Bowdoin Science Journal

Biology

Floating Systems: Jellyfish and Evolving Nervous Systems

by

Jellyfish are just one species within the phylum cnidaria. A phylum is a broad level of taxonomic classification that includes many different species, with cnidaria additionally including coral and anemones. Cnidaria provides comparative neuroscience information due to the simple behaviors that the species within the phylum exhibit. Despite their shared phylum that creates nerve cells with similar properties, the species have dramatically different nervous systems, allowing for unique perspectives on the diversity, origins, and evolution of neural systems within species (Cunningham et al., 2024). Comparative neuroscience information is the study of nervous systems across a variety of animal species. Through this research, the evolutionary changes in the brain’s structure can be examined, allowing scientists to see how differences in nervous systems shape certain behaviors (Miller et al., 2019). Neuroscience researchers can use an all-optical interrogation, in which they study and manipulate neural systems using light, upon these species, allowing them to image and photograph the neuronal networks in the creature for further examination. 

Fig 1. Photo of Clytia hemisphaerica (Clytia Hemisphaerica Medusa – 13673149 ❘ Science Photo Library, n.d.)

Jellyfish are major contributors to ocean ecosystems. Their reproductive, foraging, and defensive behaviors all uniquely impact the ecosystem at large. What is notable about jellyfish, however, is that these behaviors are shaped out of decentralized, regenerative nervous systems. Rather than the creature being controlled by the neurons in its brain, the jellyfish’s neurons are spread throughout the body (“Thinking without a Centralized Brain,” n.d.). This allows the various parts of its body to have a role in controlling and processing information. Additionally, the nervous system itself has the ability to repair and restore itself, allowing damaged nerves to be replaced by new ones (Gaskill, 2018). 

Jellyfish are the most complicated species of Cnidaria, due to various behaviors that demonstrate their higher level functioning compared to other species in the phylum. They have the ability to move in 3-dimensions, capture and consume other creatures, and the ability to escape from predators and other potential threats. Notably, jellyfish also exhibit courtship behaviors and sleep states, despite lacking a central brain. These behaviors are  due to their sensory structures, made up by two nervous systems: one which controls their swimming and another that controls all other behaviors. The jellyfish’s nervous systems can respond to each other, despite the lack of a central controller (Cunningham et al., 2024). 

A recent scientific investigation conducted at Caltech by Anderson et al. sought to explore how the jellyfish can be used to conduct neuroscience research. Clytia hemisphaerica is a species of jellyfish that has recently been adopted into a genetic neuroscience model. It has previously been used as a model to study evolution, embryology, regeneration, and other fields. This species of jellyfish is a particularly useful model for neuroscience research because its genome is already sequenced and assembled from the birth of the creature, with whole-animal single-celled Ribonucleic Acid (RNA) sequences formed within the species. Rather than using multiple animals to sequence the RNA, Clytia hemisphaerica has the capability to provide the necessary amounts of cells needed to be examined. Using multiplexed single-cell RNA sequencing, in which individual animals were indexed and pooled from control and perturbation conditions into a single sequencing run (Chari et al., 2021). Clytia hemisphaerica is the only jellyfish whose RNA sequences are being used to rapidly develop genomic tools. These tools can be tested and utilized by researchers, allowing them to explore brain function and neurological disorders through this model (Cunningham et al., 2024).

The last common ancestor of Clytia hemisphaerica was a hydrozoan jellyfish, which are able to perform specific behaviors even if certain body parts are detached from the body. Hydrozoan jellyfish, notably, have the ability to cycle back and forth between various stages of their life–allowing them to live for large expanses of time. When the body parts exist in an intact organism, they also have the ability to perform more complex behaviors. These include different feeding behaviors and mechanisms. The swimming behavior of the Clytia hemisphaerica also reveals key information about the neuromechanics behind different behaviors of jellyfish. As an example, although jellyfish spend a majority of their lives swimming, there are periods where they may start and stop. These periods are only exhibited when there is food passing or defensive behaviors are exhibited. When these behaviors are examined, neuroscientists can ponder and develop further conclusions about multi-sensory integration, motor control, and the mechanisms that underlie behavioral states (Cunningham et al., 2024). Figure 1

Fig 2. The Evolution, Life Cycle, and Genetic Tools of Clytia hemisphaerica (Cunningham et al., 2024)

Through using neural population imaging, in which researchers have the ability to monitor large groups of neurons through calcium and voltage imaging, on the whole-organism scale through the Clytia hemisphaerica, emergent properties of function networks can be uncovered (Zhu et al., 2022). Without this model, scientists would have to use traditional single-cell unit recordings, requiring using fine tools just to see the individual activity of a single neutron, or anatomical studies, which would not provide the same amount of potential discoveries that new techniques with Clytia hemisphaerica provide. Through using this species as a model, researchers can uncover more knowledge and data about nervous system evolution and function, particularly for neural regeneration.

Neural regeneration is particularly important in the treatment of injury and disease in the nervous system. It aids in cognitive recovery following neurodegeneration, helping rebuild neurons and nervous tissue (Steward et al., 2013). Through neural regeneration, the nervous system may regain its functions, allowing for betterment of quality of life. By continuing to examine species capable of neural regeneration, we may learn to apply this to the human nervous system, allowing us to move forward in curing traumatic brain injuries and degeneration of the brain and its abilities (Neuroregeneration – an Overview | Sciencedirect Topics, n.d.).

