[TRC] Summer 2023 Research Journal

A systematic review of the application of CAR- T Cells within CRISPR/CAS-9 Technology: An insight into its abilities and limitations regarding various diseases Helena Kaaua, Helen Ejigu, Zena Brantuo, Kayla Shaw, and Arya Soppanawar Mentor: Giovanna Napoleone, Columbia University

Abstract

Materials and Methods

Chimeric antigen receptor (CAR) T-cell therapy has been successful in treating leukemias, lymphomas, and myelomas. Within CAR T-cell therapy, the CAR cells, which are receptor T-cells that have been manufactured in a lab, contain a new receptor so that they can attach to cancer cells while killing them. With a 50-80% average success rate in utilizing CAR T-cell therapy, this mechanism is currently being used for applications associated with CRISPR technology. Despite the triumphs of CAR T-cell therapy, there are still drawbacks such as lethal toxicities, refusal to accept in B-cell malignancies, as well as its varied efficiency against solid tumors. With the rise of CRISPR gene editing, it is possible to mitigate some of these drawbacks though an intersection between the two methods. CRISPR (Clustered regularly interspaced short palindromic repeats) is a gene editing tool that can transform DNA entirely through adding, omitting and altering the genetic material at locations throughout the organism. With CRISPR technology, various diseases have been treated, including but not limited to: breast cancer, colon cancer, lung cancer, sickle cell disease, and beta thalassemia. New research highlights additional CRISPR-Cas system varieties, including miniCas or CRISPRI which can be supplemented for gene editing. This review evaluates the abilities and restraints of CRISPRCas9 editing with the application of CAR- T cells in clinical trials.

This systematic review follows a comprehensive list of clinical trials in regards to CAR T-cell therapy treatments for future applications with the CRISPR system. The clinical trials were collected from PubMed, ClinicalTrials.gov, and the National Center for Biotechnology. The following searches were performed: “CAR T-cell therapy,” “CRISPR treatment with leukemia,” and “CRISPR-Cas9 treatment in Sickle Cell Disease, Alzheimer’s, Beta Thalassemia, and Lymphoma.” Only trials conducted within the past 5 years were selected. The following information was collected across studies: disease type, number of people tested, and number of people cured. The data collected from the trials were supplemented with published science journals and articles that explained new CRISPR and CAR T-cell therapy techniques and their applications to various diseases. Any limitations to this study may include variable experimental factors conducted in each clinical trial not controlled through the analysis of this literature review, for the purpose of individual laboratory studies outside the scope of this review. Trials that did not meet our analysis standard of five years and off a clinicals trials database or website. or were unavailable to open review were excluded from the data collection process.

Discussion CRISPR Technology As new advancements of gene therapy begin to surface, CRISPR-Cas9 has already made strides in the research and application of genome editing technology, despite its short lifespan. The system not only recognizes genetic mutations within the human genome, but directly alters DNA sequences and modifies existing genetic material— with far more precision and accuracy in comparison to its counterparts. CRISPRCas9 is composed of two main components: 1) the Cas9 protein linked to the target cell, and 2) the guide RNA which directs the protein to modify the precise location of the mutation. As the RNA first recognizes the targeted sequence and is met with the matching DNA sequence, the guide RNA is coupled with the Cas9 protein, at which point the RNA sequence is identified to either be replaced or added on to an existing DNA strand. In Figure 1, the system demonstrates either a modification (paired with the homologous combination) or complete replacement (non-homologous combination) of a DNA sequence using the CRISPR-Cas9 system:

Figure 1 displays the CRISPR-Cas9 system producing an intended DSB (double-strand break) that can be controlled for the purpose of gene mutation and editing.

Applications of CAR-T related methods to tackle varied diseases

Beta Thalassemia and Sickle Cell Disease Sickle Cell Disease has seen unprecedented success with its applications regarding CRISPR therapy. Most commonly known as sickle cell disease, a blood disorder that is genetic causing red blood cells to shrink into a “sickle” shape, these cells die prematurely leaving healthy blood cells by themselves. Beta thalassemia is another similar blood disorder that reduces the production of hemoglobin, an protein carrying iron in red blood cells that distributes oxygen to cells amongst the body. The contrasting factor between the differentiation of the two diseases is that SCD is generated by a specific mutation in the HBB gene while BT can arise as a result of several mutations within the same gene. Treating SCD alongside CRISPR utilizes an ex vivo method where HSCs (stem cells) are omitted from the body, altered, then inserted back into the body. As doing such will stimulate the production of new erythrocytes, this mechanism also generates attacks on BCL11A which inhibits the production of HBG1, thus preventing the protein from expanding and HBG1 can grow. The specific type of HSCS’ that are passed on is CD34+ cells, these cells are able to reconstruct erythrocytes into the hematopoietic system. Following this, damaged or disease-causing cells are omitted through chemotherapy, and CRISPR edited cells are reinjected into a patients body.

Patients with BT and SCD have shown unremarkable outcomes in trials, specifically the CTX001 trial. Results from a trial containing patients treated once with CTX10001 display the intended results with most test subjects displaying higher levels of hemoglobin in their blood. Within CTX001, the stem cells are tweaked to generate HbF, a form of oxygen with hemoglobin that is present at birth, then it’s regenerated to the adult form of hemoglobin. Phase 1 of the trial included 75 patients (31 with Sickle Cell Disease and 44 with Beta Thalassemia), of which these patients had a follow-up ranging from 1.2 to 37.2 months. Out of the BT patients, 26 exhibited beta-zero genotypes, however 42 of the BT patients were transfusion free, and the other two patients who were not transfusion free had an 89% and 75% reduction in their transfusion volume. Likewise, all 31 patients with SCD were free of VOCs, a crisis occurring when compromised red blood cells obstruct blood flow to where the tissues become oxygen deprived. Their HbF levels had risen by about 40% and continued to remain the same for months. Among the BT patients, only 2 had symptoms, such as ARDS and HLN as well as an unknown pneumonia symptom that arised. The study has now progressed to Phase 3, now allowing for ages 2 through 11 years to participate and will translate to children 2 and under later. In regards to CAR-T Cell Therapy, this application has not been attributed to either of these diseases. As such, CAR-T cell therapy must be conducted on these two diseases before forming a valid conclusion on whether CAR-T cells with CRISPR technology could be applicable to SCD and BT.

Figure 3: CTX001 Therapy displayed in regards to SCD and BT.

Introduction CAR-T Therapy Genes are a foundational part of the human body, as they are portions of Deoxyribose Nucleic Acid (DNA). By altering specific sequences within DNA, gene editing technology has the potential to cure genetic disorders and cancers. Part of this new technology includes the gene editing technology of CRISPR-Cas9. The CRISPR technology is able to rewrite genetic material through utilizing RNA as a guide for Cas-9, an enzyme to lock onto a specific spot on the DNA, therefore unzipping it and splitting the genetic material apart causing the organism to self-heal. While CRISPR is taking control of gene therapy, there is also another alternative named CAR T-cell therapy. CAR T-cell therapy contains the CAR cells, which are receptor T-cells that have been manufactured in a lab, containing a new receptor so that they can attach to cancer cells while killing them. As diseases continue to wipe out populations, scientists utilize both CAR T-cells and CRISPR, aiming to discover remedies. As such, there is a clear need and ability to conjoin the two in forming CRISPR therapy that has an application with CAR-T cells.

Results With the data collection stemming from multiple clinical trials, each with its own uniqueness and specificity, it is imperative to draw correlation analysis and formulate inductive conclusions regarding CRISPR-CAS9 and CAR-T therapy.

Meanwhile, as CAR-T cell therapy trials were only available for two diseases, the limited data cannot produce a valid conclusion as to whether CAR-T cells can be implemented with CRISPR. Specifically with Leukemia in regard to CRISPR therapy, the clinical trial at GOSH yielded a lower recovery rate than the trial with CAR-T. It should be noted, however, the trial with CRISPR-edited T cells had only 6 people and a 25% recovery rate while the CAR-T trial had 75 people and a 73%. While the CRISPR recovery rate in Leukemia was low, an ongoing Lymphoma CRISPR trial with CAR-T cells has a 69% recovery rate, thus providing a platform for a logical conclusion that CRISPR and CAR-T combined could yield a higher recovery rate than any trial that uses only one of the methods.

CAR T-cells are modified t-cell immune cells used to tackle certain cancers. CARTcells use a chimeric antigen receptor (CAR) which gives them the ability to more effectively seek out and destroy cancerous cells than a host’s native t-cells. The chimeric antigen receptor, seen in Figure 2, is an artificial protein and sources its cancer fighting properties from its unique combination of structures specific to a targeted disease. As seen in Figure 2, the “head” or extracellular portion of the chimeric antigen receptor consists of a protein known as scFv. ScFv is sourced from a specific antibody’s heavy and light chains, and combined with a peptide linker ranging anywhere from 10-25 amino acids. ScFv contains the same antigen-binding specificity of the antibody used to make it, which contributes to the specificity of the CART-cell being created to target a disease. On the other hand, the “tail” intracellular portion of the chimeric antigen receptor consists of a CD3 zeta domain. This portion of the chimeric antigen receptor is sourced from the CD3 complex, which is responsible for activating a t-cell during an immune response in the presence of a specific antigen to aid the t-cell receptors (TCR). The CD3 zeta domain is responsible for connecting the intracellular, signal transduction pathways responsible for triggering a T-cell immune response to the extracellular antigen recognition and binding. The chimeric antigen receptor possesses both scFv and CD3 zeta proteins, hence the term “chimeric.” The chimeric antigen receptor couples the antigen specificity of scFv and the ability of CD3 zeta to trigger an immune response of a given T-cell.

Figure 2 : Fig. 2 displays the structure of a CAR (chimeric antigen receptor). A normal CAR has a binding domain link, hinge region, transmembrane domain, and a stimulatory/activating domain.

References Beaudoin F, Thokala P, Nikitin D, Campbell J, Spackman E, McKenna A, Pearson SD, Rind DM. Gene Therapies for Sickle Cell Disease: Effectiveness and Value; Draft Evidence Report. Institute for Clinical and Economic Review, April 12, 2023.

Britannica, The Editors of Encyclopaedia. Leukemia. Encyclopedia Britannica; 2023.

