104463. https://doi.org/10.1016/j.ebiom.2023.104463

Sabin Receives Additional $21.8 Million From BARDA to Advance Marburg Vaccine. (2022, September 13). Sabin Vaccine Institute. Retrieved July 21, 2023, from https://www.sabin.org/resources/sabin-receives-additional-21-8-million-from-barda-to-advance-marburg-vaccine/

Texas Department of State Health Services. (n.d.). Viral Hemorrhagic Fevers and Bioterrorism.

Tucker, J. B. (1999). Biological weapons in the former Soviet Union: An interview with Dr. Kenneth Alibek. The Nonproliferation Review, 6(3), 1–10. https://doi.org/10.1080/10736709908436760

Filed Under: Biology, Science

New Development of a Skin Probiotic to Combat Eczema

December 8, 2024 by Anton Schmeissner

 

The underlying factors contributing to the common condition of atopic dermatitis, more commonly referred to as eczema,  are generally related to an imbalance in the skin microbiome. The skin is home to an abundance of different species of bacteria, and most are symbiotic with humans and provide many defenses against invading pathogens. One of these symbiotic bacteria is called Roseomonas Mucosa (R. Mucosa), and it is this bacteria that has been found to be essential to maintaining a well-balanced and healthy skin microbiome, which in turn protects us from invaders such as Staphylococcus Aureus, the primary cause of eczema. Researchers from the National Institutes of Health were recently able to find genetically different versions of R. Mucosa that were better in their protective ability and were able to incorporate them into a skin probiotic cream that is effective in safely treating eczema.

  In their study, different strains of R. Mucosa, based on their differing metabolic profiles, were applied to eczema-affected patients, and the amount of recovery was quantified and compared. (Myles, et al.,2018) These differing metabolic profiles are important because they refer to the type and amount of certain lipids (fats) that are excreted by R. Mucosa that are essential in initiating a sequence in which the epithelial (skin) layer is repaired. (Myles, et al.,2020) In addition to comparing the different strains of R. Mucosa, researchers tested the responses to different environmental conditions to see how the possible treatment would be impacted by other topically applied solutions and the general presence of certain chemicals on the skin. Part of this was done by testing the growth of different strains of R. Mucosa, as well as S. Aureus, in the presence of different commonly marketed treatment lotions with known names. (Myles, et al.,2018)

               The study found that certain strains of R. Mucosa were more effective at reducing the impacts of eczema (NIAID, 2024)(Myles, et al.,2018) and the lipids produced by the effective strains were isolated and noted. The strains that produced the helpful lipids and a sufficient quantity of them were identified (Categorized as R. Mucosa HV). (Myles, et al.,2018) When the strains of R. Mucosa and S. Aureus were placed in differing environments, it was found that while most current market treatment products don’t inhibit the beneficial R. Mucosa growth, they may aid in the harmful eczema-causing bacteria S. Aureus. This suggested that these market products not be taken in conjunction with the new probiotic treatment. (Myles, et al.,2018)

  The study and subsequent clinical trial found that the transplantation of R. Mucosa onto an affected skin microbiome that is susceptible and/or subjected to eczema can lead to a reduction of the harmful effects related to eczema. It was tested further through clinical trials and has since been rolled out under the name Defensin, produced by Skinesa. Further studies are working to form an application to the FDA in order to roll out the probiotic cream as a regulated non-prescription drug so as to be more widely available to those who may benefit from it. (NIAID, 2024)

 

 

 References

(1) Myles, I. A., Castillo, C. R., Barbian, K. D., Kanakabandi, K., Virtaneva, K., Fitzmeyer, E., Paneru, M., Otaizo-Carrasquero, F., Myers, T. G., Markowitz, T. E., Moore, I. N., Liu, X., Ferrer, M., Sakamachi, Y., Garantziotis, S., Swamydas, M., Lionakis, M. S., Anderson, E. D., Earland, N. J., & Ganesan, S. (2020). Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair. Science Translational Medicine, 12(560). https://doi.org/10.1126/scitranslmed.aaz8631

(2) Myles, I. A., Earland, N. J., Anderson, E. D., Moore, I. N., Kieh, M. D., Williams, K. W., Saleem, A., Fontecilla, N. M., Welch, P. A., Darnell, D. A., Barnhart, L. A., Sun, A. A., Uzel, G., & Datta, S. K. (2018). First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis. JCI Insight, 3(9). https://doi.org/10.1172/jci.insight.120608

