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Are We Facing a New Era of Medical Science? mRNA-Based Therapies beyond the Covid-19 Vaccines

Are We Facing a New Era of Medical Science? mRNA-Based Therapies beyond the Covid-19 Vaccines

I am a high school student who has been living the highs and lows of a pandemic that I am being told will likely define my generation. I’m just days away from being vaccinated and the anticipation is palpable; I feel like I am waiting to pick up my superhero wings. Amidst the stress, the Zoom fatigue, the waiting, I became a bit obsessive and read everything I could find about the COVID-19 vaccines. I learned a couple of things. First, skills of critical inquiry are more necessary right now than ever. Second, this pandemic has brought about the unleashing of a new therapeutic technology that could help millions of patients with a variety of illnesses.

In the fight against COVID-19, one of humanity’s greatest weapons has turned out to be something very small—microscopic, in fact. That something is mRNA, a type of biological molecule that is the basis for two vaccines that have been shown to be effective in protecting against COVID-19: Pfizer-BioNTech’s BNT162b2 and Moderna’s mRNA-1273. Besides being key tools in the continuing effort to end the pandemic, these vaccines are notable in that they are the first mRNA-based vaccines to be approved for use against an infectious disease. However, although these vaccines are the first examples of mRNA technology being used on a large scale, they are just the tip of the iceberg when it comes to ways that mRNA could be used to help prevent and treat a wide range of diseases, including cystic fibrosis, hemophilia, and even cancer.

In order to understand how the COVID-19 mRNA vaccines work, one must first understand what mRNA is and the role it plays in the process of immunization against viruses. Most people know about DNA (deoxyribonucleic acid), the double-stranded molecule that contains the instructions that tell each cell how to construct the proteins that are essential to life. When a particular type of protein needs to be made, the portion of the DNA molecule that encodes for that protein is copied in a process called transcription, resulting in a single-stranded molecule known as mRNA (messenger ribonucleic acid). The protein-making machinery of the cell then reads the instructions encoded on that mRNA molecule, producing the required protein by linking amino acids in the correct order in a process called translation.

The mRNA in the vaccines against COVID-19 encodes a particular protein, known as a spike protein, that is found on the surface of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19 (coronavirus disease 2019). When the cells of a person who has been injected with the vaccine produce this protein, that person’s immune system mounts an immune response, including the production of antibodies—the same antibodies that it would have produced if the person had been infected with the actual virus. Once this occurs, the person’s immune system knows how to neutralize the virus if and when the person is exposed to it. Eventually, all of the mRNA molecules that were present in the vaccine dose are degraded by the body, but the immune system retains the memory of its exposure to the spike protein and thus is able to ward off future infections even after the mRNA is gone.

The production of mRNA vaccines is a complex process with many steps. First, genetic engineers must determine the structure and sequence of the mRNA that will provoke an immune response against the targeted virus, as well as of the DNA that serves as a template for this mRNA. In the case of the Pfizer-BioNTech and Moderna vaccines, a digital blueprint of the molecular structure of the spike protein found on SARS-CoV-2 is converted into a DNA template, which is then used to synthesize the analogous mRNA strands. This process requires the use of a chemical known as RNA polymerase, so named because it links nucleotide molecules, which are the building blocks of nucleic acids like DNA and RNA, into long, chain-like molecules called polymers. The tips of these mRNA strands are then capped with special enzymes (often 7-methyl-guanosine or polyadenosine), which help stabilize these large, delicate molecules. Finally, the synthesized mRNA undergoes a purification process in which it is filtered to remove any remaining DNA, nucleotides, or defective mRNA.

