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Challenges and Opportunities in Gene Regulation

Challenges and Opportunities in Gene Regulation

Deichmann, U. (2023b)

Abstract

The concept of chromatin as a complex of nucleic acid and proteins in the cell nucleus was developed by cytologists and biochemists in the late 19th century. It was the starting point for biochemical research on DNA and nuclear proteins. Interest in chromatin declined rapidly at the beginning of the 20th century, but a few decades later a new focus on chromatin emerged, which was not only related to its structure, but also to its function in gene regulatory processes in the development of higher organisms. Since the late 20th century, research on chromatin modifications as well as DNA methylation that emerged in the 1970s have also been conducted under the label epigenetics, a term originally introduced for the complex processes between genotype and phenotype during development. These processes – in particular gene regulation – were subsequently scrutinized by molecular biologists.

Research termed epigenetics remained marginal until the end of the 20th century but experienced a rapid rise when heritability was added to its definition. This was accompanied by an increasing diversity in researchers’ understanding and definitions of epigenetics. Epigenetics now includes research on histone and DNA-modifying enzymes, nucleosome remodelers, histone chaperones, chromatin-binding proteins to facilitate transcription factor and polymerase action, and the role of long non-coding RNA and small interfering RNA in transcriptional regulation.

This article highlights the major phases of chromatin and epigenetics research until the present time and illuminates how different scientific contexts changed the relevance and meaning of chromatin from the 19th century. The paper also points to misconceptions and media hype about epigenetics, for example unsupported claims about transgenerational inheritance in humans or questioning of the basic biological principles of gene regulation based on specific regulatory sequences of the genome.

Ohara, S., & Halpern, J. (2024)

Abstract

In the United States, advocates have successfully fought for accelerated pathways for FDA approval of novel promissory technologies to address severe unmet medical needs. These pathways can blur the distinction between clinical trials as experiments vs. treatment. In addition, a recent focus on developing individual therapeutics through small clinical trials for people with rare diseases has not included early phases to test safety with healthy human volunteers. Rather, the clinical trials are offered as a therapeutic intervention for those with the targeted genetic condition.

This lack of clarity about the distinction between early-in-human trials and treatment is compounded by the unknowns of innovative promissory technologies, impairing the ability of researchers to convey an accurate and thorough picture of the risks and benefits of participation. In addition, researchers are responsible for ensuring that the potential research subject has understood the information provided about the study and for obtaining informed consent, which is considered valid only under conditions where a person makes a voluntary decision about participation. Scientists’ belief that research subjects may not appreciate what is involved in clinical trials and incentives to recruit participants despite this may create a context in which voluntariness is not fully considered.


When physicians recruit their own patients for clinical trials, the dual role of patient care and trial recruitment may create a communicative context that undermines voluntariness. Physicians may be unaware that the patient’s consent is not truly voluntary for several reasons. One is the normalization of their dual role – both scientists and physicians know they are influential in patients’ decisions. Another is when the physician is convinced of the trial intervention’s benefit as a treatment, despite its experimental status.


In this study, we used qualitative interviews to explore whether and how genome editing scientists and physicians are taking care to ensure research subject voluntariness in the face of potentially irresistible enticements to participate in testing unproven interventions. Moreover, we sought to understand whether the connection between one’s professional role and enrollment of clinical trial subjects influenced how scientists and physicians saw the benefits of trial participation as in the subject’s best interests.

Walker, M., Peppercorn, K., Kleffmann, T., Edgar, C. D., & Tate, W. P. (2023)

Abstract

Viral infection in most people results in a transient immune/inflammatory response resulting in elimination of the virus and recovery where the immune system returns to that of the pre-infectious state. In susceptible people by contrast there is a transition from an acute immune response to a chronic state that can lead to an ongoing lifelong complex post-viral illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. This susceptibility is proposed to be genetic or be primed by prior health history. Complex abnormalities occur in immune cell functions, immune cell metabolism and energy production, and in cytokine immune modulator regulation. The immune system of the brain/central nervous system becomes activated leading to dysfunction in regulation of body physiology and the onset of many neurological symptoms.

