The Role of mRNA in Personalised Medicine

First published 2023

Messenger RNA (mRNA) has long played a crucial role in cellular function, acting as the intermediary that translates genetic codes into the proteins vital for life. This fundamental role of mRNA has recently been harnessed in the field of personalised medicine, marking a significant shift in therapeutic approaches. The ability to adapt and scale mRNA for individual medical needs positions it as a groundbreaking tool in this area. It offers a new pathway for treating diseases, tailored to each person’s unique genetic makeup, thereby opening up a wealth of possibilities in healthcare. The adaptability and scalability of mRNA are not just incremental improvements; they represent a transformative approach, potentially changing the landscape of medical treatment.

In every cell, messenger RNA (mRNA) plays a pivotal role in synthesising proteins, which are essential for numerous cellular functions. This process begins with DNA, the repository of genetic information. When a protein is needed, the cell transcribes a segment of DNA into mRNA. This mRNA then acts as a messenger, carrying the genetic instructions from the DNA in the cell’s nucleus to the ribosomes, the cell’s protein factories. In the ribosomes, these instructions are translated into amino acid sequences, forming the proteins necessary for various cellular activities. The significance of mRNA extends beyond this fundamental role; its ability to carry specific genetic instructions makes it a potential tool for correcting genetic errors. By altering the mRNA sequence, scientists can influence the production of proteins, providing a means to address diseases caused by genetic anomalies. This capability underscores the vital role of mRNA in both maintaining cellular health and offering new avenues for medical treatment.

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The medical applications of mRNA have evolved significantly, transitioning from a basic understanding in molecular biology to a powerful tool in medicine. This evolution is rooted in the ability to customise mRNA sequences, allowing for the creation of specific protein recipes tailored to individual medical needs.

The early stages of mRNA research were marked by both significant challenges and groundbreaking discoveries. Initial experiments in the late 1980s by Robert Malone demonstrated the potential of mRNA in medicine, particularly when combined with liposomes. However, the path to mRNA vaccine development was not straightforward. Researchers faced numerous hurdles, including the inherent instability of mRNA and the complexity of delivering it effectively into cells. The development of lipid nanoparticles in the 1990s and 2000s, which facilitated the delivery of mRNA into cells, was a pivotal advancement. Furthermore, the discovery of modified nucleotides like pseudouridine by Katalin Karikó and Drew Weissman significantly reduced the immune response to synthetic mRNA. This work highlights the persistence, collaboration, and innovative thinking that were crucial in overcoming the initial scepticism and technical obstacles to develop mRNA-based medicines.

This research paved the way for the development of vaccines, most notably the mRNA-based vaccines for COVID-19, which showcased the potential of this technology in rapid vaccine development and adaptability to changing viral strains. This narrative underscores the transformative impact of mRNA in medicine, marking a shift from traditional approaches to more dynamic and personalised treatments.

The development and success of COVID-19 mRNA vaccines stand as a landmark in medical history. These vaccines, notably from Moderna and Pfizer-BioNTech, were developed at an unprecedented speed, demonstrating the rapid response capability of mRNA technology. A critical advantage of these vaccines is their adaptability to new viral variants. The mRNA sequence can be quickly modified to target mutations in the virus, enabling a swift update of the vaccines in response to evolving strains. Beyond COVID-19, ongoing research is exploring the application of mRNA technology to other diseases, broadening the potential impact of this innovative approach in the field of immunology and beyond.

The concept of mRNA cancer vaccines marks a significant shift in cancer treatment, aligning with personalised medicine approaches. These vaccines work by training the immune system to target cancer cells, leveraging mRNA’s capability to encode for specific proteins found in tumours. A striking example of this approach is the development of individualised vaccines tailored to a patient’s specific tumour profile. By analysing the mutations in a patient’s tumour, scientists can create custom mRNA sequences that stimulate the immune system to recognise and attack the cancer cells, offering a highly personalised treatment strategy. This method exemplifies the potential of mRNA in revolutionising cancer therapy.