Cao A, Galanello R. Beta-thalassemia. Genet Med. 2010 Feb;12(2):61-76. doi: 10.1097/GIM.0b013e3181cd68ed. PMID: 20098328.

Cushman-Vokoun AM, Voelkerding KV, Fung MK, et al. A primer on chimeric antigen receptor T-cell therapy: what does it mean for pathologists?.

Arch Patho Lab Med. 2021; 145(6): 704-16.

Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):1-11.

De Plano LM, Calabrese G, Conoci S, Guglielmino SPP, Oddo S, Caccamo A. Applications of CRISPR-Cas9 in Alzheimer's Disease and Related Disorders. Int J Mol Sci. 2022 Aug 5;23(15):8714. doi: 10.3390/ijms23158714.

PMID: 35955847; PMCID: PMC9368966.

Dimitri, A., Herbst, F. & Fraietta, J.A. Engineering the next-generation of CAR T-cells with CRISPR-Cas9 gene editing. Mol Cancer 21, 78 (2022).

Ding Y, Li H, Chen L-L and Xie K (2016) Recent Advances in Genome Editing Using CRISPR/Cas9. Front. Plant Sci. 7:703. doi: 10.3389/fpls.2016.00703 Devkota, Gaurav Gupta, Dinesh Kumar Chellappan, Sachin Kumar Singh, Kamal Dua, Janne Ruokolainen, Mohammad Amjad Kamal, Shreesh Ojha, Niraj Kumar Jha, CRISPR/Cas9 gene editing: New hope for Alzheimer's disease therapeutics, Journal of Advanced Research, Volume 40, 2022, Pages 207-221 Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2. PMID: 34515338; PMCID: PMC8436585.

Hughes-Parry Hannah E., Cross Ryan S., and Jenkins, Misty R. The Evolving Protein Engineering in the Design of Chimeric Antigen Receptor T Cells. Volume 21 Issue 1. MDPI; 2019.

Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR, McGettigan SE, Nace AK, Dentchev T, Thekkat P, Loew A, Boesteanu AC, Cogdill AP, Chen T, Fraietta JA, Kloss CC, Posey AD Jr, Engels B, Singh R, Ezell T, Idamakanti N, Ramones MH, Li N, Zhou L, Plesa G, Seykora JT, Okada H, June CH, Brogdon JL, Maus MV. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med. 2015 Feb 18;7(275):275ra22. doi: 10.1126/scitranslmed.aaa4963. PMID: 25696001; PMCID: PMC4467166.

Katti, A., Diaz, B.J., Caragine, C.M. et al. CRISPR in cancer biology and therapy. Nat Rev Cancer 22, 2022;259–279.

Keen C., Blood test detects risk of neurotoxicity from CAR T-cell therapy..

Healthcare in Europe. 2022 3 p.

Kliegman RM, et al. The leukemias. In: Nelson Textbook of Pediatrics.

21st ed. Elsevier; 2020..

Maggs L, Cattaneo G, Dal AE, Moghaddam AS and Ferrone S. CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma. Front.

Neurosci. 2021; 15:662064. doi: 10.3389/fnins.2021.662064 Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. doi: 10.1056/NEJMoa1709866. PMID: 29385370; PMCID: PMC5996391.

Morgenstern Daniel A.,Irwin Meredith S., Chapter 15 - Current and Future Strategies for Treatment of Relapsed Neuroblastoma, Editor(s): Swapan K. Ray, Neuroblastoma, Academic Press, 2019,Pages 263-281, Razeghian, E., Nasution, M.K.M., Rahman, H.S. et al. A deep insight into CRISPR/Cas9 application in CAR-T cell-based tumor immunotherapies.

12,428. Stem Cell Res Ther; 2021 Salas-Mckee J, Kong W, Gladney WL, Jadlowsky JK, Plesa G, Davis MM, Fraietta JA. CRISPR/Cas9-based genome editing in the era of CAR T cell immunotherapy. Hum Vaccin Immunother. 2019;15(5):1126-1132. doi: 10.1080/21645515.2019.1571893. Epub 2019 Apr 2. PMID: 30735463; PMCID: PMC6605860.

Sarkar E, Khan A. Erratic journey of CRISPR/Cas9 in oncology from bench-work to successful-clinical therapy. Cancer Treat Res Commun.

2021;27:100289. doi: 10.1016/j.ctarc.2020.100289. Epub 2021 Feb 10.

PMID: 33667951.

Shanu Bhardwaj, Kavindra Kumar Kesari, Mahesh Rachamalla, Shalini Mani, Ghulam Md. Ashraf, Saurabh Kumar Jha, Pravir Kumar, Rashmi K. Ambasta, Harish Dureja, Hari Pra

A systematic review of the application of CAR- T Cells within CRISPR/CAS-9 Technology: An insight into its abilities and limitations regarding various diseases Helena Kaaua, Helen Ejigu, Zena Brantuo, Kayla Shaw, and Arya Soppanawar Mentor: Giovanna Napoleone, Columbia University

References

Discussion Leukemia

Cancers Cancer is a disease that originates from mutations in genetic codes of DNA, leading to abnormal cell division and growth. Protooncogenes, tumor suppressor genes, and DNA repair genes become most affected by genetic changes that contribute to cancer, due to their important roles in the cycle cycle. Both protooncogenes and tumor suppressor genes are responsible for controlling cell growth, and when an alteration occurs to these genes they might divide in an uncontrollable manner. When protooncogenes are overactivated, they become oncogenes genes (cancer causing genes). When tumor suppressor genes become inactivated, they allow the growth of a tumor, and are also cancer-causing. DNA repair genes are involved in fixing damaged DNA, thus when a mutation occurs within these genes, uncontrollable duplications and deletions of chromosomes can occur, which may develop into cancerous cells. Uncontrollable cell growth can ultimately lead to the formation of cancerous tumors that spread throughout the body, a process called metastasis. In order to prevent cancerous gene mutations from occurring, scientists over the years have been searching to find methods of controlling tumor growth and the genetic errors that can lead to cancer. Based on recent studies, both CRISPR Cas-9 and CAR T-cell therapies can potentially be used to target cancer causing genes and tumors.

Scientists are using CRISPR to genetically alter immune system cells— known as T-cells— from healthy donors to effectively attack cancers through CAR-Tcell immunotherapy. Using this approach, T- cells are taken from a patient’s blood and become genetically modified by adding a gene within the CRISPR editing complex to a chimeric antigen receptor (CAR)chimeric antigen receptor (CAR). By re-engineering the t-cell receptor proteins, the CAR can recognize and bind to specific antigens present on the surface of cancer cells. This allows the T- cells to effectively attack a specific cancer cell, target antigen.

Cancer cells can evade the immune system by blocking immune checkpoint receptors and overstimulating peripheral tolerance. Cancer cells can also mimic immune checkpoint receptors, leading to T-cells not detecting them as harmful. For example, one of the main immune receptor proteins called PD-1 interacts with another receptor called PD-L1 to signal when a healthy cell is present, and its expression on cancerous tumor cells creates an immunosuppressive environment for the tumor. This effect is detrimental towards CAR T- cells as it lowers its activation and response rates. CRISPR assists in the construction of CAR T-cells able to detect these cancerous cells by ensuring the correct “off” signals are placed on the receptor through a checkpoint inhibition. Activated or “on” CAR T- cells multiply and signal through cytokines (signaling proteins). Both activated CAR- T- cells and cytokines then causes significant inflammation of the cancer cell, leading to apoptosis. The revamped CAR T- cells are infused back into the patient to multiply and strengthen the immune system. Sometimes CAR-T- cells are turned “off” and stop killing cancer cells, a phenomenon known as T-cell exhaustion. Scientists believe T-cell exhaustion may be linked to transcription factors: proteins that regulate a cell turning on and off via gene activation or inactivation during translation. However, CRISPR Cas-9 has the capability to create edits that can minimize T-cell exhaustion and increase their long term proliferation, while limiting CAR-T-cell toxicity. Most trials done on cancer using CRISPR and CAR T-cell technology today are to treat lymphoma and leukemia. There are several different clinical trials involving cancer that are currently ongoing, two of which this review will consider for analysis that will take both CRISPR and CAR T-cell therapy technologies into consideration.

Lymphoma Lymphoma is a cancer of the lymphatic system and is an overarching term to describe a cluster of blood diseases that punctures bone marrow and produces an enlargement of lymph nodes. There are two main types of lymphomas: Hodgkin and Non Hodgkin's. Hodgkin lymphoma has a specific type of lymphocyte (Reed-Sternberg) associated with the disease, and Non Hodgkin’s lymphoma does not have this cell type present. Many trials focused on treating lymphoma have been effective through the treatment of regular CAR-T Cell therapy. Because of its effectiveness, recent research indicates that these trials may be improved through the implementation of new CRISPR technology.. In a phase III trial containing patients with B-cell lymphoma who received axi-cell CAR T cell therapy, 180 patients had axi-cell therapy and 179 patients had “standard car treatment,, with an intended outcome of-event-free survival. After 4.5 years, researchers found that the number of deaths had risen to 45% in the axi-cell therapy group, and 53% in the standard care group. In addition, a 14.7 month Progression-free survival rate (PFS) was found in the axi-cell cohort and 3.7 month PFS was found in the standard care group. A Phase 1 clinical trial utilizing CRISPR jointly with CAR T-cells emerged in 2023 to treat non-Hodgkin lymphoma. The trial administered T-cells with an increased efficiency by adding a molecule named 1XX within the CAR and injecting it in the DNA.The mesothelin 1XX is engineered to prolong CAR-T cells without developing exhaustion within the cells. The trial was conducted at the Memorial Sloan Kettering Cancer Center (MSK), and is progressing onto Phase 2 trials with a response rate of 69% -a rate which remained intact after a 155 day follow up. The CRISPR model will be essential in creating new CAR cells able to target cancers at more specific locations by targeted DNA strand sequences relating to lymphoma, or any blood cancer. Figure 3 displays the cycle of CRISPR in regards to blood cancer, highlighting the production of TRAC, PDCD1, and TRBC loci which are then binded with a lentiviral vector and then put back into the bloodstream.

These findings indicate that there is a potential for applying this joint therapy to other diseases. However, it is challenging to prove the efficacy as the trial of the CAR- T Cells and CRISPR has not yet finished and will not for another year.