(3) NIAID Discovery Leads to Novel Probiotic for Eczema. (2024, June 26). Nih.gov. https://www.niaid.nih.gov/news-events/niaid-discovery-leads-novel-probiotic-eczema?utm_medium=social&utm_source=linkedin&utm_campaign=news_probiotic_eczema_6262024

 

Filed Under: Biology, Science Tagged With: Dermatology, Microbiology

An Overview of Alzhimer’s Disease Pathogenesis

December 8, 2024 by Alex Alessi

Keywords: pathogenesis, cholinergic changes, oxidative stress, amyloid plaque, Tau protein, mutation

Introduction

As people get older, many health complications begin to arise, many of which are cognitive. One such health complication is Alzheimer’s Disease (AD), which is one of the most common cause of dementia. AD is a disease that impacts fifty-five million people worldwide and one in three people over the age of eighty five experience advanced symptoms and signs of AD (Twarowski and Herbet 2023). AD is incurable and often leads to death, and currently a lot about how this disease works and about how it can be treated is unknown. AD is a complex multifactorial disease, and scientist are looking at many different causes (Twarowski and Herbet 2023). I will be covering the current understanding of AD pathogenesis (the process by which a disease is formed) through multiple lenses and discuss current treatments for AD. 

AD Pathogenesis Overview 

Cholinergic changes: 

One of the major neurotransmitters that allows for muscle movement, regulating heartbeat and blood pressure, and certain brain functions, is acetylcholine. Acetylcholine is active in the cerebral cortex, the basal ganglia, and the forebrain, and one of the first hypotheses for AD was cholinergic changes (Twarowski and Herbet 2023). A cholinergic change refers to the changes in the cholinergic system which is a neurotransmitter (acetylcholine) system that plays a role in memory, digestion, control of heartbeat, and movement (Sam and Bordoni 2023). When the nucleus basalis degenerates, there is a loss of synaptic connections that result in the deficiency of neurotransmission  (Twarowski and Herbet 2023). This can thus impact memory and movement, which are some of the most common symptoms of AD. The initial stages of AD are related to cholinergic changes and as the disease progresses, the cholinergic system loses its function until it all function is lost, resulting in death  (Twarowski and Herbet 2023).  

Figure 1. Demonstration of the cholinergic system in a neuron (Hall 2020 Mar 13).

Amyloid plaques and Tau proteins:

Amyloid plaques and the malfunction of Tau proteins are suspected to be two of the causes of AD that both lead to disease progression. Beta amyloids are small water-soluble peptides, and plaques will form if the beta amyloids do not have a stable structure (Twarowski and Herbet 2023). This lack of structure is thought of to be a cause of mutations. These plaques exhibit toxic properties to neuronal cells which causes neurons to degenerate (Twarowski and Herbet 2023). A Tau protein is a protein that promotes the assembly of tubulin which is a protein that is involved in cell division and cell movement. A Tau protein that is not functioning due to neurotoxins will bind to other Tau proteins and create tangles inside a neuron that lead to apoptosis of the neuron (Twarowski and Herbet 2023). This accumulation of plaques can cause the Tau proteins to form together and lead to tangles, revealing how there is a link between the two cause of AD (What Happens to the Brain in Alzheimer’s Disease? 2024 Jan 19). This process usually occurs in the final stages of AD pathogenesis.  

Figure 2. Amyloid beta plaques and Tau protein tangles impact on Neuron (McLoughlin).

 

Oxidative Stress: 

Another cause of AD is increased oxidative stress, which has many implications on people with AD. Oxygen is particularly important to the brain as the brain uses around twenty percent more oxygen than other organs in the body (Twarowski and Herbet 2023). Changes related to oxidative stress, which is an imbalance of free radicals and antioxidants in the body that leads to cell damage, are often seen in people with AD. This damage is caused by lipid oxidation as a result of oxidative stress breaks bonds in DNA molecules which increases the aging and death of neurons. These changes can also influence the mutation of Tau protein into advanced glycoxidation end products (AGEs) which are toxic to neurons and also lead to the progression of AD (Twarowski and Herbet 2023).  

Figure 3. Cell undergoing oxidative stress (Moore 2022 May 17).