Luckily, the scientists and engineers who developed the COVID-19 mRNA vaccines and the processes through which they are manufactured were not starting from scratch. In fact, research on mRNA vaccines and other medical technologies has been underway for years. One of the first efforts to harness the power of mRNA for use as a medical treatment began in 2008, over a decade before the onset of the COVID-19 pandemic. That year, Shire Pharmaceuticals, a biotechnology company headquartered in Lexington, Massachusetts, began working on a treatment that uses mRNA to treat cystic fibrosis, a hereditary disease in which the body produces thick, gluey mucus that clogs the lungs and the pancreas. In people with this disease, a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) is either made incorrectly or is not made at all. In collaboration with Ethris, a German company focused on the development on mRNA-based therapeutics, Shire experimented with the administration of mRNA that encoded for the correct, functional version of CFTR into the lungs of people with cystic fibrosis via the inhalation of aerosolized lipid nanoparticles infused with the mRNA molecules. Vertex Pharmaceuticals, headquartered in Boston, has experimented with similar treatment strategies for this deadly disease, further increasing the prospect that mRNA could someday be used to help patients who might otherwise require lung transplants or other invasive interventions.
The use of mRNA has also been explored in the treatment of hemophilia, a hereditary disorder that severely reduces the ability of the blood to clot and thus often leads to severe bleeding, both internally and externally. This disease is generally caused by a lack of the factor VIII (FVIII) protein, a coagulation factor sometimes referred to as anti-hemophilic factor (AHF), which plays an essential role in blood clotting. As with mRNA treatments being developed for cystic fibrosis, experimental mRNA treatments for hemophilia involve encapsulating mRNA molecules in lipid nanoparticles. In experiments with mice, these particles have been administered intravenously, delivering the mRNA, which encodes for the FVIII blood-clotting protein, to cells throughout the body. With repeated injections, this treatment has been found to instigate a prolonged period of FVIII production, strongly suggesting that mRNA therapy could hold tremendous promise for the effective treatment of this incurable and potentially fatal disease.

Some of the most incredible work being done in the field of mRNA therapeutics involves vaccines—not for communicable diseases, but for another great scourge: cancer. These experimental therapeutic vaccines work in a similar way to the COVID-19 mRNA vaccines: by teaching the body to recognize disease-causing agents, whether they are viruses or cancer cells, and thus training the immune system to destroy them. In fact, two of the same companies involved in the development of COVID-19 mRNA vaccines, the Germany-based BioNTech and the Massachusetts-based Moderna Therapeutics, have also been working on mRNA-based cancer vaccines. BioNTech has been testing one such vaccine, known as BNT122, which has been designed to treat melanoma, a type of skin cancer that derives its name from the fact that it affects pigment-producing cells known as melanocytes. In experimental trials, BNT122 has been shown to be effective at shrinking cancerous lesions in people with melanoma, demonstrating the potential of this innovative treatment method.

The use of mRNA could even allow cancer vaccines to be personalized for each patient. Moderna is currently testing mRNA-4157, a personalized cancer vaccine that is meant to treat certain types of metastatic epithelial cancers. The first step in the production of this personalized vaccine is to compare the DNA sequence of the patient’s cancerous cells to that of the patient’s healthy cells—a comparison that allows researchers to identify the mutant proteins being produced by the tumor. mRNA that encodes for one or more of those proteins can then be produced and administered to the patient, instigating an immune response against those specific proteins and thus training the immune system to attack and destroy the cells that express those proteins—that is, cancerous cells. If these trials are successful, as preliminary results indicate they very well could be, they could open the door to personalized mRNA-based treatments for a number of different cancer types, as well as for other maladies—an extremely exciting prospect.

The lessons learned during these and other efforts to develop mRNA-based medical treatments informed and facilitated the development of the Pfizer-BioNTech and Moderna vaccines that, today, are being administered to people around the world in the ongoing global effort to end the COVID-19 pandemic. While no other mRNA-based therapeutics have, as of yet, been approved for widespread clinical use (indeed, the United States Food and Drug Administration has issued only an Emergency Use Authorization, not a standard approval, for the Pfizer-BioNTech and Moderna vaccines), the demonstrated effectiveness and safety of these vaccines will doubtless spur further research into other uses of this promising biological technology. As Dr. Dan H. Barouch, the director of the Center for Virology and Vaccine Research at Harvard Medical School, has stated, “The vaccine field has been forever transformed and forever advanced because of COVID-19.”

I would take this statement a step further and say that the COVID-19 pandemic has forever transformed the field of medicine as a whole, as the advent of the widespread use of mRNA-based therapeutics could open up treatment possibilities that seemed impossible not too long ago. If there is one good thing to come out of the COVID-19 pandemic, it is that, in their efforts to fight it, scientists have revealed the enormous potential of mRNA-based medical interventions, both in the fight against the pandemic and the larger fight against disease in general. Indeed, it is quite possible that we might one day look back on the COVID-19 pandemic as the beginning of a revolutionary new era of medical science.

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