Software of Life
The phrase Software of Life was used by Moderna to describe the mechanism of action in which their mRNA medicines deliver therapeutic effects.[1]. In this analogy, the body’s DNA is the “storage unit” that preserves instructions within the nucleus for protein production and the mRNA, “software” is a temporary small set of these instructions, carried from static DNA information, that are directly translated by ribosomes into dynamic proteins[1]. The proteins are then the actual “application” responsible for all cellular functions and activities that drive life[1]. Where these processes naturally occur in the human body, mRNA medications deliver this “Software of Life” externally using instructions that were not previously stored in the DNA to facilitate expression of any protein of interest that wouldn’t have otherwise been produced[1]
Background
Messenger ribonucleic acid (mRNA) made its first therapeutic debut in the form of a vaccine to combat a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which brought about detrimental economic effects globally and severe mortality rates.[2] [3]. This highly contagious viral illness, Coronavirus disease (COVID-19), started in an outbreak in Wuhan, China in December of 2019 and has infected 232,636,622 people and killed 4,762,089 as of September 29th, 2021[2]. During this rapid spread, 321 vaccine candidates, documented in the global research and development (R&D) community, were being developed since vaccines offer the best solution for immunity against infectious diseases[3]. This research involved a broad range of vaccines including traditional approaches that use live or inactivated coronavirus, and also next generation vaccines that can be categorized into protein-based and nucleic acid-based, which includes both DNA and RNA vaccines[3]. In this race for vaccines, mRNA-based vaccines emerged as saviors after being developed at a record-breaking speed of only 11 months, with only 63 days between the release of the SARS-Cov-2 genome sequence and the start of the first stage of clinical trials[2][4][5]. It received approval for emergency use by the Food and Drug Administration (FDA) in December of 2020 at an astonishing 94.1% efficacy[5]. As of September 29th, 2021 mRNA vaccines have been administered to 212,564,346 people[2].
Technology
The approval of these two mRNA vaccines (mRNA-1273 and BNT162b2) for COVID-19 accelerated all development efforts in mRNA technology, creating an entire new field in the biopharmaceutical industry[3]. The reason for this radical evolution in medicinal development is its new method of action with software-like technology, where synthetic mRNA, acting as information bearers, efficiently utilize a cell’s own translational machinery to generate a needed quantity of any encoded immunogen[6][7]. In the case of COVID-19, the mRNA delivers instructions to the cells on how to produce the spike protein (S), prevalent on the virus’s cell membrane, which then circulates in the body and stimulates an immune response, teaching the immune system how to bind to the harmless protein and neutralize it so that it would detect and do the same to the virus if infected[8]
This technology has been under development since the 1990s at the University of Pennsylvania by scientist Dr. Katalin Karikó, who proposed a mRNA-based therapy to replace DNA based therapies but encountered many issues as gene therapy with DNA had favorable permanent effects while mRNA was temporary and caused severe inflammation with low translational efficiency[7]. This was until Dr. Katalin Karikó and her colleague Dr. Drew Weissman discovered that chemically modifying the nucleoside uridine to pseudouridine caused the mRNA to evade immune sensors, bringing inflammation levels to optimal levels and the translational efficiency to levels higher by a thousand times[7].
In addition, the instability has been solved by introducing various mRNA delivery systems that drastically improved cellular uptake efficiency and targeting ability[9]. To stress safety, over the past thirty years, with the main clinical mechanism of action behind mRNA-based therapeutics remaining the same, it has been proven that no genomic mutations occur nor do any toxic immune responses initiate[10]. The clinical trials funded by the National Institute of Allergy and Infectious Diseases, which involved trials on 30,420 volunteers, concluded that the mRNA vaccine developed to prevent COVID-19 met all safety standards[11]
Industry Impact
Biologics, the fastest growing field in the biopharmaceutical industry before COVID-19, manufactured complex specific recombinant proteins in a therapeutic effort to either address protein deficiencies or to train the immune system. Now, mRNA has the potential to completely replace this technology by simply providing instructions for cells on how to produce the most complex proteins themselves, with an added ability to also target specific tissue where expression is most needed.[7][9]. mRNA has the potential to treat any disease including cancer, where they represent a most promising platform in their special ability to induce potent cytotoxic T lymphocyte and natural killer cell responses against targeted tumors[7][9]. mRNA is also on track to substitute DNA therapies as it does not need to enter the nucleus and await transcription at nuclear envelope destruction during cell division, and this makes the therapeutic process with mRNA much more efficient[9]
Another major issue that mRNA therapeutics would resolve is traditional manufacturing methods that do not support growth and cannot meet urgent demands such as that of a pandemic.[6]. For producing vaccines specifically, biotechnology leaders desire products with better production lead times, less complex processes, and broadened compatibilities[6]. mRNA fits the bill perfectly here as the chemistry is generally transferable across different genomic sequences and so whenever a new immunogen is characterized, a therapeutic could be rapidly developed with relatively known safety outcomes, highlighting the therapeutic’s dynamic and versatile development potential against emerging diseases[6]
Future
In the last two years alone, dozens of mRNA vaccines for infectious diseases and cancer have released preclinical and clinical trial reports that have verified their reliability and efficacy.[5]. With its potential to revolutionize therapeutics in the near future, there are aspects of the technology that need to be addressed, especially for tumor targeting, that include problems with delivery, off-target effects, and immunogenicity[9]. mRNA has been largely neglected in the field of drug discovery but has now attracted well deserved recognition with billions of dollars of funding to transform traditional pharmaceutical routes into next generation mRNA routes with shorter production times, cheaper costs, less pollution, and broadened disease adaptability capable of addressing infectious diseases, cancer, and gene diseases, putting it on track to become the future form of medicine[9]
References
- ↑ 1.0 1.1 1.2 1.3 "mRNA Platform: Enabling Drug Discovery & Development". Unknown parameter
|url-status=ignored (help) - ↑ 2.0 2.1 2.2 2.3 "WHO Coronavirus (COVID-19) Dashboard". covid19.who.int. Retrieved 2021-11-23.