 

 

 

 

 

References:

Chari, T., Weissbourd, B., Gehring, J., Ferraioli, A., Leclère, L., Herl, M., Gao, F., Chevalier, S., Copley, R. R., Houliston, E., Anderson, D. J., & Pachter, L. (2021). Whole animal multiplexed single-cell rna-seq reveals plasticity of clytia medusa cell types. bioRxiv. https://doi.org/10.1101/2021.01.22.427844

Cunningham, K., Anderson, D. J., & Weissbourd, B. (2024). Jellyfish for the study of nervous system evolution and function. Current Opinion in Neurobiology, 88, 102903. https://doi.org/10.1016/j.conb.2024.102903

Gaskill, M. (2018, November 20). No brain? For jellyfish, no problem | blog | nature | pbs. Nature. https://www.pbs.org/wnet/nature/blog/no-brain-for-jellyfish-no-problem/

Miller, C. T., Hale, M. E., Okano, H., Okabe, S., & Mitra, P. (2019). Comparative principles for next-generation neuroscience. Frontiers in Behavioral Neuroscience, 13. https://doi.org/10.3389/fnbeh.2019.00012

Neuroregeneration—An overview | sciencedirect topics. (n.d.). Retrieved April 27, 2025, from https://www.sciencedirect.com/topics/neuroscience/neuroregeneration

Steward, M. M., Sridhar, A., & Meyer, J. S. (2013). Neural regeneration. Current Topics in Microbiology and Immunology, 367, 163–191. https://doi.org/10.1007/82_2012_302

Thinking without a centralized brain: The intelligence of the octopus. (n.d.). WHYY. Retrieved April 27, 2025, from https://whyy.org/segments/thinking-without-a-centralized-brain-the-intelligence-of-the-octopus/

Zhu, F., Grier, H. A., Tandon, R., Cai, C., Agarwal, A., Giovannucci, A., Kaufman, M. T., & Pandarinath, C. (2022). A deep learning framework for inference of single-trial neural population dynamics from calcium imaging with sub-frame temporal resolution. Nature Neuroscience, 25(12), 1724–1734. https://doi.org/10.1038/s41593-022-01189-0

Biological ChatGPT: Rewriting Life With Evo 2

by

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.

 

POTS vs Atomoxetine: The Unseen Interaction

by

Postural Orthostatic Tachycardia Syndrome (POTS) is a malfunction in the body’s autonomic nervous system. Rather than the blood vessels below their heart compensating by constricting, when a person with POTS goes from a lying to a standing position, a large amount of blood pools in the legs and abdomen. Normally, the blood vessels in the lower extremities constrict to maintain appropriate blood pressure throughout the whole body and help return the blood to the heart and head. The autonomic system (the part of the nervous system that is in charge of the involuntary aspects of the body) responds to low blood pressure by releasing norepinephrine and adrenaline, which cause vasoconstriction and a rise in heart rate. In POTS patients, vessels do not respond to the hormones and remain vasodilated. This combination of high heart rate and insufficient blood flow to the brain causes characteristic dizziness, fainting, and fatigue. POTS can be aggravated by a variety of things, including strenuous exercise, caffeine, hot environments, and certain medications (POTS, n.d.). 

One such class of medications is norepinephrine reuptake inhibitors (NOIs). Used to treat ADHD, major depressive disorder, and narcolepsy, NOIs block the uptake of norepinephrine in the synapses (De Crescenzo et al., 2018). This type of medication allows norepinephrine to stay in the blood longer, elevating mood and energy levels and enhancing focus. A common side effect is an elevated heart rate, which aggravates POTS. 

Green et al. conducted the first study examining the acute effects of atomoxetine on POTS patients. The study was composed of 27 patients and a variety of tests. A baseline was created to manage the patients’ diets. This entailed removing methylxanthines from their diet, which includes caffeine among other compounds, and moderating sodium and potassium intake. Additionally, all long-term medications were suspended for at least 5 half-life periods to ensure no hormonal effects would be present. All of these measures were taken to minimize the exacerbation of POTS symptoms (Green et al., 2013). 

All patients received the atomoxetine and the placebo (on different days). During this time, a posture study was done. Measurements of heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and plasma catecholamines were taken during a lying position and a standing position. This targets the effects of POTS, highlighting the possible impact of the atomoxetine. 

The posture study was paired with the medication study. During the medication study, patients were asked to fill out a symptom feedback form before the experiment, and every hour up to 4 hours after drug administration. This is because peak atomoxetine concentration occurs 1-2 hrs after ingestion. The Vanderbilt Orthostatic Symptom Score (VOSS) was used on the symptom feedback form, where patients are asked to rank the following on a scale from 1-10: mental clouding, brain fog, shortness of breath, palpitations, tremors, headache, tightness in the chest, blurred vision, and nausea. The lowest (1) is no symptom burden, and 10 is the worst. 