Mutations:

One of the main and most significant factors that is related to the pathogenesis of AD and ties all of the previous factors together is genetic mutations as mutations are related to both cholinergic changes and oxidative stress. However, mutations in the genes that encode for the amyloid precursor protein have been identified as the most dangerous genetic risk factor associated with the development of AD (Twarowski and Herbet 2023). These are mutations in the 34 allele which is the allele of apolipoprotein E have been found to occur within one and five Alzheimer’s patients, and the risk of developing AD increases threefold with this mutation. Furthermore, this mutation may lead to the amyloid beta plaques and thus cause AD (Twarowski and Herbet 2023). Mutations are thus the largest contributing cause to AD because they can have so many implications that lead to the pathogenesis of AD. 

Figure 4. DNA that has undergone a mutation (Scoville 2019).

Conclusion

AD is a disease that impacts many people and causes many deaths annually, so being able to find a cure is incredibly important. AD pathogenesis is extremely complex, and as of today, scientists do not fully understand its pathogenesis, but we are getting closer. Understanding how the processes that lead to AD pathogenesis is the first step to being able to help find treatments that will help millions of people. Thus, scientists are still working diligently to understand how this disease works and how our current understanding can be improved. 

 

 

Literature Cited

Hall A. 2020 Mar 13. ChAT in 3D: Understanding the central cholinergic system. LifeCanvas Technologies. https://lifecanvastech.com/whole-brain-imaging-of-the-central-cholinergic-system-through-immunolabeling-chat/.

McLoughlin L. A Guide To Tau Proteins & Tauopathies. Assay Genie. https://www.assaygenie.com/blog/protein-tau-and-tauopathies.

Moore M. 2022 May 17. Effects of Oxidative stress | HHC. Life Science product | Helvetica Health Care. https://www.h-h-c.com/what-is-oxidative-stress-and-how-does-it-affect-your-health/.

Sam C, Bordoni B. 2023. Physiology, Acetylcholine. PubMed. https://www.ncbi.nlm.nih.gov/books/NBK557825/.

Scoville H. 2019. 4 Types of DNA Mutations and Examples. ThoughtCo. https://www.thoughtco.com/dna-mutations-1224595.

Twarowski B, Herbet M. 2023. Inflammatory Processes in Alzheimer’s Disease—Pathomechanism, Diagnosis and Treatment: A Review. International Journal of Molecular Sciences. 24(7):6518. doi:https://doi.org/10.3390/ijms24076518.

What Happens to the Brain in Alzheimer’s Disease? 2024 Jan 19. National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/what-happens-brain-alzheimers-disease.

 

Filed Under: Biology, Science Tagged With: Alzheimer's Disease

From Milk to Malignancy – Breast Cancer and its Metabolic Implications 

December 8, 2024 by Gisela Contreras '27

The annual rise of cancer cases has created a high demand for new innovative treatments and has made cancer a prominent topic in the scientific community. According to the American Cancer Society (ACS), approximately 20 million new cancer cases were diagnosed worldwide in 2022, leading to 9.7 million deaths [1]. It is expected that by 2050, cancer cases will reach 35 million, largely due to population growth [1]. While significant advancements have been made in cancer research, the complexity of different cancer types presents challenges. 

One of the most prevalent forms is breast cancer, which, in 2022, was the second most common cancer in the U.S., with 2.3 million new cases, predominantly affecting women [2]. Unlike many cancers, breast cancer is not a single disease but a collection of subtypes characterized by distinct clinical, morphological, and molecular features. This heterogeneity makes it challenging to study and treat effectively. A recent study published in Nature Metabolism explores the metabolic differences between normal mammary cells and breast cancer cells [4]. Understanding these metabolic processes could pave the way for new, targeted therapies. Researchers have identified specific metabolic vulnerabilities in mammary epithelial cells, which line the breast tissue.

 

Figure 1. Non-tumorigenic Mammary Gland Components. A diagram of a non-tumorigenic mammary gland showing a cluster of alveoli containing luminal and basal cells. Luminal cells line the milk ducts and alveoli and are responsible for milk secretion during lactation. Basal cells are believed to play a role in transporting milk to the nipple during lactation. Source: Created in BioRender, [4], [10], [11].

In the normal mammary gland, various types of cells carry out specific functions, one of which is the progenitor cells. These progenitor cells generate distinct alveolar structures that continuously form in the adult breast, and their activity is crucial for maintaining normal mammary homeostasis [5]. Progenitor cells are located in the luminal compartment [6], which is also home to the luminal cells. The luminal cells play a key role in lactation by lining the milk ducts and alveoli, where they secrete milk (Figure 1)[7]. In contrast, basal cells are located around the luminal cells and are believed to function during lactation by helping to transport milk to the nipple (Figure 1)[7]. Although these mammalian epithelial cells (luminal and basal cells) are important to the function of normal mammary glands, these also serve as a tumour cell of origin [4].