Leukemia describes a broad spectrum of cancers targeting the blood, especially ones that involve blood cell formation, development, and function. Leukemia is characterized by mutations in both the cell cycle and the stem cell cycle, which are classified as lymphocytic or myelogenous leukemias. Normally, immature stem cells known as lymphoid or myeloid form and process as white blood cells. These cells are typically extracted from the spongy tissue composed inside of bone structures and are critical to the generation of new cells. Leukemia occurs when a mutation occurs within the normal cell cycle.

Acute Leukemia involves immature stem cells that have not fully developed yet, but proliferate beyond control. In comparison, chronic Leukemia involves mature or partially mature cells that have become mutated, preventing them from carrying out their intended function. Once a cell mutates, it rapidly multiplies and overcrowds healthy blood cells from occupying the space available within the bone marrow. If left untreated, these cells may spread throughout the body, and the disease can spread to create tumors and affect tissues and organs from functioning properly. It is critical for patients to receive the right care and attention to eradicate these cancerous cells before further progression of the disease occurs. Currently, scientists are assessing the effectiveness of CAR-T-cell therapy and CRISPR-Cas9 for a complete remission of leukemia patients in several clinical trials. Prior to CRISPR-Cas9 technology, CAR-T-cell therapy has produced significant results in the remission rates of thousands of patients battling all four types of leukemia. Trial ELIANA (Novartis) involved children and young adults with B-cell Acute Lymphocytic Leukemia (B-ALL) who previously relapsed or did not respond to other forms of therapies. Phase 1-2a involved the usage of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy via tisagenlecleucel—resulting in high complete remission rates amongst participants. The trial was later found to have produced serious toxic, but mainly reversible adverse effects among child related and young adults. In Phase 2 of the clinical trial, the study expanded to a global study, where a single cohort was treated to test tisagenlecleucel in pediatric patients and young adults. At the end of the trial, scientists hoped to achieve full complete remission of all patients within 3 months of timed-interval infusions. Within the study, 75 patients received a single dose of tisagenlecleucel, an anti-CD19 CAR T-cell therapy in the form of infusions. Optimal results were defined as high remission rates (complete remission or complete remission with incomplete hematologist recovery) within 3 months of the first dosage. At the end of the study, the event-free overall survival rate was estimated at 73% of all patients. New corrective measures in CAR T-cell therapy aligned with CRISPR technology to increase total recovery rates amongst patients. In a clinical trial conducted by researchers at Great Ormond Street Hospital for Children (GOSH) and UCL Great Ormond Street Institute of Child Health (UCL GOS ICH), researchers used CRISPR-Cas9 technology to genetically edit donor T-cells used for CAR-T-cell therapy. Within the trial, T-cells were modified via the CRISPR-Cas9 technology to insert a genetic code which helps direct the T-cell in revealing the chimeric antigen receptor used to detect a target marker and rectify tumorous b-cells. The trial consisted of 6 patients ranging from 14 months to11 years of age with B-ALL who relapsed or were unresponsive to previous forms of therapy. Of the 6 patients, 4 went into remission for 28 days after trial analysis. Currently, 2 patients remain in remission for 9 months and 18 months. Although these results may not include high remission rates amongst all participants, the 2 remaining patients in remission reveal recovery results that call for future clinical trials involving both CAR-T-cell therapy and CRISPR technology. Because of the limitations and possible side effects present in CAR-T therapy, CRISPR technology can utilize T-donor cells and effectively revolutionize the future of immunotherapy altogether.

Alzheimer's Disease Alzheimer’s disease is the most common neurodegenerative disorder. It is defined by the abnormal accumulation of tau, a protein essential in maintaining the structure and stability of the cell’s internal transport system in the neurons, and amyloid beta Aβ, a protein fragment that is a key component of amyloid plaques. The CRISPR-Cas9 system was developed to improve sequence-specific gene editing in cell lines and animals. Including cancers and other blood disorders, the technology has served as a tool for treating human genetic diseases, including Alzheimer’s. In previous years, animal models of Alzheimer’s have been generated by overexpressing mutated genes from humans involved in the production of the tau and Aβ proteins. Testing the protein’s functions within mouse models, researchers at the University of California San Diego found that CRISPR gene editing treatments have led to the reduction of beta-amyloid plaques and associated markers of brain inflammation. These studies have also found an increase in neuroprotective APP (amyloid precursor protein) products and a correction of behavioral and nervous system function deficits. These animal models have been helpful, but have been unable to develop overt neurodegeneration symptoms found in humans. As a result, CRISPR-Cas9 technology is now being used to create Alzheimer’s disease models that show a more accurate disease phenotype for the purpose of finding new avenues of treatment and therapy. To reduce Aβ production, Cas9 activators and inhibitors have been employed. A catalytically inactive Cas9 (dCas9) has been combined with gene activators and inhibitors, which are driven to the target gene through the guidance of RNA. However, instead of prompting a double-strand break of DNA, a general transcriptional activator or inhibitor is carried with the dCas9 system to increase or decrease the expression of the target gene. Several research groups have generated Cas9 activator nano complexes, and non-viral delivery systems with potential therapeutic applications. This approach has been successful in vivo to decrease the expression of BACE-1. The result was the reduction of Aβ production and the concomitant amelioration of AD-like pathology. The potential applications of CRISPR-Cas9 have been successfully tested in a variety of animal models, and emerging clinical trials are being planned to test it on humans.CAR-T cells have also attracted the attention of scientists over the past 10 years. CAR-T cells have made strides in treating neurological cancers such as Glioblastoma and Neuroblastoma, due to their ability to cross the blood-brain barrier and use various targets. However, the use of CAR-T cell therapy in treating neurological disorders/diseases, such as Multiple Sclerosis is still being investigated as a potential treatment option. In Multiple Sclerosis, CAR-T cell therapy has been well tolerated and rarely associated with irreversible CNS adverse events. Thus, anti-CD19 CAR-T cells represent a highly potent tool for depleting CD19+ B cells in the periphery and the CNS, making them a viable treatment strategy for testing in patients with MS, as well as in other neurodegenerative diseases.

Limitations Figure 4: Displays T-cells being detached from a patient with blood cancer. CRISPR-Cas9 proteins are filled with 3 sgRNAs yielding a gene edit to create TRAC, PDCD1, TRBC loci. A lentiviral vector is applied to the cells intended for gene expression for specific antigens. Finally, the CRISPR manufactured T-cells are reinjected back into the patient.

While CRISPR/Cas9 is a revolutionary technology that has limitless applications when used to improve CAR T-cell therapy, it has notable limitations.

CRISPR Cas-9 is not 100% accurate and reliable, and as such, off-target edits (unwanted or unexpected changes to the gene) can occur. This may result in undesired mutations which can affect the viability of a patient’s DNA to a larger extent.

CAR T-cell therapy has been linked to neurotoxicity. Two side effects are common as a result of the treatment: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

CRISPR material is difficult to deliver to mature cells in large quantities, remaining a problem for many clinical applications.

The long-term consequences of CRISPR genetic modifications are not well understood, and the ability to edit a human germline raises ethical concerns.

CRISPR-Cas9 technology yields ethical debates about its regulatory safety measures, possible gene mutations that could transfer reproductively or affect future generations and genetic diversity, as well as a possible exploitation of patients who choose to be test subjects.

Conclusion The implications of CRISPR and its potential effects when being used with CAR T-cell therapy is highly varied amongst different disease conditions. Being naturally related as well as the fact that CAR-T cells can be a product of CRISPR technology refers to the similarities in the conditions that they excel at treating. Conditions with genetic predispositions and proteins with genetic targets largely fare better with patient recovery outcomes, and possible implementation of CRISPR as opposed to CAR T-cell therapies. Such conditions encompass, but are not limited to, Beta Thalassemia and Sickle Cell Anemia, as well as several neurodegenerative diseases such as Alzeimher’s. However, when it comes to treating blood cancers and cell cycle diseases which more largely involve the immune system, CAR T-cell therapy is most effective. Although this is known in current research, the implementation of CRISPR within CAR T-cell therapies may prove to be even more effective for these cancer diseases as opposed to former versions of the therapy. While the target-specific nature of CAR T-cells in identifying cells that are diseased poses many advantages over CRISPR therapies for leukemia and lymphoma, a CAR’s function can be enhanced through the use of CRISPR. Ultimately, both CRISPR and Car T-cells technologies demonstrate how varied and adaptable modern day treatments are for different conditions. While growing at a rapid pace, the future of these two intersections appears promising for biomedical engineers. The brevity of biotechnology that people have access to today far outclasses anything that those in the past decade could have conceived of. As such, the human innovations today proceed to push the boundaries of what can be achievable.

Sulaiman, Amal,Al-Shamaa, Amer, Al-Assadi, Mohammad. EVOLVING ROLE OF CAR TCELL IN CANCER IMMUNOTHERAPY. VL - 11. International Journal of Current Pharmaceutical Research. 2019.

Shinwari ZK, Tanveer F, Khalil AT. Ethical Issues Regarding CRISPR Mediated Genome Editing.

Curr Issues Mol Biol. 2018;26:103-110. doi: 10.21775/cimb.026.103. Epub 2017 Sep 7. PMID: 28879860.

Staff National Cancer Institute. How CRISPR Is Changing Cancer Research and Treatment.

National Cancer Institute. 2020 6 p.

Stefanoudakis D, Kathuria-Prakash N, Sun AW, Abel M, Drolen CE, Ashbaugh C, Zhang S, Hui G, Tabatabaei YA, Zektser Y, Lopez LP, Pantuck A, Drakaki A. The Potential Revolution of Cancer Treatment with CRISPR Technology. Cancers (Basel). 2023 Mar 17;15(6):1813. doi: 10.3390/cancers15061813. PMID: 36980699; PMCID: PMC10046289.

Tavakoli K, Pour-Aboughadareh A, Kianersi F, Poczai P, Etminan A, Shooshtari L. Applications of CRISPR-Cas9 as an Advanced Genome Editing System in Life Sciences. BioTech (Basel). 2021 Jul 6;10(3):14. doi: 10.3390/biotech10030014. PMID: 35822768; PMCID: PMC9245484.

University College London, Children with resistant leukemia given CRISPR-edited T cells: Phase 1 study results reported. London: ScienceDaily; 2022 2 p.