Researchers found that when patients took atomoxetine, their symptom burden increased. This presented a statistically significant increase in heart rate and a general upward trend in blood pressure throughout the 4 hours. In the case of the placebo, there was a decrease in symptom burden as the 4-hour period progressed. 

Atomoxetine is a non-stimulant medication used to treat ADHD; unfortunately, the stimulant alternatives are found to have similar effects on POTS patients. Due to a susceptibility to heart rate changes, ADHD medication negatively interacts with the condition and must be administered with exceeding caution. This interaction is important for prescribing professionals to be aware of. As this is a relatively under-researched intersection, consideration of mechanisms and close patient-doctor communication is necessary when considering medication. 

Figure 1: Results of VOSS with and without atomoxetine (Green et al., 2013)

Graph describing the effects of the medication on POTS symptoms

References

De Crescenzo, F., Ziganshina, L. E., Yudina, E. V., Kaplan, Y. C., Ciabattini, M., Wei, Y., & Hoyle, C. H. (2018). Noradrenaline reuptake inhibitors (NRIs) for attention deficit hyperactivity disorder (ADHD) in adults. The Cochrane Database of Systematic Reviews, 2018(6), CD013044. https://doi.org/10.1002/14651858.CD013044

Green, E. A., Raj, V., Shibao, C. A., Biaggioni, I., Black, B. K., Dupont, W. D., Robertson, D., & Raj, S. R. (2013). Effects of norepinephrine reuptake inhibition on postural tachycardia syndrome. Journal of the American Heart Association, 2(5), e000395. https://doi.org/10.1161/JAHA.113.000395

POTS: Causes, Symptoms, Diagnosis & Treatment. (n.d.). Cleveland Clinic. Retrieved April 8, 2025, from https://my.clevelandclinic.org/health/diseases/16560-postural-orthostatic-tachycardia-syndrome-pots

 

Groundbreaking Ebola Virus Disease Treatment In Development to Reduce Infections and Case Fatality

by

Introduction

The Ebola virus disease (EVD) was discovered in Africa in 1976. It causes excessive bleeding in humans and some primates and is often fatal. EVD is highly transmissible and is spread by direct contact (Jacob et al., 2020). There are six known strains of EVD today: Zaire, Sudan, Tai Forest, Bundibugyo, Reston, and Bombali. All except the Reston and Bombali strains can cause diseases in humans. Its transmission into humans is believed to have occurred when Patient Zero went hunting and consumed the meat of an infected animal (Jacob et al., 2020). In the years since its discovery, there have been dozens of outbreaks worldwide, mostly in Africa and Europe (Mohd et al., 2024).

The Sudan strain of EVD has nearly a 90% case-fatality rate, and the disease is usually fatal within a month. This virus appears and disappears in sporadic epidemics, which makes it difficult to find cures for. Viruses are more difficult to preserve in a lab than bacterial or fungal samples since viruses require host cells to stay alive, and since EVD is caused by a virus rather than a bacteria, it is difficult to keep samples intact in a laboratory for ongoing studies after an outbreak ends. Survivors of EVD generate antibodies to the virus, which serves as an EVD-specific line of defense should they be infected again (Jacob et al., 2020). The search for a cure to EVD has centered around the production of such antibodies without exposing patients to the disease first.

Vaccines are created by introducing weakened or inactive forms of a virus to the body. This agent does not have the capacity to cause disease in the patient. However, it demonstrates for the immune system what the active form of that virus would look like and allows the body to create antibodies to prepare for a full infection, should one ever occur. The immune system uses this experience to prepare for an infection by generating antibodies specific to the pathogen introduced. Monoclonal antibodies (immune signaling chemicals that alert B and T cells of the presence of specific pathogens) can also be artificially created and introduced directly into the body, which is another type of treatment made possible by this study.

EVD infects hosts when individual virus particles bind to healthy body cells and hijack the cell’s machinery to create more viruses. All cells have receptor sites on their membranes that are used for communication. Each receptor type is unique and fits the shape of a specific messenger chemical (ligand) which is absorbed into the cell for processing. Some ligands, however, are structurally similar enough to pathogen surface proteins that their respective receptors can be used to absorb pathogens into a cell. The cell has no way of knowing what is attached to the molecule binding to it, so a pathogen can easily enter a cell this way (Hastie et al., 2025).

EVD’s RNA genome codes for seven proteins, five of which contribute to the external structure of virus particles. One such structural protein is the glycoprotein (a molecular signal composed of protein-like and sugar-like parts) on the surface of Ebola particles, which is essential for the pathogen to bind to and enter host cells.

Methods

Glycoproteins, which are sometimes called spike proteins, are diverse among pathogens and therefore are an effective segment to use to create an array of effective vaccines. In this experiment, researchers at the La Jolla Institute for Immunology used x-ray crystallography to visualize the structure of an Ebola particle. The surface glycoproteins 1 and 2 were isolated from the Ebola virus to investigate the sites where the virus is able to bind to human cells (Hastie et al., 2025).

Results

This experiment revealed through in vitro and mouse trials that a receptor known as 3A6 on human cell membranes is the binding site for EVD through both glycoproteins 1 and 2 (Hastie et al., 2025). Since site 3A6 binds to these unique proteins, monoclonal antibodies that would target EVD pathogens would have a similar structure. Once such antibodies can be created, the body has a method for detecting EVD particles in the bloodstream and destroying them before they can replicate beyond control.