- ↑ 3.0 3.1 3.2 3.3 Chakraborty, Chiranjib; Sharma, Ashish Ranjan; Bhattacharya, Manojit; Lee, Sang-Soo (2021-07-07). "From COVID-19 to Cancer mRNA Vaccines: Moving From Bench to Clinic in the Vaccine Landscape". Frontiers in Immunology. 12: 679344. doi:10.3389/fimmu.2021.679344. ISSN 1664-3224. PMC 8293291 Check
|pmc=value (help). PMID 34305909 Check|pmid=value (help). - ↑ Pardi, Norbert (2021-05-11). "mRNA Innovates the Vaccine Field". Vaccines. 9 (5): 486. doi:10.3390/vaccines9050486. ISSN 2076-393X. PMC 8151794 Check
|pmc=value (help). PMID 34064557 Check|pmid=value (help). - ↑ 5.0 5.1 5.2 Liang, Yongjun; Huang, Liping; Liu, Tiancai (2021-07-27). "Development and Delivery Systems of mRNA Vaccines". Frontiers in Bioengineering and Biotechnology. 9: 718753. doi:10.3389/fbioe.2021.718753. ISSN 2296-4185. PMC 8354200 Check
|pmc=value (help). PMID 34386486 Check|pmid=value (help). - ↑ 6.0 6.1 6.2 6.3 Jackson, Nicholas A. C.; Kester, Kent E.; Casimiro, Danilo; Gurunathan, Sanjay; DeRosa, Frank (2020-02-04). "The promise of mRNA vaccines: a biotech and industrial perspective". NPJ Vaccines. 5 (1): 11. doi:10.1038/s41541-020-0159-8. ISSN 2059-0105. PMC 7000814 Check
|pmc=value (help). PMID 32047656 Check|pmid=value (help). - ↑ 7.0 7.1 7.2 7.3 7.4 Ryan Cross (2018-09-03). "Can mRNA disrupt the drug industry?". C&EN Global Enterprise. 96 (35): 35–40. doi:10.1021/cen-09635-cover. ISSN 2474-7408.
- ↑ Vitiello, Antonio; Ferrara, Francesco (2021-05-01). "Brief review of the mRNA vaccines COVID-19". Inflammopharmacology. 29 (3): 645–649. doi:10.1007/s10787-021-00811-0. ISSN 0925-4692. PMC 8087898 Check
|pmc=value (help). PMID 33932192 Check|pmid=value (help). - ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Weng, Yuhua; Li, Chunhui; Yang, Tongren; Hu, Bo; Zhang, Mengjie; Guo, Shuai; Xiao, Haihua; Liang, Xing-Jie; Huang, Yuanyu (May 2020). "The challenge and prospect of mRNA therapeutics landscape". Biotechnology Advances. 40: 107534. doi:10.1016/j.biotechadv.2020.107534. ISSN 0734-9750. PMID 32088327 Check
|pmid=value (help). Unknown parameter|s2cid=ignored (help) - ↑ Ouranidis, Andreas; Davidopoulou, Christina; Tashi, Reald-Konstantinos; Kachrimanis, Kyriakos (2021-08-31). "Pharma 4.0 Continuous mRNA Drug Products Manufacturing". Pharmaceutics. 13 (9): 1371. doi:10.3390/pharmaceutics13091371. ISSN 1999-4923. PMC 8466472 Check
|pmc=value (help). PMID 34575447 Check|pmid=value (help). - ↑ Baden, Lindsey R.; El Sahly, Hana M.; Essink, Brandon; Kotloff, Karen; Frey, Sharon; Novak, Rick; Diemert, David; Spector, Stephen A.; Rouphael, Nadine; Creech, C. Buddy; McGettigan, John (2021-02-04). "Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine". New England Journal of Medicine. 384 (5): 403–416. doi:10.1056/nejmoa2035389. ISSN 0028-4793. PMC 7787219 Check
|pmc=value (help). PMID 33378609 Check|pmid=value (help).
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