The future of mRNA-based medicine extends far beyond its current applications. Ongoing research is exploring the use of mRNA in treating a wide range of diseases, signaling a shift towards more personalised medical treatments. This potential is rooted in the ability of mRNA to be easily customised to meet the specific needs of individual patients. The historical context of mRNA research, marked by challenges and breakthroughs, sets the stage for these future prospects.

In conclusion, mRNA stands as a pivotal element in modern medicine, offering a versatile approach to treating various diseases. Its ability to be customised for individual needs has opened new doors in personalised medicine, shifting the focus from one-size-fits-all solutions to targeted therapies. As the healthcare sector continues to evolve, mRNA technology will likely face challenges, including ethical considerations, accessibility, and the continuous need for innovation. Nevertheless, the potential of mRNA to revolutionise treatment strategies offers a promising outlook for the future of healthcare.

Links

https://www.nature.com/articles/s41587-022-01430-y

https://pubmed.ncbi.nlm.nih.gov/37978542/

https://theconversation.com/tenacious-curiosity-in-the-lab-can-lead-to-a-nobel-prize-mrna-research-exemplifies-the-unpredictable-value-of-basic-scientific-research-214770

https://www.genome.gov/genetics-glossary/messenger-rna

https://www.nature.com/articles/d41586-021-02483-w

The Role of Telomeres in Human Health and Aging

First published 2023

In the complex world of human biology, telomeres stand out as critical yet often overlooked components. These specialised structures, situated at the ends of chromosomes, perform a vital protective function. They are made up of repetitive nucleotide sequences that act similarly to the plastic tips on shoelaces, preventing chromosomes from deteriorating or fusing with neighbouring chromosomes. However, telomeres are more than just static protectors; they are dynamic entities that play a crucial role in the cellular aging process.

Each time a cell divides, its telomeres undergo slight shortening, a phenomenon often compared to a biological clock that marks time at the cellular level. As cells reach a critical telomere length, they enter a state of senescence or programmed cell death, which is a natural part of aging. This shortening is not merely a symptom of aging but has profound implications for overall human health, influencing risks for various diseases such as cardiovascular disorders and certain types of cancer. The relationship between telomere length and aging, health, and disease has garnered significant interest in the scientific community. Studies have shown that shorter telomeres are associated with a higher risk of several age-related diseases, including Alzheimer’s disease, heart disease, and osteoporosis. This has prompted extensive research that covers various aspects, from the molecular underpinnings of telomere biology to the impact of lifestyle factors on telomere maintenance.

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The structure and function of telomeres are central to understanding their role in health and disease. Telomeres are DNA-protein complexes that protect the genome from degradation and interchromosomal fusion. In human cells, telomeres comprise tandem repeats of a specific DNA sequence (TTAGGG), repeated hundreds to thousands of times, forming a cap at each chromosome end. This cap is crucial for maintaining the integrity and stability of chromosomes as the DNA-protein complexes protect chromosomes from degradation and prevent them from fusing with one another. Due to limitations in the DNA replication process, these ends cannot be fully replicated, leading to the gradual shortening of telomeres with each cell division.

Telomere shortening occurs with each DNA replication, and continued shortening can lead to chromosomal degradation and cell death: when telomeres become too short, they can no longer protect the chromosome ends, leading to cellular senescence (aging) or apoptosis (programmed cell death). Telomerase, an enzyme that adds the TTAGGG telomere sequence to the ends of DNA strands in the telomere region, plays a vital role in maintaining telomere length.

In most somatic cells, telomerase activity is limited, leading to a gradual reduction in telomere length over time. However, in stem cells and certain types of cancer cells, telomerase activity is high, allowing these cells to maintain their telomere length and divide indefinitely. This selective activity of telomerase is an important aspect of telomere biology. In cancer cells and immortalised cells (cells that have somehow bypassed normal cellular aging and continue to divide), telomerase is often reactivated or alternative mechanisms to lengthen telomeres are employed. This is a key factor in how these cells evade the normal aging process and continue to divide uncontrollably. The shortening process is thereby critical because it acts as a safeguard against potential genomic instability and uncontrolled cell proliferation, which are hallmarks of cancerous cells.