Vo Van Giau, Hyon Lee, Kyu Hwan Shim, Eva Bagyinszky & Seong Soo A. An Genome-editing applications of CRISPR–Cas9 to promote in vitro studies of Alzheimer’s disease, Clinical Interventions in Aging, 2018;p. 221-233, DOI: 10.2147/CIA.S155145 Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A, Rapoport AP, Sureda A, Jacobson CA, Farooq U, van Meerten T, Ulrickson M, Elsawy M, Leslie LA, Chaganti S, Dickinson M, Dorritie K, Reagan PM, McGuirk J, Song KW, Riedell PA, Minnema MC, Yang Y, Vardhanabhuti S, Filosto S, Cheng P, Shahani SA, Schupp M, To C, Locke FL; ZUMA-7 Investigators; Kite Members. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med. 2023 Jul 13;389(2):148-157. doi: 10.1056/NEJMoa2301665. Epub 2023 Jun 5. PMID: 37272527.

Zarghamian P, Klermund J and Cathomen T (2023) Clinical genome editing to treat sickle cell disease—A brief update. Front. Med. 9:1065377. doi: 10.3389/fmed.2022.1065377

Acknowledgments The authors of this paper gratefully acknowledge mentor Giovanna Napoleone for her time and effort in developing this research project. Her knowledge and research guidance was extremely helpful in aiding the authors to success. The authors of this paper would like to also thank The Research Catalyst Fellowship Program for giving them the resources and foundational structure to conduct research and develop their ideas in a welcoming environment.

Deep analysis on why atrial septal defects occur in infants Surya Ani, Shantosmita Biswas, Vidhi Patel, Katie Vo Giovanna Napoleone, Columbia University

Abstract A hole in the atrial septum, which divides the two upper chambers of the heart, is the hallmark of an atrial septal defect (ASD), a congenital heart condition. Infants are affected by this illness, which if neglected, can cause a number of difficulties. For early detection, prevention, and efficient care of ASD, it is essential to comprehend the underlying causes of the disorder. By evaluating a number of variables, including genetic predisposition, environmental impacts, and embryological development, this study attempts to provide a deeper insight of why ASD occurs in children.

Introduction Atrial septum defect (ASD) is a congenital heart defect where a hole in the heart's septum divides the left and right atrium.

This causes oxygen-rich blood to leak into oxygen-poor blood, reducing oxygen delivery to infants. This raises blood pressure and heart rate, causing the heart to pump harder. If not diagnosed early, ASD can damage organs and shorten lifespans. Most children with an ASD do not show symptoms, but severe cases may cause longterm damage to lungs' blood vessels.

Infancy-onset ASD is influenced by genetic factors, with gene variants and chromosomal abnormalities linked to increased risk. Small hole openings do not cause symptoms, but severe ASDs can cause long-term damage to lungs' blood vessels. Early diagnosis and testing are crucial for early detection and treatment.

Materials and Methods Diagnosing Atrial Septal Defect in infants involves detecting a heart murmur and ordering an echocardiogram to determine potential leakage. Treatment depends on the severity and location of the lesion, with surgical or non-surgical procedures commonly used to treat ASD in babies: Surgical repair is often recommended for newborns with larger ASDs or symptoms linked to the abnormality. Atrial septal defect closure is the most popular treatment, sealing the atrial septum hole with a patch or sutures after a chest incision. Catheterbased interventions have replaced open heart surgery in some cases, entering the heart via blood arteries. Transcatheter ASD Closure involves inserting a catheter into a blood artery, sealing the atrial septum hole with a device. Balloon atrial septostomy is a temporary treatment for severe ASDs, temporarily improving blood flow and alleviating discomfort.

Results By the second trimester of pregnancy, a baby's heart fully develops, allowing for the development of ASD. Medical conditions, genetic abnormalities, and lifestyle factors can significantly affect organogenesis. Screening for ASD during pregnancy is crucial, especially if the defect is inherited. Small defects aren't fatal, but large ones can cause serious illness.

Discussion Atrial septal defects occur during pregnancy during the formation of a fetus’s organs. The main components that play a role in the development of this condition were found to be genetics, rubella, or German measles, diabetes, lupus, alcohol or tobacco use, illegal drug use, and use of particular medications. The genetic component of ASD may be linked to potential mutations in genes like NKX2-5 and GATA4.

NKX2-5 is involved in the regulation of transcribing genes during morphogenesis where the shape of tissues or organs form during embryonic growth. Because disruptions in NKX25 transcription factor functions are associated with the lack of heart development in Drosophila melanogaster model organisms, further research suggests that it may be a target of future research regarding ASDs in humans. Similarly, GATA4 is a major regulatory transcription factor associated with heart development. In addition to genetic factors, viruses and diseases are also thought to play a role in ASD development. Maternal rubella during pregnancy was found to spread to the placenta and fetus. This infection results in the infection of cardio fibroblasts that are meant to assist in the building of the heart’s cellular structure. This includes regulating the growth of embryonic cardiomyocytes, which form the mature heart chamber, create scaffolding for cardiac cells to attach to, and overall assist in the growth and building process required to form the heart. Moreover, lifestyle choices and diseases, such as unregulated diabetes, is also thought to play a major role in ASD development.

Unregulated diabetes during pregnancy was shown to be likely related to nearly 24% of atrial septal diseases in the United States.

References 1. Atrial Septal Defect (ASD). American Heart Association CPR & First Aid Emergency Cardiovascular Care. [accessed 2023 Aug 17]. https://cpr.heart.org/en/health-topics/congenital-heart-defects/aboutcongenital-heart-defects/atrial-septal-defect-asd 2. Atrial septal defect (ASD). Mayo Clinic. 2022 Mar 1 [accessed 2023 Aug 17]. https://www.mayoclinic.org/diseases-conditions/atrial-septal-defect/symptomscauses/syc-20369715 3. Atrial septal defect (ASD) (2023) www.heart.org. Available at: https://www.heart.org/en/health-topics/congenital-heart-defects/aboutcongenital-heart-defects/atrial-septal-defect-asd (Accessed: 17 August 2023).

4. Diz, O.M. et al. (2021) Personalized genetic diagnosis of congenital heart defects in newborns, Journal of personalized medicine. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235407/ (Accessed: 17 August 2023).

5. professional, C.C. medical (no date) ASD closure: Procedure, risks and Recovery, Cleveland Clinic. Available at: https://my.clevelandclinic.org/health/treatments/22461-asd-closure (Accessed: 17 August 2023).

6. UCSF Health (2023) Minimally invasive closure of atrial septal defect, ucsfhealth.org. Available at: https://www.ucsfhealth.org/treatments/minimallyinvasive-closure-of-atrial-septal-defect (Accessed: 17 August 2023).

7. Atrial septal defect transcatheter repair for children (2023) JHM. Available at: https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/atrialseptal-defect-transcatheter-repair-forchildren#:~:text=ASD%20transcatheter%20repair%20uses%20a,folded%20up%2 0like%20an%20umbrella. (Accessed: 17 August 2023).

8. AboutKidsHealth. Available at: https://www.aboutkidshealth.ca/Article? contentid=1668&language=English (Accessed: 17 August 2023).

9. professional, C.C. medical (no date b) Atrial septal defect (ASD): Symptoms, causes and treatment, Cleveland Clinic. Available at: https://my.clevelandclinic.org/health/diseases/11622-atrial-septal-defect-asd (Accessed: 17 August 2023).

10. Congenital heart defects - facts about atrial septal defects (2023) Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/ncbddd/heartdefects/atrialseptaldefect.html (Accessed: 17 August 2023).

11. Cause‐specific mortality of patients with atrial septal defect and up ...

Available at: https://www.ahajournals.org/doi/10.1161/JAHA.122.027635 (Accessed: 17 August 2023).

Acknowledgments We would like to thank our mentor, Giovanna Napoleone, from Columbia University, and our executives, Vy Ly, Aryana Wadhwani, and Katie Kee, for providing us with the resources and knowledge that we needed in order to make our project a success!

Deep analysis on why atrial septal defects occur in infants Surya Ani, Shantosmita Biswas, Vidhi Patel, Katie Vo Giovanna Napoleone, Columbia University

Introduction

Results

The atrial septum, a crucial part of heart development, can be disrupted during embryological development, leading to ASD. Abnormalities in the septum's formation or fusion, linked to heart development signaling networks, can cause ASD.

Types of ASD include: Secundum: This is the most common type of ASD. It occurs in the middle of the wall between the upper heart chambers (atrial septum).

Primum: This type of ASD affects the lower part of the atrial septum and might occur with other congenital heart defects.

Sinus venosus: This rare type of ASD usually occurs in the upper part of the wall separating the heart chambers. It's also associated with other heart structure changes present at birth.

Coronary sinus: In this rare type of ASD, part of the wall between the coronary sinus — which is part of the vein system of the heart — and the left upper heart chamber (left atrium) is missing.

Secundum

Balloon Atrial Septostomy

Larger atrial septal defects cause symptoms like right-sided heart failure, difficulty breathing, irregular heartbeats, heart murmurs, swelling, stroke, early death, and high blood pressure. Factors contributing to ASD include genetics, German measles infection, diabetes, Lupus, alcohol, tobacco, illegal drugs, and certain medications.

ASD Captured in fetal ultrasound

Primumm

Sinus Venosus

Methods

Transcatheter ASD Closure

Transthoracic echocardiography showing the process of transcatheter device closure of atrial septal defect.

Surgical Repair

Atrial Septal Defect Closure Device

Coronary sinus

Types of ASD

The Role of Neurogenesis in the Curing of Alzheimer's Sherin Biji, Mana Seto Sofia Seewald, Emory University in Atlanta, GA

Abstract

Materials and Methods

Discussion

References

This research presents a synthesis of its topics via X sections, which are as follows:

As Alzheimer's remains a constant topic in medicine, researchers have been in the process of discovering and developing possible cures and preventions.

Alzheimer's is a neurological disorder that slowly destroys the brain leading to the loss of memory and other functions of the brain. This paper explores the depths of whether Alzheimer's can be cured with the help of neurogenesis; the regeneration of the brain cell. The resulting implications may lead to further research and discoveries in order to cure patients and engineer technology that will innovate new openings in the field. keywords: Alzheimer's, neurogenesis, genetic, cure

Introduction Can Alzheirmers be cured via neurogenesis? Alzheimer's is a currently incurable neurological disorder that leads to the loss of memory, communication, and other mental functions (Mayo Clinic n.d).