Conclusion and Discussion

Now that the method of cell entry for Ebola virions has been studied, the next step is to create accessible treatments – both preventative and therapeutic – for people at risk of contracting EVD. It is known that the glycoproteins 1 and 2 studied here have a relatively slow rate of mutation on a viral scale, which means that any treatments that can be manufactured to focus on these spike proteins will be effective for a long time. In other words, a person who has been exposed to a vaccine containing an inactive Ebolavirus glycoprotein 1 or 2 will have a better outcome if infected than they would if they had been vaccinated with a different piece of the virus. On the other hand, flu vaccines need to be renewed every year because influenza spike proteins mutate much faster, which means that immunity to the spike protein of last year’s strain becomes obsolete as soon as a new strain takes hold.

Knowledge of the 3A6 binding site is valuable for eventual immunity to EVD and related filoviruses. As with any disease, when more people become vaccinated against it, it becomes less likely that deadly outbreaks will continue appearing as sporadically as they do.

Works Cited:

Hastie, Kathryn M., et al. “Anti-Ebola Virus MAb 3A6 Protects Highly Viremic Animals from Fatal Outcome via Binding GP(1,2) in a Position Elevated from the Virion Membrane.” Nature Communications, vol. 16, no. 1, Nature Portfolio, Feb. 2025, https://doi.org/10.1038/s41467-025-56452-2. Accessed 7 Feb. 2025..

Jacob, Shevin T., et al. “Ebola Virus Disease.” Nature Reviews Disease Primers, vol. 6, no. 1, Feb. 2020, www.nature.com/articles/s41572-020-0154-4..

Mohd, Omar B., et al. “The Development of Ebola Virus Outbreaks: A Review of Epidemiological Trends, Clinical Features, and Treatment Advances.” Cureus, Cureus, Inc., Nov. 2024, https://doi.org/10.7759/cureus.74078. Accessed 11 Jan. 2025..

TMJ Arthroscopy: How well does it work in Ehlers Danlos patients?

by

The temporomandibular joint (TMJ) is responsible for the mandible’s chewing, talking, and all movement. As a condylar joint, this joint allows motion in two planes: side to side and up and down. A disc cushions the bone to facilitate this motion and serves as a lubricant. 

 

Figure 1: TMJ diagram (TMJ Disorders – Symptoms and Causes, n.d.).

 Temporomandibular disorders (TMD) often arise from damage or irritation relating to the disc. To determine the condition of the joint, physicians use the Wilkes scale, which allows for the assessment of internal derangement/damage of the TMJ. TMD is often a symptom of a larger condition, it can arise from connective tissue disorders, injury, teeth grinding, etc.

 

Figure 2: Wilkes Scale descriptive table (Table 1 . Wilkes Classification of TMJ Internal Derangement, n.d.)

 

 

A patient’s placement on this scale indicates the type of treatment they could be a candidate for.  This could range from over-the-counter medications to physical therapy, to Botox injections, and a variety of surgeries. A surgery often seen is a TMJ arthroscopy.  The arthroscopic element refers to the minimally invasive approach assisted by a camera called an arthroscope. Done under general anesthesia, a surgeon will enter the joint space through a small incision. The image of the joint is delivered to a screen through an arthroscope. During the procedure, the surgeon may reposition the disc, flush the joint, and remove scar tissue to alleviate pain (Arthroscopy for Temporomandibular Disorders (TMDs) | Kaiser Permanente, n.d.). This, however, is not the only option, and can only be decided upon looking at the full picture of a patient’s history—for example, a connective tissue disorder. 

Ehlers-Danlos (EDS) is a group of connective tissue disorders that can affect many systems, including the joints and, in turn, the TMJ.  Within the group, each particular variation has a different set of symptoms. For example, vascular EDS causes the blood vessels to rupture, whereas hypermobile EDS (hEDS) causes frequent joint dislocations. Some types of EDS have a clear genetic link, however, the origins of hEDS have yet to be understood. Due to the overly flexible nature of their joints, hEDS patients often encounter issues with their TMJ.  (Ehlers-Danlos Syndrome – Symptoms and Causes, n.d.).

Jerjes et al. conducted a retrospective case study that looked at the outcomes of 18 hEDS patients who underwent arthroscopic surgery to treat their TMDs. All patients were female and between the ages of 23-60 years old. Due to the EDS, TMJ dislocation was a common history within the sample. In turn, the dislocations were linked to the damage and pain, which were visualized during the arthroscopies. This demonstrated a link between the state on the TMJ and hEDS status. Moreover, 12 out of the 18 experienced TMD bilaterally, meaning there was pain on both sides (Jerjes et al., 2010). 

Furthermore, it seemed as though the intervention was most commonly done at/by the Wilkes Stage III (9 patients at Stage III and 5 at Stage II ). As seen in Figure 2, Stage III is characterized by moderate disc deformity and frequent pain/dislocations.  As the Wilkes Scale goes on, the condition becomes more painful and harder to treat. However, although minimally invasive, arthroscopy is considered a more extreme treatment for TMJ. Over the years, the procedure has developed and improved, reaching an 80-90% success rate (Insel et al., 2020). Despite this, the National Institute of Dental and Craniofacial Research brochure still has a negative outlook on the surgical route as a treatment for TMDs (Jerjes et al., 2010). 