Furthermore, the differential activity of telomerase is a key area of research, as it offers insights into potential therapeutic targets for both cancer treatment and anti-aging interventions. For example, some researchers are exploring telomerase activators as a means to slow down the aging process, while others are investigating telomerase inhibitors as a potential cancer therapy.

Pulmonary Fibrosis (PF), a fibrotic lung disease with high mortality, has been closely linked to telomere shortening. This connection extends beyond heritable forms of the disease to idiopathic pulmonary fibrosis (IPF), suggesting a broader implication of telomere health in respiratory diseases. In both men and women, there is a notable association between sex hormone levels and telomere length. Women with early menopause or premature ovarian failure and men with lower testosterone levels are found to have shorter telomeres, indicating that hormonal balance plays a significant role in telomere dynamics. Additionally, slower progression of PF is linked to higher levels of sex hormones, emphasising the potential therapeutic role of hormone restoration in managing telomere-related diseases.

Genetic studies also show a bi-directional causal relationship between sex hormone binding globulin (SHBG) concentration and telomere length in males. High SHBG leads to shorter telomeres, suggesting its involvement in disease causality. This evidence points to a complex interaction between genetic factors, hormonal levels, and telomere length, providing crucial insights for future research and potential treatments.

The impact of lifestyle factors on telomere health is profound. Studies have shown that diet, physical activity, and other lifestyle choices can either accelerate or slow down the rate of telomere shortening, thus affecting aging and the onset of age-related diseases. A healthy diet and regular physical activities can prevent excessive telomere attrition, potentially delaying the onset of diseases associated with aging and extending lifespan.

Telomere length decreases with age and is a potential predictor of lifespan. The rate of telomere shortening varies among different tissues and is influenced by a combination of genetic, epigenetic, environmental, and lifestyle factors. Accelerated telomere shortening has been associated with various age-related diseases, including coronary heart disease, diabetes, cancer, and osteoporosis. Smoking and obesity, in particular, have been shown to expedite telomere shortening, contributing to genomic instability and an increased risk of cancer. Exposure to harmful environmental agents and stress can also affect telomere length, further linking lifestyle and environmental factors to telomere health.

Diet and exercise play a significant role in preserving telomeres. Dietary intake of fibre, antioxidants, and reduced protein intake have been associated with longer telomeres. In contrast, diets high in polyunsaturated fatty acids and obesity are linked to shorter telomeres. Dietary restriction has been shown to reduce oxidative stress, thereby preserving telomeres and delaying aging. Regular exercise is associated with reduced oxidative stress, elevated telomerase activity, and reduced telomere shortening, underscoring its importance in maintaining telomere health and potentially reducing the pace of aging and age-related diseases.

In conclusion, the study of telomeres offers a window into understanding the complex interplay of genetics, environment, lifestyle, and disease. The ongoing research in this field holds promise for developing new therapeutic strategies targeting telomere biology, with the potential to treat diseases and extend healthy human lifespan. This exploration of telomeres illuminates a fundamental aspect of human biology and opens doors to novel approaches in medicine and therapeutics.

Links

https://www.genome.gov/genetics-glossary/Telomere

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370421/

https://www.nature.com/articles/s41556-022-00842-x

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376948/

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30364-7/fulltext

https://www.frontiersin.org/articles/10.3389/fmed.2021.739810/full

https://onlinelibrary.wiley.com/doi/full/10.1111/resp.13871

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795650/

https://www.medrxiv.org/content/10.1101/2022.09.29.22280270v1.full

https://journals.lww.com/epidem/fulltext/2014/01000/leukocyte_telomere_length_and_age_at_menopause.23.aspx

Advancing Cancer Treatments Through Immunological Research

First published 2020; revised 2023

Cancer remains a formidable global health challenge, causing significant morbidity and mortality worldwide. Traditional cancer treatments, such as chemotherapy and radiation therapy, have made substantial progress but often come with severe side effects and limited efficacy. Immunological research has emerged as a promising avenue to revolutionise cancer treatment. A haemotologist-oncologist working at a research laboratory offering clinical trials for cancer patients said, “What we are trying to do is to mount an immune response against that cancer. Not only would the primary cancer shrink, but you’re left with a memory of that cancer immunologically, and it can guard you against further incidents … Immunotherapy has changed the world for a number of cancer patients.”