Neurogenesis is the process by which the neurons are developed. The purpose of this paper is to find out whether Neurogenesis can cure Alzheimer's

The sources for this research have been consolidated from Medical review Organizations, University Articles, and others using Google's common research tool Google Scholar through a meticulous process of filtering, to obtain concise and relevant papers and articles that contribute to solving the questions that were proposed.

Results Bax, a gene that causes cell deaths can be removed using genetic engineering, resulting in the person affected by Alzhemires to have better spacial recognition and contextual memory tasks. As the production of new cells has proven to delay symptoms, Alzheimer's may be cured by genetically modifying the brain to produce more cells, mimicking the brain's natural process of neurogenesis.

Introduction to Alzhemires: Alzheimer's is one of the main reasons why most people get dementia. The majority of the people with this disease are in the age of 65 or over. Those with it below the age of 65 are accounted to have younger-onset Alzhemiers or early-onset. Alzheimer's gradually worsens over the years. In the first few years, people have mild memory loss, but as years pass, they cannot talk or respond to their surroundings. On average, a person with Alzheimer's can live for 5-8 years and 20 years depending on other factors. Alzheimer's destroys one part of the brain which affects all the other parts and gradually leads to all the cells in the brain dying. The damage caused by this disease is irreversible.

(Alzheimer's n.d ) Introduction to Neurogenesis: The process in which new neurons are made in the brain is known as Neurogenesis. This process starts from the embryo and continues throughout life. Each part of the brain has many specialized neurons. For example, the part that plays an important part in memory and spatial navigation is known as the hippocampus. This part has over 27 neurons that are specialized for the hippocampus.

During the process of Neurogenesis the stem cells specialized cells in different parts of the brain and at different times. Stem cells can produce an infinite amount of stem cells, which then turn into different specialized cells. For example, progenitor cells. The progenitor cell then turns into specific types of neurons.

(Research 2018) Treatment for Alzheimer's through neurogenesis A study conducted in 2019 shows that people who are affected by Alzheimer's and have more frequent neurogenesis are more likely to have less cognitive impairment as new cells develop.

Cognitive decline and Dementia could be delayed if the brain cells can regenerate. The same study done on mouse models led by Orly Lazarov from the University of Illinois Chicago discovered that the increase in the production of neurons in the brain can restore one's memory (Spichack 2022).

The researchers at UIC found that when the production of neurons with Alzheimer's mutations was increased and the gene causing cell deaths was removed, the mice had better spatial recognition and contextual memory tasks. These mice were also discovered to have developed dendritic spine structures which play an important role in memory formation. The neurons also achieved to have a more normal profile. Further, when the cells in the mice were edited to deactivate neurogenesis, their spatial recognition and contextual memory worsened, demonstrating the importance of neurogenesis in reversing Azheimer's (Fletcher 2022). Another study by the Massachusetts General Hospital figured out that by genetically increasing the neurons in the brain structure where memories are encoded, Alzheimer's-affected mice showed improved levels of cognitive function.

However, the effects on improved cognition were seen to be blocked by the environment that is created by Alzheimer's in one's brain. Different physical exercises can help in clearing these environments which will help in the growth of new cells (Research 2018).

Implications and further studies Further research should be conducted to find the extent to which neurogenesis and gene editing can retract or delay symptoms, and to develop possible technology and / or medication that is safe for human use in order to retract symptoms.

1. Fletcher L. UIC scientists discover method for restoring memory loss from Alzheimer’s disease. UIC Today [Internet]. 2022 Aug 19 [updated 2023 Aug 17; cited 2023 Aug 17]. Available from: https://today.uic.edu/uic-scientists-discovermethod-for-restoring-memory-loss-from-alzheimers-disease/ 2. Research Study Finds Neurogenesis Can Help Improve Cognition Function in Mouse Model of Alzheimer’s. The Hearing Review [Internet]. 2018 Sept 12 [cited 2023 Aug 16]. Available from: https://hearingreview.com/insidehearing/research/research-study-finds-neurogenesis-can-help-improve-cognitivefunction-mouse-model-alzheimers 3. Spichack S. Neurogenesis: Helping the Brain Grow New Cells in Alzheimer’s.

Beingpatient.com [Internet]. 2022 Feb 24 [cited 2023 Aug 16]. Available from: https://www.beingpatient.com/neurogenesisalzheimers/#:~:text=These%20findings%20came%20with%20an,did%20in%20fact %20improve%20cognition.

4. What is Alzheimer’s Disease? Alzheimer’s Association [Internet]. Available from: https://www.alz.org/alzheimers-dementia/what-is-alzheimers 5. What is Neurogenesis? Queensland, Australia: The University of Queensland, Queensland Brain Institute [Internet]. Available from: https://qbi.uq.edu.au/brainbasics/brain-physiology/whatneurogenesis#:~:text=Neurogenesis%20is%20the%20process%20by,birth%20and %20throughout%20our%20lifespan.

6. Alzheimer [Internet]. Mayo Clinic. [cited 2023Aug.16]. https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptomscauses/syc-20350447.

7. Early-Onset Dementia and Alzheimer [Internet] February 27, 2020. Blue Cross Blue Sheild. [cited 2023Aug.16]. https://www.bcbs.com/the-health-ofamerica/reports/early-onset-dementia-alzheimers-disease-affecting-youngeramerican-adults.

Acknowledgments

Limitation: This project is archival research and merely a collection of implications gathered from existing sources. There were also limitations in the availability of free, accessible sources.

We thank the TRC executives and mentors for providing us with this research opportunity, as well as our mentor who reached out with her support, and our team members who have contributed to this project.

(Early-Onset 2020)

Evaluating the Application of Exosomes in Disease Immunotherapy R. Sleimna, J. Chan, N. Yam S. Seewald, Emory University in Atlanta, GA

Abstract Exosome-based immunotherapy has many methods to its implementation.in this research paper we will be discussing exosome isolation, characterization and immunotherapeutic strategies for some diseases advatages and disadvantages and even in vitro and vivo experiments and the results of some clinical trials

Introduction Exosomes in immunotherapy. In addition to exosome-mediated delivery of anti-cancer drugs to target cancer cells, exosomes can be used in immunotherapy to achieve a sustained and specific immune response against cancer cells. Exosomes can present tumor antigens to dendritic cells (DC cells) and promote DC maturationDue to their nano-size (30–150 nm) and biological functions, exosomes have been used as nano-carriers for small molecules and macromolecules (siRNA and pDNA) in cancer therapy in preclinical studies, as well as biomarkers for cancer diagnosis and prognosis

Materials and Methods According to the title of this experiment, an outline of main components constituting to the applicability of exosome-based therapy was developed. In which extensive research was conducted according to th following subtopics.

1. Exosome Isolation and Chategrizaiton 2. Exosome Loading and Modification 3. Immunotherapeutic Strategies 4. In Vitro and In Vivo Experimentation The above subtopics aim to encapsulate both the procedure of exosome study and utilization, and to pinpoint the main areas in which constitute greatly to the applicability of the vesicle in disease therapy.

Results The Advantages and Disadvantages of different exosome separation technologies

Analysis of exosome-based biomarker clinical trials (A, B) and exosome therapy-based clinical trials for different diseases (C)

Fig A: Showing the percentage of clinical trials conducted, utilizing exosome based bio-markers, of which cancer is the most prominent at 74.13%

Analysis of exosome-based biomarker clinical trials Fig 1: Survey results from ClinicalTrials.gov on the major applications of exosomes Results show the most prominent application of exosomes to be biomarkers, being followed by exosome therapy, for analytical use, as a drug-delivery systems and cancer vaccines.

Fig B: Showing the respective amounts of clinical trials conducted on different diseases using exosome based biomarkers , of which trials regarding lung cancer have been conducted most (>12 trials)

Fig C: Showing the respective amounts of therapy based exosome trials for different diseases, of which SARS Cov2 Pneumonia holds most prominence at ~9 trials

Evaluating the Application of Exosomes in Disease Immunotherapy (cont.)

R. Sleimna, J. Chan, N. Yam Soifa Seewald, Emory University in Atlanta, GA

Discussion The Methods of drug loading in exosomes

Conclusion Specialised exosomes for organ targeting

Exosome drug loading strategies include incubation, electroporation, sonication, freeze–thaw cycle, transfection, extrusion, chimeric exosome method, and endogenous loading. Different methods need to be performed under different conditions and the drug loading efficiency of exosomes depends on different loading methods.

The potential of exosomes in immunotherapy is essentially the effect of Exosomes in the Regulation of Immune Responses: The transfer of exosomes between immune cells can have a strong functional effect on immune responses and either promote, deviate or suppress immune responses. As we have discussed the isolation , characterization, Advantages and disadvantages and much more the fate of exosomes based immunotherapy is looking bright

Acknowledgements

Conditions of drug loading, loading efficiency, and exosome source under different drug loading strategies The authors would like to express their gratitude towards all authors of the journals and articles both referenced and cited, the mentor of our group for her guidance and support, all members for their contribution and last but not least the members of TRC for this wonderful and eye-opening opportunity.

Analyzing the potential modifications of exosomes for clinical applications

Displaying analysis for drug loading methods, categorized according to the following factors: 1. loading method 2. type and nature of drug loaded 3. loading efficiency of drugs 4. exosome source

Prospects for future modifications future research will be needed to explore potential modifications on exosomes Topics of future research extending on current data include: constructing exosomes to specifically serve drug delivery and clinical efficacy alternative drug delivery options predictions of exosome long-term safety and efficacy exploring methods to safely and effectively anchor targeting peptides on exosomes is still a problematic issue

References Arima Y, Liu W, Takahashi Y, Nishikawa M, Takakura Y. Effects of Localization of Antigen Proteins in Antigen-Loaded Exosomes on Efficiency of Antigen Presentation. Molecular Pharmaceutics. 2019 March 25; 16 (6), 2309-2314; doi: 10.1021/acs.molpharmaceut.8b01093 Liu C, Su C. Design strategies and application progress of therapeutic exosomes. Theranostics. 2019 Jan 30;9(4):1015-1028. doi: 10.7150/thno.30853. PMID: 30867813; PMCID: PMC6401399.

