The story of the multi-decade uphill battle Katalin Karikó and her fellow researchers fought to prove messenger RNA can viably be used in medicine is widely known today. In just as little as two years, the world has learned about mRNA technology and how fast it can react when the need arises holding almost unlimited promises in future applications. As always is the case with “instant hits” in science, the ride was actually very long and bumpy, but more on that later.
What is mRNA?
In very simple terms: messenger ribonucleic acids (or mRNAs in short) are the body’s natural way to transport messages from our DNA to our cells, telling cells what kind of proteins they should produce to make sure everything works as expected. We can imagine it as a user manual for IKEA furniture where the instructions are all created from a combination of the four nucleotides that form the “letters” of the RNA.
What does it do in a vaccine?
mRNA vaccines differ from earlier vaccines in this: instead of introducing the body to (living or dead [parts of]) the actual pathogen, they carry a set of instructions that allows our bodies to produce a tiny but significant part of the pathogen – without producing the virus itself. In the case of the COVID vaccine, this is the infamous spike protein of COVID.
Why is that good?
Replicating the COVID spike protein – without the presence of the virus itself – allows the body to develop the specific antibody capable of fighting the pathogen – in advance. So by the time we meet the virus, our immune system has already been trained to recognise and efficiently fight it.
The below illustration helps to understand the concept. Although the body has only ever met a tiny part of the pathogen, it was still trained to fight it.
Not exactly a new thing
Discovered in the early 60s, our knowledge of the existence and purpose of mRNA is not a new thing. Despite the long history, scientists had a hard time figuring out how this messenger molecule can be utilised for medicine.
The first experiment in which scientists successfully managed to make mice’ bodies produce specific proteins by injecting mRNA took place in 1990. Although it proved the theoretical viability of the technology, they had to overcome two major obstacles: 1. the instability of the mRNA molecule in the body (so it doesn’t disappear within minutes) and its tendency to cause inflammatory responses.
Fast forward 15 years to 2005 (and note that at this point we were actually in year 44 of the mRNA research already – so much for the myth of the vaccine developed in haste). The major breakthrough of Karikó’s team was that they discovered how it is possible to safely “wrap” the mRNA in just the right kind of lipid “coating” – a method addressing both major earlier hurdles. Finding the perfect lipid nanoparticles was also a 30+ year story, but that is for another day.
And yet, another 15 years go by with vigilant research until we arrive at 2020 and the COVID pandemic stopping the world as nothing we have ever seen before.
This novel crisis presented an unprecedented opportunity for the mRNA technology, diverting never-before-possible funds and opportunities to the field. The long depicted and neglected research segment of mRNA suddenly became the favourite, creating new vaccines seemingly overnight.
The pandemic and the success of the mRNA vaccines gave huge momentum to find possible applications. Here are what we can expect in the near future and mid-, and long-term.
What’s next? Short-term future: combined flu shots
Moderna launched the human trial for a combined mRNA flu shot in mid-2021. The promise of the technology is that it can be manufactured much faster than traditional flu vaccines, thus the jab could be more closely matched to the years’ actual pathogens. Moderna is not the only one, Pfizer-BioNTech, Sanofi and Translate Bio all have similar ventures underway.
The plan with the combined flu shots is to create a vaccine that prepares patients for all kinds of respiratory pathogens in one jab.
Infectious diseases: malaria
Pfizer-BioNTech announced in 2021 that they would use part of their profit to develop a malaria vaccine using the same mRNA technology.
“Malaria is a complex infection caused by a parasite that evades recognition by the immune system, ” BioNTech Chief Executive and co-founder Ugur Sahin told Reuters, adding the goal is to develop a vaccine that makes the parasite visible and attackable from the very beginning.
Although the initial reports called for clinical testing in 2022, we have not yet seen new developments for the malaria mRNA vaccines recently.
What has been reported on the other hand is that the company started building an mRNA vaccine manufacturing facility in Rwanda, the first of such on the African continent. This is expected to be followed by the setting up of additional factories in Senegal and South Africa. According to the published info, the plants will manufacture COVID, malaria and HIV mRNA vaccines in the future.
Infectious diseases: HIV
“Two of Moderna’s mRNA-based HIV vaccines could start human trials this week, according to a new posting in The National Institutes of Health’s clinical trial registry. The Phase I study would test the vaccines’ safety, as well as collect basic data on whether they’re inducing any kind of immunity, but would still need to go through Phases II and III to see how effective they might be.” – said this 2021 report.
Advanced melanoma, breast cancer and other solid tumours
Following a successful trial in mice, BioNTech and Sanofi started testing the safety of a four-mRNA mixture on 231 people. The first preliminary results were reported here, showing no serious side effects.
For now, the treatment is only suitable for tumours that are near the surface of the body, since the mRNAs must be directly injected into the tumours.
“A new vaccine using the same mRNA technology as the Pfizer jab against COVID-19 could be a breakthrough in the fight against pancreatic cancer. In a promising early study conducted by BioNTech, half of the patients remained cancer-free 18 months after having their tumors removed and receiving the jabs.” – was reported in June 2022.
The results showed that the vaccine could train the immune system to kill pancreatic cancer cells by boosting immune cells that target tumours. The trial was carried out on 16 patients, each of whom was given eight doses of the individualised vaccine made using the mRNA genetic code found in each of their tumours.
Vaccines preventing skin cancer
Here is another fascinating line of research from the Oregon State University. The research was based on a protein within the thioredoxin antioxidant system called TR1. This protein is believed to be capable of preventing oxidative stress on melanocytes, the cells in the skin that are triggered by the sun’s UV radiation.
In a study using mice, the researchers removed TR1 from their antioxidant systems to evaluate how the protein affected the protection of melanocytes. They found that without TR1, melanocyte proliferation was significantly reduced. They thus concluded that TR1 directly affects melanocytes, which are responsible for preventing skin cancer, and that if a vaccine could generate more TR1s it could protect against sun-induced UV damage.
Maybe, in the not-so-far future, we can get an annual vaccine for added sun protection.
Individual inherited genetic problems
“Moderna has been researching the use of mRNA for the potential treatment of the metabolic disorder Glycogen Storage Disease Type Ia (GSD-Ia) caused by an enzyme deficiency where the liver fails to break down glycogen into glucose, causing the body’s blood sugar levels to drop.”
Where do we stand now?
We see that mRNA technology has immense potential. Billions of doses of mRNA vaccines have been administered across the globe in the past two years, accelerating the field by decades.
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