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Immunotherapy has gained widespread recognition as a groundbreaking approach in the fight against cancer. This therapeutic strategy harnesses the body’s immune system to identify and eliminate cancer cells. Checkpoint inhibitors, such as PD-1 (Programmed Cell Death Protein 1) and CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) inhibitors, are a class of immunotherapy drugs that have been revolutionary in the treatment of various cancer types. They work by targeting specific proteins that regulate the immune system’s response to cancer cells. 

PD-1 is a protein found on the surface of immune cells called T cells. Cancer cells can exploit the PD-1 pathway by expressing a protein called PD-L1 (Programmed Death-Ligand 1). When PD-L1 on cancer cells binds to PD-1 on T cells, it sends a signal that inhibits the T cells’ ability to attack the cancer. PD-1 inhibitors, such as Pembrolizumab (Keytruda) and Nivolumab (Opdivo), block the interaction between PD-1 and PD-L1. This “unlocks” the T cells, allowing them to recognize and attack cancer cells more effectively. These drugs are used to treat various cancer types, including melanoma, lung cancer, bladder cancer, kidney cancer, and more.

CTLA-4 is another immune checkpoint protein that regulates T cell activity. CTLA-4 inhibitors, like Ipilimumab (Yervoy), block CTLA-4 from inhibiting T cells. This enhances the immune system’s response against cancer. Ipilimumab is primarily used in the treatment of advanced melanoma. Immunotherapy has therefore shown impressive long-term remission rates in certain patients, offering a potential cure for some cancers.

One of the key contributions of immunological research to cancer treatment is the development of personalised medicine approaches. Understanding the unique genetic and immunological profiles of individual patients has enabled the creation of targeted therapies. For example, chimeric antigen receptor (CAR) T-cell therapy involves genetically modifying a patient’s immune cells to target specific cancer antigens. This level of customisation enhances treatment effectiveness while minimizing side effects.

Current immunological research also emphasises the importance of combination therapies. Cancer cells often develop resistance mechanisms to single treatments. Combining immunotherapy with traditional treatments like chemotherapy or radiation therapy can improve treatment outcomes. Furthermore, research is ongoing to discover new combinations and strategies, such as using oncolytic viruses or tumor vaccines alongside immunotherapies.

While immunological research holds great promise, significant challenges remain. First, not all patients respond equally to immunotherapy, and predicting who will benefit most is still a challenge. Additionally, the high cost of immunotherapies poses accessibility issues. Moreover, the potential for severe immune-related side effects must be carefully managed. Lastly, the development of resistance mechanisms by cancer cells remains a hurdle that researchers are actively addressing.

Current immunological research has already made substantial contributions to advancing cancer treatments. Immunotherapy, personalised medicine, and combination therapies represent powerful tools in the fight against cancer. While challenges persist, ongoing research continues to refine these strategies and uncover new possibilities. The extent to which immunological research can advance cancer treatments is vast, offering hope for improved outcomes, enhanced quality of life for patients, and ultimately, a path towards curing cancer. The ongoing collaboration between researchers, clinicians, and the pharmaceutical industry is essential to realise the full potential of immunological advancements in cancer treatment.

Links

https://about.kaiserpermanente.org/health-and-wellness/health-research/news/cancer-research-the-role-of-immunotherapy

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9861770/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811907/

https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-019-0662-6

https://www.nature.com/articles/s41423-020-0488-6