BioMed Central [Internet]. Isolation and characterization of exosomes for cancer research - Journal of Hematology & Oncology; [cited 2023 Aug 17]. Available from: https://jhoonline.biomedcentral.com/articles/10.1186/s13045-020-00987-y BioMed Central [Internet]. A review on exosomes application in clinical trials: perspective, questions, and challenges - Cell Communication and Signaling; [cited 2023 Aug 17]. Available from: https://biosignaling.biomedcentral.com/articles/10.1186/s12964022-00959-4#Sec6 Chaput N, Taïeb J, Schartz NE, André F, Angevin E, Zitvogel L. Exosome-based immunotherapy. Cancer Immunol Immunother. 2004 Mar;53(3):234-9. doi: 10.1007/s00262-003-0472-x. Epub 2004 Jan 16. PMID: 14727085.

Fu S, Wang Y, Xia X, Zheng JC.Exosome engineering: Current progress in cargo loading and targeted delivery, NanoImpact, Volume 20,2020, 100261, ISSN 2452-0748, https://doi.org/10.1016/j.impact.2020.100261.

Gangadaran P, Madhyastha H, Madhyastha R, Rajendran RL, Nakajima Y, Watanabe N, Velikkakath AKG, Hong CM, Gopi RV, Muthukalianan GK, Valsala Gopalakrishnan A, Jeyaraman M, Ahn BC. The emerging role of exosomes in innate immunity, diagnosis and therapy. Front Immunol. 2023 Jan 16;13:1085057. doi: 10.3389/fimmu.2022.1085057. PMID: 36726968; PMCID: PMC9885214.

Hu K, McKay PF, Samnuan K, Najer A, Blakney AK, Che J, O'Driscoll G, Cihova M, Stevens MM, Shattock RJ. Presentation of antigen on extracellular vesicles using transmembrane domains from viral glycoproteins for enhanced immunogenicity. J Extracell Vesicles. 2022 Mar;11(3):e12199. doi: 10.1002/jev2.12199. PMID: 35233930; PMCID: PMC8888812.

Hussain MWA, Jahangir S, Ghosh B, Yesmin F, Anis A, Satil SN, Anwar F, Rashid MH. Exosomes for Regulation of Immune Responses and Immunotherapy. Journal of Nanotheranostics. 2022 March 16; 14(1):55-85. https://doi.org/10.3390/jnt3010005 Li, M., Li, S., Du, C., Zhang, Y., Li, Y., Chu, L., Han, X., Galons, H., Zhang, Y., Sun, H., & Yu, P. (2020). Exosomes from different cells: Characteristics, modifications, and therapeutic applications. European Journal of Medicinal Chemistry, 207, 112784. https://doi.org/10.1016/j.ejmech.2020.112784 Zeng H, Guo S, Ren X, Wu Z, Liu S, Yao X. Current Strategies for Exosome Cargo Loading and Targeting Delivery. Cells. 2023 May 17;12(10):1416. doi: 10.3390/cells12101416. PMID: 37408250; PMCID: PMC10216928.

GREEN COMPUTING:

The Impact on the Environment, Business Operations, and Computational Science

Arushi Dashore, Renee Cargill, Hayat Farah Prince Tufon, Massachusetts Institute of Technology

Abstract This study explored the applications of green computing in business operations, whilst taking into consideration the legislative actions to be made or improved upon to ensure green computing succeeds. Current markets for computing corporations contribute to the climate stresses through poor chip and system design that wastes materials. By exploring the idea of green computing, companies can increase efficiency in the workplace and cut back on manufacturing costs- protecting the environment. Starting with Energy Star launched by the EPA in 1992, green computing was introduced to the computing world, saving billions in costs through energy efficiency. More chips have been redesigned to mirror this, as well as using materials that are gentle on the environment and last longer. These results warrant legislative actions to solidify the future of computing in a sustainable frame.

Fig 1a.

Discussion

Fig 1b.

Introduction The primary focus of this study is to identify the intersection of green computing and business operations, harping on the impact energy efficient hardware has on company profitability and environmental health. Problems with recent computing trends consist of hardware inefficiencies that hinder business processes and lead to greater environmental degradation through harvesting materials. Through green computing, it has been found that businesses can actually cut back costs on manufacturing whilst also operating in a sustainable way. This prompted discussions of legislative actions necessary to make green computing an expectation in modern computing.

Fig 2.

Methods and Materials Environment: Resource hungry software demands for faster CPUs leading to the need for newer computer hardware. This creates an endless, wasteful cycle (2).

Another example of this is most chip designs are optimized for size, performance, and battery life. Despite the chip having about 100 square millimeters of silicon, it’s greatly inefficient as only a portion of it is actually utilized in elongating battery life, leaving the rest to waste. Additionally, the technology industry (ICT)’s estimated contribution to global carbon emission is between 1.8 to 3.9% (7).

Business Operations: Though profitability is higher in traditional IT, the operational costs are higher than profits. Green IT, in general, not only has lower operational costs but also yields a higher percentage of profitability in comparison to the cost. (refer to Fig 2.)

Computational Science: Green computing can be seen through two lenses (refer to Fig 1a). Furthermore, use of green technology in computational science varies on the specific sector. It should be noted that power profiling has the least green technology adoption whereas cloud computing and virtualization has the highest adoption (refer to Fig 1b.)

Results The correlation between green technology adoption and the 50% decrease in operating costs after the implication of Green IT practices showcases that green technology is a less expensive alternative to traditional IT.

Surprisingly, traditional computing is thought to cause minimal environmental impact, however, these practices are quite harmful. Unfortunately, the results express that many corporations focus on efficiency and disregard the environmental problems caused. It is crucial that environmental effects are considered as the elevation of carbon emissions can lead to a climate crisis, hence food shortages, and eventually mass extinction (11). One solution that this study investigated was green computing and its influence on business and computational science. Green IT minimizes the damaging effects on the environment by designing energy efficient chips, building software that does not rely on exceeding amounts of CPU & GPU, and creating technology from non harmful materials (10). Furthermore, green technology also optimizes profits for businesses (Fig 2). However, to guarantee that environmental concerns will become an important factor in business decision making, legislation is necessary.

For instance, the Green Act of 2021 offers five years of tax credit for the installation of renewable energy facilities (4). Similarly, tax credit for a certain amount of time can be awarded for implementing green technologies. The ratification of a green energy bill for the technology sector permits recording data on the emissions produced, thus, highlights who releases excessive amounts.

These extreme producers will face fines. Nonetheless, this study’s main limitation is to what extent can tax credit be rewarded and if it’ll be enough to persuade businesses to change traditional methods. In the future, researchers should explore how much tax credit is allowed to be given and expand upon more ways to easily install green technology.

The overall verdict is that green computing benefits not only the environment, but also the design and manufacturing of software and hardware used in computational science. Businesses who have already incorporated green technology earn a higher percentage of profitability. These findings demonstrate that the technology sector can aid in reducing global carbon emissions and no longer be part of the problem.

The waste produced from unused chips and outdated computer hardware is linked to the estimated 1.8% to 3.9% of global carbon emissions produced from ICT. The relationship between traditional IT practices and 1.8% to 3.9% of global carbon emissions caused by ICT.

References

Acknowledgements

See to the next slide for the list of the references used in the research of this literature review.

Many thanks to TRC (The Research Catalysts) for their guidance throughout the research process and to our mentor Prince Tufon for his valuable insights regarding direction in this literature review.

1.

1.

References 1) Agarwal S., Basu K., Nath A. Green Computing and Green Technology based teaching learning and administration in Higher Education Institutions, online journal, 2013 Sept.

2) Agarwal S., Nath A., Chowdhury D., Sustainable Approaches and Good Practices in Software Engineering, online journal, 2012.

3) Burrows L. Smaller, Faster, Greener. Cambridge: Harvard School of Engineering and Applied Sciences; 2021.

4) Congress, H.R.848: Growing Renewable Energy and Efficiency Now Act of 2021 or the GREEN Act of 2021, 2021-2022.

5) Dziurzyński, D. How is Green IT shaping the software development industry?, website, 2023.

6) Everest Global Inc., The Environment’s Calling: Sustainable Software Application Development Is the Need of the Hour, website, 2021.

7) Knowles B. ACM TechBrief: Computing and Climate Change. Lancaster: ACM Technology Policy Council; 2021.

8) Merritt R., What Is Green Computing?, website, NVIDIA, 2022 9) Salama M. Green Computing, a Contribution to Save the Environment. Lancaster: Lancaster University; 2020.

10) What is Green Computing?. Armonk: IBM; 2022.

11) With New Climate Pact, Tech Companies Take on Climate Change. Nairobi: UNEP; 2021.

12) Zajer M. Green Coding: The Secrets to Unlocking More Sustainable Software Engineering, website, 2022.

The Applications and Ethics of CRISPR-Cas9 Angela Dong, Kalie Huynh, Justin Pham, Christina Uong Sean Mintz, MIT

Abstract

Materials and Methods

Cluster regularly interspaced short palindromic repeats-associated protein 9, also known as CRISPR-Cas9, has emerged as an innovative instrument in the realm of biotechnology. This review explores the chief elements of Cas9 and sgRNA that drive the technology and its ways of delivery of microinjection, electroporation, and vector methods. This discovery has opened up vast and transformative applications in various fields, such as medical advancements in numerous diseases, medicinal supplements, and the food industry.

However, with this comes its ethical considerations. Its capability to delete, correct, and insert new genes raises complications in human genetics, where professionals can edit certain genetic traits or diseases in human embryos. This research investigates the mechanisms of CRISPR-Cas9 and its controversial implementations.

Gene-editing process: CRISPR-Cas9 consists of two main components: Cas9 (a protein) and sgRNA (single-guide RNA). The sgRNA guides Cas9 to locate and produce a double strand break (DSB) on the targeted DNA strand near a PAM site (a location on the DNA strand with the sequence of NGG). The DSB is then repaired by mechanisms, such as homology-directed repair (HDR), which uses a template to precisely repair the DSB. The product of this modification results in gene knock-in, correction, deletion, or mutagenesis.

Introduction First introduced in 2012, CRISPR-Cas9 is a gene editing tool that has gained popularity in the gene-editing world for its preciseness and efficiency. Being a versatile tool that can practically edit any segment of DNA, it can be applied to all sorts of problems, the largest being treatment for human cancer and diseases. As its applications continue to develop, ethical concerns and issues arise about its safety and potential exploitation.