In their study, Mahendralingam et al. used mass spectrometry to analyze the metabolic profiles of normal human mammary cells [8]. They discovered that luminal progenitor cells primarily rely on oxidative phosphorylation for energy, whereas basal cells depend more on glycolysis [4]. This distinction is crucial because oxidative phosphorylation is an efficient, oxygen-dependent process that generates substantial energy, while glycolysis, though faster, is less efficient and does not require oxygen — a pathway often favored by cancer cells to support rapid growth [9]. Targeting these distinct energy pathways could lead to more effective treatments for different breast cancer subtypes.

However, a new discovery was that breast cancer cells appear to adopt the metabolic programs of their cells of origin [4,9]. This complicates treatment since the cancer cells may still be vulnerable to metabolic pathways that are important for normal cell function. As a result, treatments designed to target specific metabolic pathways might not work as expected, since the cancer cells might behave similarly to the healthy cells from which they originated. 

The results from Mahendralingam et al. can form a basis for future metabolic studies that may lead to specific anti-tumoral drug therapies designed to treat specific breast cancer subtypes. This type of research lays a foundation for targeted approaches but further studies are needed to assess how findings, such as this one, can translate into clinical practice. As breast cancer continues to rise, understanding the complexity is more important than ever. 

 

Work Cited: 

  1. Global Cancer Facts & Figures. (n.d.). Retrieved October 27, 2024, from https://www.cancer.org/research/cancer-facts-statistics/global-cancer-facts-and-figures.html
  2. Global cancer burden growing, amidst mounting need for services. (n.d.). Retrieved October 27, 2024, from https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing–amidst-mounting-need-for-services
  3. Sánchez López de Nava, A., & Raja, A. (2024). Physiology, Metabolism. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK546690/
  4. Alfonso-Pérez, T., Baonza, G., & Martin-Belmonte, F. (2021). Breast cancer has a new metabolic Achilles’ heel. Nature Metabolism, 3(5), 590–592. https://doi.org/10.1038/s42255-021-00394-8
  5. Tharmapalan, P., Mahendralingam, M., Berman, H. K., & Khokha, R. (2019). Mammary stem cells and progenitors: Targeting the roots of breast cancer for prevention. The EMBO Journal, 38(14), e100852. https://doi.org/10.15252/embj.2018100852
  6. Tornillo, G., & Smalley, M. J. (2015). ERrrr…Where are the Progenitors? Hormone Receptors and Mammary Cell Heterogeneity. Journal of Mammary Gland Biology and Neoplasia, 20(1–2), 63–73. https://doi.org/10.1007/s10911-015-9336-1
  7. New Paradigm for Mammary Glands. (n.d.). Massachusetts General Hospital. Retrieved December 8, 2024, from https://www.massgeneral.org/cancer-center/clinician-resources/advances/new-paradigm-for-mammary-glands
  8. Mahendralingam, M. J., Kim, H., McCloskey, C. W., Aliar, K., Casey, A. E., Tharmapalan, P., Pellacani, D., Ignatchenko, V., Garcia-Valero, M., Palomero, L., Sinha, A., Cruickshank, J., Shetty, R., Vellanki, R. N., Koritzinsky, M., Stambolic, V., Alam, M., Schimmer, A. D., Berman, H. K., … Khokha, R. (2021). Mammary epithelial cells have lineage-rooted metabolic identities. Nature Metabolism, 3(5), 665–681. https://doi.org/10.1038/s42255-021-00388-6
  9. ZHENG, J. (2012). Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). Oncology Letters, 4(6), 1151–1157. https://doi.org/10.3892/ol.2012.928
  10. Fig. 3 Stem cell in glandular and stratified epithelia. A A schematic… (n.d.). ResearchGate. Retrieved December 7, 2024, from https://www.researchgate.net/figure/Stem-cell-in-glandular-and-stratified-epithelia-A-A-schematic-model-depicting-the_fig3_374804603
  11. Model of normal mammary gland structure. This tissue is composed of… (n.d.). ResearchGate. Retrieved December 8, 2024, from https://www.researchgate.net/figure/Model-of-normal-mammary-gland-structure-This-tissue-is-composed-of-ducts-which-are_fig1_357239665

Filed Under: Biology, Chemistry and Biochemistry, Science Tagged With: Breast Cancer, Cancer Biology, Metabolic Pathways

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