Notwithstanding the controversy, Jerjes et al. demonstrate positive post-operative results. The pain subsided quickly (within 1 week post-operative) for 15 out of 18 patients and 5-6 weeks for the remaining 3. Delayed healing occurred in 4 out of 18 patients. Slow healing is a characteristic of hEDS and could be a potential reason in this case for the post-surgical complication. Most importantly, the mouth opening measured 6 months postoperatively increased from an average of approximately 23-28 mm,  with all final postoperative results being positive. 

Overall, the study aims to illustrate the success of TMJ arthroscopy in hEDS patients and suggests it as the first consideration for invasive procedures. Due to hEDS patients often having a difficult time with wound healing, a minimally invasive procedure is favored. Additionally, these patients have previously sought out other forms of treatment before surgery. This study does not suggest that surgery should be an initial consideration, but it should not be forgotten as an option. 

 

Figure 3: Outside view of an TMJ arthroscopy 

Figure 4: Internal photo is TMJ arthroscopy

 

The hEDS population is small; therefore, studies that center on them and how treatments interact with their condition are few and far between. Moreover, providers for TMJ-related surgeries are scarce. In turn, this middle ground (as noted by Jerjes et al. ) is a neglected area of research. Further development would focus on EDS patients more and seek to understand the interconnectedness of EDS and joint pain and how it can impact the choice of treatments. 

 

References

Arthroscopy for Temporomandibular Disorders (TMDs) | Kaiser Permanente. (n.d.). Retrieved April 8, 2025, from https://healthy.kaiserpermanente.org/health-wellness/health-encyclopedia/he.arthroscopy-for-temporomandibular-disorders-tmds.hw209368

Ehlers-Danlos syndrome—Symptoms and causes. (n.d.). Mayo Clinic. Retrieved April 8, 2025, from https://www.mayoclinic.org/diseases-conditions/ehlers-danlos-syndrome/symptoms-causes/syc-20362125

Insel, O., Glickman, A., Reeve, G., Kahan, B., Tran, T., & Israel, H. (2020). New criteria demonstrate successful outcomes following temporomandibular joint (TMJ) arthroscopy. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 130(1), e20–e21. https://doi.org/10.1016/j.oooo.2019.12.022

Jerjes, W., Upile, T., Shah, P., Abbas, S., Vincent, A., & Hopper, C. (2010). TMJ arthroscopy in patients with Ehlers Danlos syndrome: Case series. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 110(2), e12–e20. https://doi.org/10.1016/j.tripleo.2010.03.024

Table 1. Wilkes classification of TMJ internal derangement. (n.d.). ResearchGate. Retrieved April 8, 2025, from https://www.researchgate.net/figure/Wilkes-classification-of-TMJ-internal-derangement_tbl1_7691660

TMJ disorders—Symptoms and causes. (n.d.). Mayo Clinic. Retrieved April 8, 2025, from https://www.mayoclinic.org/diseases-conditions/tmj/symptoms-causes/syc-20350941

Top Five Fun Facts About The TMJ. (2022, July 14). Ladner Village Physiotherapy | Delta BC. https://ladnervillagephysio.com/blog/top-five-fun-facts-about-the-tmj

 

Airborne Bacteria: A Hidden Regulator of Ocean Blooms

by

Context

Marine phytoplankton are microscopic algae integral to oceanic ecosystems and global biogeochemical cycles. They contribute significantly to the process of carbon displacement into the deep ocean and primary production, forming the foundation of the marine food web. However, these phytoplankton populations are vulnerable to various environmental and biological stressors, including temperature changes, nutrient availability, and pathogen infections. When a phytoplankton bloom collapses, bacteria consume their organic matter, a process that requires oxygen. The decay of the bloom and oxygen levels can deplete oxygen and lead to “dead zones” that can suffocate marine life (US EPA, 2013). Researching the components of bloom dynamics enables us to better understand their interactions as a foundation of the food web and regulator of oxygen levels.

 

Fig 1. Demise of a phytoplankton bloom over the course of a handful of days (Demise of a Phytoplankton Bloom, 2014)

One of the most abundant bloom-forming phytoplankton is Gephyrocapsa Huxley, a species of coccolithophore, a type of phytoplankton covered in calcium carbonate plates known for its widespread blooms in the ocean. While viral infections have long been recognized as a primary cause of phytoplankton bloom collapse, researchers have questioned whether bacteria could be another potential source of pathogenicity. Recent research regarding G. huxleyi phytoplankton suggests so.

 

Fig 2. Calcium carbonate plating on a coccolithophore phytoplankton (Briggs, 2021)

 

This groundbreaking study by Lang-Yona et al. investigated whether airborne bacteria could infect G. huxleyi blooms and be an explanation for bloom collapses. This research aimed to analyze atmospheric bacteria as an ecological regulator of phytoplankton populations, an often disregarded consideration in the dynamics of oceanic microbial interactions and climate models. Understanding these interactions is critical for predicting changes in marine ecosystems and their impact on global carbon cycles.