Some CRISPR-Cas9 delivery methods: Microinjection - This method physically injects Cas9 protein and the sgRNA directly into individual cells using a needle and microscope.

Best for in vitro and ex vivo.

Electroporation - This method uses electrical currents at a high voltage to open pores in the cell membrane of cells, allowing CRISPR-Cas9 components to travel into the cell. Most commonly used for in vitro, but can be used for ex vivo as well.

Vector methods (Viruses: AAV, LV, AdV) - This method involves vectors (modified viruses) that are particles containing CRISPR-Cas9 components which are used to infect the target cells.

The Applications and Ethics of CRISPR-Cas9 Angela Dong, Kalie Huynh, Ruhi Kamdar, Justin Pham, Christina Uong Sean Mintz, MIT

Results

Discussion

CRISPR-Cas9, a gene editing tool, has led to greater development in both the medical and agricultural fields because of its ability to alter DNA sequences. Progress has been made in correcting genetic mutations so that fetuses who would have been born with them can live a normal life. Cancer and other diseases stemming from the mutation of DNA can be reversed.

Engineered crops can provide food security, while being easier to produce and tastier. CRISPR-Cas9 can also improve pharmaceutical medicines by increasing the potency of ingredients. However, the side effects of CRISPR-Cas9 should not be neglected. As the technology is still immature, gene editing may also cause consequences that have not been fully understood yet. Additionally, there is a chance of CRISPR-Cas9 modifying DNA at other locations instead of the intended target, leading to harmful genetic changes. Future generations may also have unforeseen health issues due to gene editing. Even so, there is ongoing research towards addressing these challenges and striving for safer and more precise gene editing techniques to minimize side effects, enhance accuracy, and guarantee a more responsible and ethical application for the future. CRISPR-Cas9 has the potential to eradicate genetic diseases and gain a surplus of food which can result in a thriving society with improved quality of life for all.

Despite CRISPR-Cas9 having multiple technological advancements and breakthroughs, it has also raised questions about legal, social, and ethical rules. Because CRISPR-Cas9 has the ability to edit genetics from a single cell to a whole organism, it can be used to treat cancer or neurodegenerative disorders, create allergy-free foods, or even manage diseaseridden insects. However, this technology also has the ability to also genetically edit the human embryo before it is born. For example, if the embryo has some sort of genetic disease such as sickle cell anemia or cystic fibrosis, CRISPR would technically have the ability to rid the embryo of those diseases, while still in the birthgiver’s belly. Depending on what types of genetic diseases the embryos have and the severity of them, these types of practices have started debates on what can blur the line between enhancement and treatment/therapy because scientists acknowledge that genetically altering embryos before birth can be weaponized for eugenics and other negative/harmful ethical/moral beliefs as well. In addition, CRISPR’s genetic editing on embryos can cause harmful side effects, so even if CRISPR is being considered, scientists and other healthcare professionals will still be looking for safer alternative methods.

The Applications and Ethics of CRISPR-Cas9 Angela Dong, Kalie Huynh, Ruhi Kamdar, Justin Pham, Christina Uong Sean Mintz, MIT Sean Mintz, MIT

References

Acknowledgements

Carney JP, Harper JC, Lino CA, Timlin JA. Delivering CRISPR: a review of the challenges and approaches. Drug Delivery. 2018 Feb 12;25(1):1234-1257.

Del Rio A, Marinelli E, Piergentili R, Signore F, Umani Ronchi F, Zaami S. CRISPR-Cas and Its Wide-Ranging Applications: From Human Genome Editing to Environmental Implications, Technical Limitations, Hazards and Bioethical Issues. Cells. 2021 Apr 21;10(5):969-992.

Doudna JA, Jiang F. CRISPR-Cas9 Structures and Mechanisms. Annual Review of Biophysics. 2017 Mar 30;46:505-529.

Hamideh AA, Hosseinkhani S, Khoshandam M, Mousazadeh M, Soltaninejad H. Clinical applications of the CRISPR/Cas9 genome-editing system: Delivery options and challenges in precision medicine. KeAi Publishing. 2023 Mar 26;11(1):268-282.

Khlidj Y. What did CRISPR-Cas9 accomplish in its first 10 years? Biochem Med (Zagreb). 2023 Oct 15;33(3):030601

We thank The Research Catalysts for giving us this opportunity and their guidance along the way. We also thank Sean Mintz, our mentor, for providing us feedback and assistance through our entire research process.

HOW CAN RECENT ADVANCEMENTS IN BIOELECTRONICS HELP PROVIDE BETTER ENERGY SUPPLY AND IMPROVED LONG-TERM DEVICE EFFECTIVENESS? Steven Biji, Siddh Tolia, Sophie Nguyen, Aiza Tanveer Sean Mintz, Massachusetts Institute of Technology

Abstract

Materials and Methods

Organic Bioelectronics is the development and study of organic electronic devices which translate the signals and functions of biology and use organic electronic materials to conduct biosignals.

It was observed that Bioelectronic devices have a critical challenge in sustaining energy during it's operation. Solutions include: Supercapacitors, Internal Energy Harvesting Devices, Biofuel Cells, and Wireless Power Transfer. A change in materials, energy harvesting, supplies, data transmission, and more can improve biocompatibility with bioelectronics.

Organic bioelectronics comprises the development and studies of organic electronic devices that operate as translators between the signals and functions of biology. These devices use organic materials that can conduct and process electronic and ionic biosignals, used with an electron-ion charge compensation(a slow discharge of ions, resulting in electrical potential). The use of these styles of devices in electrocardiographs, blood pressure and flow monitors, medical imaging systems, etc., has been done for a long period, although recent advancements have further improved these devices and solved two of the numerous problems faced since their conception: Energy Storage and Biocompatibility.

Both of these are further described in this paper. ( Simon, D.T., 2016)

Key Words:Organic bioelectronics,implantable devices, biocompatibility,energy storage

Introduction

Summary

This academic paper explores the rapidly developing field of Organic Bioelectronics for Healthcare, specifically devices that promote improved treatment methods, and overall health of a person. Through a thorough analysis and synthesis of the latest research findings, the paper takes into account critical factors such as energy supply and biocompatibility in these bioelectronic devices. Our meticulous review of pertinent publications has yielded a comprehensive understanding of the current state of Organic Bioelectronics and its potential for transforming healthcare.

Our objective is to contribute to the ongoing discourse on this topic and provide valuable insights for researchers and practitioners alike.

The realm of organic bioelectronics offers a plethora of innovative solutions fueled by the convergence of organic electronic materials with biology and medicine. This paper delves into the remarkable capabilities of bioelectronic devices and shows some of the recent developments that answer some pressing problems the application of these devices faces while being used in the field of medicine. By making changes to the biocompatibility and technological structure of bioelectronics, it is supported that these devices are significantly effective long-term and contain better energy supply. These findings present that the utilization of materials, supplies, and other resources can improve bioelectronics by making them more biocompatible (Yang Li, 2021)

Discussion Section 1: Problems in tradtional devices Bioelectronic devices face a critical challenge in sustaining energy during operation. This section explores problems in conventional devices and what factors are needed to account for sustainability and compatibility of these devices.

Flexibility, biocompatibility, and stable energy density are crucial to power these devices effectively. Traditional Li-ion batteries can be problematic due to hazardous components and packaging requirements. Moreover, implantable devices, which rely on rigid silicon microelectronics, encounter challenges related to poor compatibility with biological systems and high invasiveness.

In order to be effective, bioelectronics needs to be physically and chemically biocompatible. Sustainable power supplies and wireless data transmission under implantation can be adequate. Recent projects are looking to mimic the mechanical properties of tissues through materials, devices, power source technology, and wireless communication.

Section 2: Proposed Alternatives This section explores recent innovations tackling this issue and categorizes them by type and application,offering a historical context of the field's progress.

Promising solutions include utilizing body fluids as electrolytes for Supercapacitors,resulting in stable potential and cyclic stability.

Internal Energy-Harvesting Devices harness body fluids,temperature gradients,and chemical energy for power generation.

Biofuel cells, as external Energy-Harvesting Devices, convert biochemical reactions into electricity. They hold the potential for sustained energy production over time.

Wireless Power Transfer (WPT) Technology eliminates wiring needs, reducing device size and weight. WPT method has a high transmission efficiency greater than 80%.

Ultrasound-Induced Wireless Energy Harvesting (UWEH) converts ultrasound waves into power through piezoelectric- semiconducting coupling.

Hydrogels (with their loose three-dimensional network structure that encapsulates massive amounts of water) can achieve a unification of excellent properties such as mechanical properties, self-healing, adhesion, and biocompatibility, making them suitable for health monitoring bioelectronics.

Future research will need to be conducted in order to engineer satisfactory material that provides long-term stability, biocompatibility, and sustainability. In conclusion, innovative energy solutions are transforming bioelectronics, enabling more efficient and sustainable device operation.

References

Acknowledgments

1.Sheng, H. et al. (2021) Recent advances of energy solutions for implantable bioelectronics, Advanced healthcare materials. Available at: https://pubmed.ncbi.nlm.nih.gov/33930254/ (Accessed: 14 August 2023).

2. Li, Y.et.al, Implantable bioelectronics toward long-term stability and ... - cell press, Science Direct. Available at: https://www.cell.com/matter/pdf/S2590-2385(21)00056-4.pdf (Accessed: 18 August 2023).

3. Malliaras, G. and McCulloch, I. (2023) Introduction: Organic bioelectronics | chemical reviews ACS publications, ACS Publications. Available at: https://pubs.acs.org/doi/10.1021/acs.chemrev.2c00026 (Accessed: 15 August 2023).

4.Simon, D.T., et. al, Organic bioelectronics: Bridging the signaling gap ... - ACS publications, ACS Publication. Available at: https://pubs.acs.org/doi/10.1021/acs.chemrev.6b00146 (Accessed: 18 August 2023).

5. Li, Y. et al. (2021) Implantable bioelectronics toward long-term stability and sustainability, Redirecting. Available at: https://doi.org/10.1016/j.matt.2021.02.001 (Accessed: 18 August 2023).

6. Zhou, Y., Liu, C. and Huang, Y. (2020) Wireless power transfer for Implanted Medical Application: A Review, MDPI. Available at: https://doi.org/10.3390/en13112837 (Accessed: 18 August 2023).