A dysfunctional immune system is core to the development of the post-viral condition as shown with diverse strategies of immune profiling.  Many studies have shown changes in numbers and activity of immune cells of different phenotypes and their metabolism. Immune regulating cytokines show complex altered patterns and vary with the stage of the disease, and there are elements of associated autoimmunity.  These complex changes are accompanied by an altered molecular homeostasis with immune cell transcripts and proteins no longer produced in a tightly regulated manner, reflected in the instability of the epigenetic code that controls gene expression. Potential key elements of the altered immune function in this disease needing further exploration are changes to the gut-brain-immune axis as a result of changes in the microbiome of the gut, and viral reactivation from latent elements of the triggering virus or from a prior viral infection. Long COVID, an Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-like illness, is the post-viral condition that has arisen in large numbers solely from the pandemic virus Severe Acute Respiratory Syndrome Coronovirus-2. With over 760 million cases worldwide, an estimated ~100 million cases of Long COVID have occurred within a short period. This now provides an unprecedented opportunity to understand the progression of these post-viral diseases, and to progress from a research phase mainly documenting the immune changes to considering potential immunotherapies that might improve the overall symptom profile of affected patients, and provide them with a better quality of life.

Oldoni, E., Ussi, A., Andreu, A. L., & Morrow, D. A. (2023)

Abstract

Over the past few years, Advanced Therapy Medicinal Products (ATMPs), especially cell and gene therapies, have brought about a remarkable transformation in the field of therapeutics. ATMPs have the potential to be tailored to individual patients based on their distinct molecular characteristics, making them a crucial aspect of personalized medicine (PM) strategies. Unlocking the full potential of ATMPs is crucial for them to become the treatments of the future. Despite their immense promise, their success is hindered by significant complexity, as evidenced by various systemic bottlenecks in the realms of science, clinical implementation, and regulation. Presently, ATMPs face challenges such as a limited understanding and predictability of in vivo cell fate specific to each patient, regulatory issues caused by rapid technological advancements, inadequate standardization in data acquisition, limited reproducibility during preclinical development, and insufficient knowledge exchange among key stakeholders. Addressing these aspects is essential to fully harness the benefits of ATMPs in healthcare. EATRIS, the European Research Infrastructure for Translational Medicine, is actively enhancing its capabilities in the field of PM through a series of key initiatives. These efforts aim to support also ATMP development and are focused on delivering novel and innovative scientific tools for the scientific community. The final aim is to create the right ecosystem for more effective ATMP development in Europe, by better serving academia and industry in the translation of ATMPs for patient benefit.

Trojan, J., Kasprzak, H., Bierwagen, M., Quintero, G., Guzman, A. B., Santander, R. G., Abuchaibe, O., Rojas, C., Lone, Y., Popiela, T., Penagos, P., Pan, Y., Noguera, M. C., Ayala, A., Ly, A., Shevelev, A., Páez, E., Gutiérrez, Ó., Anthony, D. D., . . . Trojan, A. (2018)

Abstract

Introduction: Certain specific antigens, which behave as oncoproteins, are present in normal fetal/neonatal brain development, and are absent from mature brain tissues: among them, growth factors, especially insulin-like growth factor type I (IGF-I). When IGF-I reappears in the mature brain, this growth factor is over expressed in neoplastic glia, participating in the development of the most common human brain malignant tumor, glioblastoma multiforme, which is invariably fatal. Targeting the IGF-I system has emerged as a useful method to reduce glial malignant development.

Methodology: In practice, in case-control study, when human glioblastoma cells, and comparatively studied primary hepatocarcinoma and colon adenocarcinoma cells derived from cancer biopsy, are transfected in vitro with vectors expressing either IGF-I antisense RNA or inducing IGF RNA-DNA triple helix, the synthesis of IGF-I is stopped on translation or transcription levels, respectively (anti – gene strategy). Three cancer groups of two patients each, cancer stage I, after surgery and radiotherapy, were injected using antisense / triple helix ‘’vaccines’’ of 1 million irradiated cells. The control groups received injected placebo.

Results: Down regulation in the expression of IGF-I coincides with the reappearance of B7 and MHC class I antigens at the surface of transfected cells (immunogenicity). When injected subcutaneously, the transfected cancer cells, “vaccines”, initiate an immune reaction involving CD8+ lymphocytes, followed by tumor regression. The glioblastoma patients treated by classical surgery and radiotherapy, were “vaccinated” by three successive injections. The median survival of treated patients was 21 months (current progress in treatment of this disease involves an increase in medium survival from 8-11 months to an average of 15 months, using a chemotherapy). Using the same strategy, the patients with liver carcinoma and colon adenocarcinoma were comparatively treated. The obtained immune anti-tumor response mediated by TCD8 was similar to that of glioblastoma patients.

Conclusion: The cellular immunogene therapy using anti – gene approach constitutes one of the current efficient therapies of glioblastoma and other malignancies expressing IGF-I. The described methodology applied in Europe, and previously in the USA for glioblastoma treatment, is introduced now in university hospitals of Colombia (Bogota).