Methods of the Study

To explore whether airborne bacteria play a role in controlling phytoplankton populations, researchers collected air and water samples above a bloom of G. huxleyi in the North Atlantic. They conducted this work aboard the research vessel R/V Tara, using specialized instruments to capture airborne bacteria at different heights. These included high-volume air samplers and devices called cascade impactors, which were set up at different points on the ship, including the deck and mast. This setup allowed them to collect bacteria from various altitudes and better understand how microbes travel through the air (Lang-Yona et al., 2024)

Back in the lab, the team introduced the airborne bacteria into cultures of G. huxleyi to see what would happen. They carefully watched for signs of infection, such as a drop in the algae’s natural fluorescence (a sign they were losing their ability to photosynthesize), increased debris in the water (indicating cell death), and visible damage to the algal cells. When signs of infection appeared, they filtered out the bacteria from the cultures and grew them on a nutrient-rich surface called Marine Agar 2216. This step helped them isolate specific bacterial strains. To confirm that these bacteria were truly responsible for the infection, they then reintroduced them to fresh G. huxleyi cultures and checked whether the same effects occurred.

To track how the bacteria and algae interacted over time, researchers used a technique called flow cytometry. This method shines a laser through tiny droplets of water containing cells, measuring their size, shape, and natural glow. It allows scientists to quickly count how many algae and bacteria are present and determine how the infection is progressing.

Finally, they identified the bacteria using genetic sequencing and measured their presence in air and water samples with a technique called quantitative PCR (qPCR). This method detects and counts bacterial DNA, helping researchers understand how common these airborne microbes are in different environments.

Results of the Study and Implications

The study identified the airborne bacterium Roseovarius nubinhibens as a key bacteria capable of infecting and contributing to the collapse of G. huxleyi blooms. This bacterium was found to remain viable after atmospheric transport and effectively infects phytoplankton upon reaching ocean waters. The ability of R. nubinhibens to survive and remain pathogenic after airborne dispersal suggests a more dynamic role for bacteria in ocean-atmosphere interactions than previously recognized.

The ability of bacteria to be transported via wind patterns indicates a geologically vast and major mechanism that has previously been overlooked. The findings suggest that in addition to viral infections, bacterial pathogens may serve as natural regulators of phytoplankton populations, influencing bloom duration and oceanic carbon cycling. This discovery is particularly significant because phytoplankton blooms play a critical role in the global carbon cycle by taking carbon from the atmosphere, and upon death, sinking to the deep ocean where the carbon is stored. If bacterial infections contribute to bloom collapse and can be dispersed so vastly,  they may influence carbon fluxes in ways that need to be accounted for in climate models.

Previously, viral infections were considered the primary biological driver of bloom decline, but this study introduces airborne bacteria as an additional player in phytoplankton mortality. This raises important questions about how environmental factors such as wind patterns and ocean currents influence bacterial dispersal. Additionally, climate change may impact the spread of airborne pathogens, potentially altering bloom dynamics in unforeseen ways. A warming climate and shifting atmospheric circulation patterns could enhance or suppress the spread of algicidal bacteria, with cascading effects on marine ecosystems.

Furthermore, this research highlights the complexity of microbial interactions in the ocean. Many bacterial species exhibit “Jekyll-and-Hyde” dynamics, shifting between mutualism and pathogenicity depending on environmental conditions and the physiological state of their algal hosts. In the case of R. nubinhibens, it is possible that under certain conditions, it exists in a neutral or even beneficial relationship with G. huxleyi, but when environmental factors such as nutrient depletion or increased bacterial density trigger a shift, it becomes pathogenic. The study’s infection experiments demonstrated that R. nubinhibens could rapidly induce algal demise, suggesting a transition from a benign to an algicidal state. This aligns with previous findings that some marine bacteria can switch between cooperative and harmful interactions based on chemical signaling. Understanding these complex interactions is essential for developing a more accurate picture of microbial regulation in marine environments, as such shifts can significantly alter bloom dynamics and oceanic food webs.

This study provides new insight into the role of airborne bacteria in regulating marine phytoplankton populations, demonstrating that Roseovarius nubinhibens can contribute to G. huxleyi bloom collapse. These findings expand our understanding of ocean-atmosphere microbial interactions and introduce airborne bacteria as an important but previously overlooked factor in bloom dynamics. Incorporating airborne bacterial processes into ecological and climate models will be crucial for accurately predicting future oceanic changes. Further research is necessary to determine whether other phytoplankton species are similarly affected and how environmental shifts may influence the prevalence and impact of airborne bacterial infections on marine ecosystems. Understanding these dynamics is essential for assessing ocean health and resilience in a rapidly changing climate.