7. Hua, J. et al. (2023) Hydrogel-based Bioelectronics and their applications in health monitoring, MDPI. Available at: https://doi.org/10.3390/bios13070696 (Accessed: 18 August 2023).

We would like to thank the Program Executive's Katie, Vy, Aryana for organizing this well-organised research program. We would also like to thank our mentor Sean Mintz, who gave us guidance throughout the whole program. We would also like to thank all the contributors of the paper for their invaluable effort and time spent in contributing to the field of Science.

The Effects of Childhood Trauma on the Development of the Brain Josephine Monette (Author) Lakewood High School, Aghoghotobore Oghenekaro (Author) Glen Burnie High School Aryana Wadhwani (Mentor), Katie Kee (Mentor) Brea Olinda High School, Vy Ly (Mentor) UC Berkely

Abstract

Materials and Methods

Discussion

The lasting effects of childhood trauma on the composition and development of the brain greatly impact the lives of those who experienced such. Trauma is one of the contributing factors that have a hand in the development of mental disorders such as Post-Traumatic Stress Disorder (PTSD). But a certain type of trauma has been often overlooked in significance and importance.

That is Childhood trauma. Childhood trauma is classified as developed trauma obtained through one's exposure to adverse events in their childhood. According to the National Institutes Of Health, Childhood trauma is associated with developing mental disorders that negatively affect one's adult life. Thus, an in-depth analysis of the effect of such trauma on the development of the brain is relevant so that solutions to such trauma can be obtained shortly.

There are many negative encounters that a child may experience that will result in maladaptive infant mental health and brain development, but “sexual trauma and childhood abuse may simply be the most commonly encountered severely aversive events inherent in our culture” (Sirven & Glasser, 1998, p. 232) These events have been studied and researched in order to discover the direct links between certain childhood traumas and later effects in life. A study conducted by Matthia Gunther in 1960 observed newborns and infants between the ages of 0-6 months, keeping note of events in the children's lives and their following behaviors and actions as an immediate result of the events; as the infants matured, their behaviors and responses were also documented and compared based on the different circumstances in infancy. A common connection between infants who experienced trauma is the later experience of PTSD. In a study (Gilbertson 2010), a "case-control design" was used to examine a pair of male twins. One twin was a Vietnam combat veteran, and the other twin had no exposure to combat. It was later observed as to which twin developed PTSD, and how the hippocampal volume of the twin with PTSD differed from the twin without PTSD.

These studies display that infants can experience many traumas that lead to PTSD or later fears while maturing. In adult psychopathologies, PTSD is the only one that can be directly linked to early childhood trauma. PTSD can immediately impact a child that has experienced a seriously traumatic experience but also can manifest later in adulthood, especially in children that were subject to any manner of abuse in their early years. Because infants are in the predisposed care of their parents, it can be thought that negative treatment induced by caregivers is the most detrimental to an infant compared to any other socially or physically induced stress. Another potential stressor that infants can experience happens during the ages of zero to two months, in which a lot of newborns experience painful medical procedures There is now agreement that repetitive, sustained emotional abuse is at the core of childhood trauma (O’Hagan, 1995). In the context of neurobiological studies, the impacts of childhood traumas are a relative breakthrough concerning the development of children and their brains.

Many studies have been conducted in the field of infant mental health and development, and have concluded that there is great importance in positive infant-mother attachment in the early stages of life, and negative reinforcement or child neglect or abuse can lead to many issues in the development of the brain. Modern neuroscience has produced more results that focus not just on the pathological processes of a mature brain, but also on the early developmental failures of the brain.

It can therefore be concluded that negative experiences in early childhood often lead to development in the brain, and later disorders in adulthood. When the brain is not fully developed, it is ever more vulnerable to distressing external stimuli. Even in the earliest stages of infancy, the brain can remember and interpret traumatic events, which will cause an effect on the child not only during growth but also well into adulthood. It is of great importance for children to be in a healthy and nurturing environment with supportive and involved caregivers, as trauma is not singularly a negative interaction, but a lack of interaction as well.

Introduction According to the Centre For Addiction & Mental Health (CAMH), Trauma “is a term used to describe the challenging emotional consequences that living through a distressing event can have for an individual.” In other words, it is an emotional response to an adverse event, such as rape, molestation, death, etc (APA, n.d.). On the other hand childhood trauma is the emotional response to an adverse event that took place within your childhood. During such an event, the brain experiences a change in its original structure, which then causes the development of mental disorders.

PTSD can be characterized as a neuropsychiatric disorder that causes intense or prolonged distress at a factor that resembles a traumatic experience that an individual has experienced.

PTSD in the context of infants and adolescents will be categorized as any adverse or extreme reaction to being exposed to an occurrence that is similar to any traumatic event that the child has experienced.

Results In Freud’s last work (1940), he observed that trauma early in life was even more detrimental to infants as “the ego . . . is feeble, immature and incapable of resistance.” In more contemporary terms, this can be interpreted as noticing that the immature brain is in a state of rapid development and therefore is much more susceptible to adverse factors in development and growth. It is a matter of debate about whether a newborn can register or remember a traumatic event, but data can show that this is possible, although the memories may be primitive. Responses similar to Post Traumatic Stress Disorder (PTSD) can be displayed when an infant shows an adverse reaction to an influence that in the past elicited a negative effect on the infant. Infant trauma responses and subsequent memories from traumas can be observed (Gunther 1960) when an infant experienced an anoxic airway obstruction during feeding, and then would later be opposed to being put to the breast. The hippocampus is located in the back of the brain and is considered the “learning center,” by many. Research (Gilbertson, 2010) shows that in individuals who have experienced severe or repetitive trauma, the hippocampus is less active and smaller than normal. In children especially, this trauma will be detrimental to the maturing of the undeveloped brain, and thus result in abnormal aspects of the brain.

References

Acknowledgments I would like to thank all of the wonderful people at The Research Catalysts who helped to make this project happen. Additionally, to all the people in my group helped to research, write, and format this paper.

Most of all I would love to thank my friends and teachers who have supported me in anything I have wanted to pursue. More specifically, I owe many thanks to Savannah Finn, who allowed me to attend meetings for The Research Catalysts Program while we were together and supported me on this journey. Finally, a large and grateful thanks to Jenny Boehlke, for inspiring me to further pursue science and keep me interested in why things occur. I would not have finished writing this paper without all of the people aforementioned, and I am very honored to have been able to be a part of this endeavour.

The Behavioral Changes of Convicted Felons Before and After Imprisonment Areebah Lashirah, Zohie Betts, Risha Rao, Ayush Sinha Shifa Malik, University of Michigan

Abstract

Materials and Methods

The psychological and neurological effects imprisonment has on an individual can result in detrimental mental health outcomes. To procure the effects imprisonment has on those who are incarcerated: Intensive search on articles and papers ensured the validity of information Studying surveys, interviews, and experiments to gather adequate data.

Studies have shown the status of prison confinement leads to depression and the decline in mental health has contributed to the repeating of criminal offenses. The claim of prison being a corrective measure for felons, has been repeatedly falsified based upon the negative psychological effects it burdens many prisoners with.

In the methods section of the research project, a detailed study of articles and information available on the behavior of convicted felons was conducted.

Introduction The information and research provided will delve into: Psychological effects prison has on convicted felons How the brain changes from before too after imprisonment.

Neurological effects confinement has on the recipient.

The mental health of individuals after serving prison is up for question. Does the institution intended to punish but also correct the behaviors of felons leave a positive impact on their mental status, or does their mental health decrease based on the harsh nature of prison conditions?

The research conducted explores the outcomes prison has on the mental health of former prisoners and how it impacts their daily life back in society.

This involved a systematic approach to gather relevant data and information from various academic journals and online literature.

Additionally, utilized various research methodologies such as studying surveys, interviews, experiments and to gather primary data on the topic.

By critically reviewing and synthesizing existing studies and information, a foundation was established to contextualize and inform the research objectives.

This methodological approach provided a solid foundation for the research project.

The aim was to comprehensively explore the subject matter by combining existing knowledge and new insights.

Results Rehabilitation programs implemented within the prison system play a crucial role in promoting positive behavior change and reducing recidivism rates. Due to lack of mental health after release, it may lead to ex-felons relapsing.

These programs focus on education, vocational training, mental health services, and substance abuse treatment from ex-felons to newly released felons (Apa.org, 2022).

Successful rehabilitation programs have been shown to increase the chances of successful rehabilitation and reduce the likelihood of repeated criminal behavior along with tackling the mental trauma, that leads them to become stable mentally and socially.

Hypothesis

References

1. Convicted felons would have reduced criminal activities and better psychological behaviors after incarceration.

Apa.org. (2022). Available at: https://www.apa.org/monitor/2022/10/lifeafter-prison.

Discussion

Graves, S. (2020). Many Californians in Prisons and Jails Have Mental Health Needs. [online] California Budget & Policy Center. Available at: https://calbudgetcenter.org/resources/prisonsand-jails-have-mental-health-needs/.

This study demonstrated how prisoners' psychological behaviors altered once they were released from jail, showing how being imprisoned changed their conduct in Petersilia, J. (2011) 'Beyond the prison bubble', The Wilson Quarterly, 35(1), 50+, available: the outside world. https://link.gale.com/apps/doc/A275575034/AO NE?u=nysl_me_midhsl&sid=bookmarkThe findings show a downward shift in the AONE&xid=97b9204b [accessed 10 August behaviors of convicted felons from before and after 2023]. imprisonment. Many convicted felons have deteriorated mental health after being separated Quandt, K.R. and Jones, A. (2021) Research from family members for long periods of time roundup: Incarceration can cause lasting (Quandt & Jones, 2021). damage to mental health, Prison Policy Initiative. Available at: The World Health Organization claims that violent conditions, a lack of social interaction, play a role https://www.prisonpolicy.org/blog/2021/05/13/ mentalhealthimpacts/ (Accessed: 14 August in the decline of offenders who are released, causing 2023) them to relapse into the habit rather than improve (Quandt & Jones, 2021).

r

Potential limitations to this experiment include sample or self-reporting bias, as the results may not encompass the results of all prisoners.

Acknowledgments We would like to thank our mentor, Shifa Malik, for providing us insight and helping us throughout our research.

(Graves, 2020)