 

References:

Briggs, G. M. (2021). Coccolithophores, photosynthetic unicellular algae. https://milnepublishing.geneseo.edu/botany/chapter/emiliana-huxleyi/

Demise of a Phytoplankton Bloom. (2014, November 26). [Text.Article]. NASA Earth Observatory. https://earthobservatory.nasa.gov/images/84797/demise-of-a-phytoplankton-bloom

Lang-Yona, N., Flores, J. M., Nir-Zadock, T. S., Nussbaum, I., Koren, I., & Vardi, A. (2024). Impact of airborne algicidal bacteria on marine phytoplankton blooms. The ISME Journal, 18(1), wrae016. https://doi.org/10.1093/ismejo/wrae016

US EPA, O. (2013, March 12). The Effects: Dead Zones and Harmful Algal Blooms [Overviews and Factsheets]. https://www.epa.gov/nutrientpollution/effects-dead-zones-and-harmful-algal-blooms

 

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

by

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-

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

by

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. 

Auspicious Algae: Using Diatoms to make Disease-fighting Human Antibodies

by

Arrangement of diatoms (art by Klaus Kemp)

Besides appearing like a lovely spread for an I Spy book, the above image holds many scientific secrets and perhaps solutions. Diatoms, known as “jewels of the sea,” are a type of single-celled phytoplankton (aka algae) that create their own glass shell and produce at least 20% of Earth’s atmospheric oxygen. And perhaps, they can contribute to the treatment of many different diseases, including cancer.

As promising specimens of microalgae, they have been co-opted by the biotech industry for their ability to make complex lipids, sugars, and even proteins through a process called recombinant production. Traditionally, these molecules are made through classical systems such as yeasts, bacteria, and other single-celled organisms that are easy to manipulate in a lab. Microalgae, a more recent biotech specimen, is more efficient because it can produce its own energy from sunlight and air alone through photosynthesis, whereas other cells must be fed carbon. Thus, algae propose the possibility of a solar-powered system that can manufacture specific proteins with high efficiency. In 2012, microbiologists Franziska Hempel and Uwe G Maier modified the diatom P. tricornutum through recombinant production to make IgG antibodies, a protein that immune cells use to fight foreign pathogens in the blood.

Diatom expression of antibodies (illustration by author)

To understand how recombinant production works, we’ll look at the central dogma of molecular biology—a name both dramatic and apt. In short, the central dogma states that proteins are made in cells through the flow of information from DNA to a protein. DNA, the keeper of all protein “instructions,” is copied into RNA, the messenger which carries this information to ribosomes, the actual protein “factories.” From here, ribosomes translate the information in the RNA into the form of protein. After this, the protein is modified (post-translational modifications) to be sent off or used within the cell. This entire process—DNA information being transformed into proteins—is called gene expression.

Because proteins are made from whatever information is in DNA, biotechnologists discovered that by altering DNA, you can also alter the proteins created. In recombinant production, foreign DNA (DNA from another cell) is inserted into a host cell’s DNA  (the cell that is making the protein). Through the central dogma, this results in the expression of genes from the foreign DNA to make specific proteins. In the diatom-antibody experiment, Hempel and Maier injected the human DNA  for making CL4mAb IgG antibodies (a type of protein used by the immune system) into diatom DNA, so that human DNA will be expressed into IgG antibodies by the diatom. You can think of DNA as the instructions to make the antibodies, and the diatom as the machine. Once new protein instructions are injected into the machine’s existing instructions, the machine will begin to create the new proteins based on the instructions. The kind of protein produced depends on the specific instructions, on the specific segments of foreign DNA inserted into the diatom’s DNA.

In using diatoms to make recombinant proteins, Hempel and Maier made five promising discoveries:

1) The diatom P. tricornutum very efficiently produces antibodies, accounting for a significant 9% (efficient in the biotech world)  of total soluble protein.

2) It secretes antibodies directly into the extracellular medium . This is a big economic advantage because the cells don’t need to be lysed (broken) to harvest the product.

3) Diatoms don’t naturally secrete many proteins, so the secreted antibodies are already very pure.

4) The antibodies are fully assembled and functional. In fact, the diatom has mechanisms to guarantee that only fully assembled antibodies can leave the cell . This makes it act virtually like a human plasma cell, an immune cell that secretes antibodies. This ability is absent in other recombinant producing species, such as bacteria.

5) The antibodies are stable for at least 2 days. When the diatoms become unproductive, they can easily be stimulated again when the culture medium is replaced.

Due to these findings, diatoms and other species of microalgae on the whole present great economic and scientific potential for making antibodies as well as other proteins. When tested against the Hepatitis B virus, the IgG antibodies were proven functional.

Why would scientists want to make antibodies anyway? In the naturally functioning human body, antibodies are proteins secreted by plasma cells that bind to antigens (specific protein receptors) on the surface of germs and other harmful foreign cells, rendering them harmless. Laboratory-made antibodies—such as the antibodies created by diatoms—are also known as monoclonal antibodies (mAbs) and have similar applications. In Hempel and Maier’s study, specific IgG antibodies were made to target the Hepatitis B virus. In other instances, mAB shape can be modified to bind to certain targets, such as antigens on cancer cells, viruses, and other bacteria. Because antibodies are proteins that bind to receptors unique to specific cells, they are also used to locate certain cells. For example, monoclonal antibodies are used in identifying where there is cancer in the body and even in carrying drugs to cancer cells.

Thus, the efficiency of monoclonal antibody production, as demonstrated in the diatom experiment, is key in treating specific ailments on a microscopic level. Currently, mammal cells are used for 60-70% of recombinant pharmaceuticals, but cultivation is expensive (due to having to feed them) and there’s always the risk of pathogenic contamination. Algae, if modified to be as efficient as mammalian cells, may prove to be a more economically and sustainably suitable alternative. They perform very well in producing recombinant proteins, without needing to be fed. Additionally, any aquarium owner knows that they grow at rapid rates.

It is no secret that global cancer rates have been on the rise. These growing biotechnological methods allows scientists to creatively explore different possibilities of treatment, from nanotechnology to photodynamic therapy, to our beloved monoclonal antibodies. Solutions may be found everywhere, from the tiniest protons to the inconspicuous jewel of the sea. And so the search continues!

 

Sources

Hempel, F., & Maier, U. G. (2012, September 13). An engineered diatom acting like a plasma cell secreting human IGG antibodies with high efficiency – microbial cell factories. BioMed Central. https://microbialcellfactories.biomedcentral.com/articles/10.1186/1475-2859-11-126

NCI Dictionary of Cancer terms. Comprehensive Cancer Information – NCI. (n.d.). https://www.cancer.gov/publications/dictionaries/cancer-terms/def/monoclonal-antibody

 

 

Microscopic X-men Survive Thousands More X-rays Than Humans

by

New study finds novel protein linked to water bears’ extreme radiation resistance with applications to cancer treatment.

Water bears, or tardigrades, are microscopic creatures with eight legs. They are so hardy, Stan Lee may very well have drawn inspiration from them while writing X-men. What they lack in telekinesis, invisibility, and shapeshifting, they make up for in resilience to extreme temperatures, high pressures, vacuum environments, dehydration, starvation, and DNA-damaging ionizing radiation (IR). To put things into perspective: Humans can tolerate at most 5 grays (unit of radiation), while tardigrades can survive upwards of 4,000 grays. The exact mechanisms behind their IR resistance remain unclear, prompting researchers to investigate their genetic code in hopes of uncovering insights that could benefit human health.

When IR comes in contact with DNA, it can cut through one or both strands of the DNA double helix structure, leaving behind single or double-stranded breaks. To prevent genomic instability and cell death, some genes encode proteins that form mini shields against IR, while others encode corrective proteins involved in repair mechanisms after IR damage. A team of researchers at Paris-Saclay university in Orsay, France found that human and tardigrade cells sustain similar damage after IR exposure, but that human cells died, whereas tardigrade cells did not. This suggests humans and tardigrades have similar preventative strategies, but only tardigrades are equipped with the repair mechanisms needed to recover.

To explore the possible genes involved in these repair mechanisms, the researchers used a technique called transcriptomics on three species of tardigrades. With this technique, they sequenced RNA from cells of the three species after IR exposure. The sequences told the researchers which genes were turned on in response to IR, and how those differed among the three species. They found upregulated expression of numerous previously described DNA repair genes across all three species. However, one gene – also shared across the three species – stood out in particular. When examining its RNA sequence, the researchers realized they had encountered the code to a novel protein. They called it TDR1, or Tardigrade Damage Response 1.

The exact role TDR1 plays in DNA repair is unclear. Nevertheless, observations of TDR1 aggregates in tardigrade cells suggest TDR1 might be involved in a DNA condensation mechanism. In other words, when DNA experiences breakage from IR, TDR1 proteins mobilize to change the DNA’s three-dimensional structure into a densely packed cellular space around the breakage. This structural change introduces DNA pockets where crucial repair enzymes are more likely to come in contact with broken DNA segments. This way, TDR1 helps restore the DNA’s structural integrity.

Besides merely describing TDR1, the researchers also sought to understand whether TDR1 protein could be applied to human cells. They found that, when expressed in human cells, the TDR1 gene also helped our cells recover from IR damage. This advance in understanding IR resistance could have immediate applications to cancer treatment because today’s methods still often rely on heavy doses of ionizing radiation. IR does not only cut through the cancer cells’ DNA, it cuts through all the healthy cells caught in its crosshairs as well. Therefore, with the development of new IR resistance tools, we may be able to reduce the side effects resulting from healthy cell damage after radiation therapy.

Sources:

Dall’Agnese, G., Dall’Agnese, A., Banani, S. F., Codrich, M., Matilde Clarissa Malfatti, Giulia Antoniali, & Tell, G. (2023). Role of condensates in modulating DNA repair pathways and its implication for chemoresistance. Journal of Biological Chemistry, 299(6), 104800–104800. https://doi.org/10.1016/j.jbc.2023.104800

M. Anoud, E. Delagoutte, Q. Helleu, Brion, A., E. Duvernois-Berthet, M. As, Marques, X., K. Lamribet, C. Senamaud, L. Jourdren, A. Adrait, Heinrich, S., G. Toutirais, S. Hamlaoui, G. Gropplero, Giovannini, I., L. Ponger, M. Gèze, C. Blugeon, & Coute, Y. (2024). Comparative transcriptomics reveal a novel tardigrade specific DNA binding protein induced in response to ionizing radiation. PubMed Central, 13:RP92621. https://doi.org/10.7554/elife.92621

Cover image credit: “Mikrofoto.de-Baertierchen3” by Frank Fox at http://www.mikro-foto.de/ is licensed under CC BY-SA 3.0 Germany.