The mRNA revolution: How COVID-19 hit fast-forward on an experimental technology

The mRNA revolution: How COVID...
Years of research has been condensed into less than 12 months due to the COVID-19 pandemic
Years of research has been condensed into less than 12 months due to the COVID-19 pandemic
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Years of research has been condensed into less than 12 months due to the COVID-19 pandemic
Years of research has been condensed into less than 12 months due to the COVID-19 pandemic
How mRNA vaccines work
How mRNA vaccines work

Over the past few months several hundred million people around the world have safely received a wildly effective COVID-19 vaccine based on mRNA technology that was still relatively experimental just one year ago. But what exactly is an mRNA vaccine, where did the technology come from, and what other diseases could it be useful for?

Despite the seemingly sudden appearance of this cutting-edge mRNA technology it is, like many scientific innovations, actually the product of decades of piecemeal research. mRNA was first discovered around 60 years ago after scientists worked for years trying to understand how DNA co-ordinated protein production in cells.

Inside all living cells are tiny protein-making factories called ribosomes. These factories make whatever proteins they are directed to produce, and those directions come from mRNA molecules.

For decades scientists suggested it was hypothetically possible to hijack this mechanism and deliver artificially designed mRNA to a cell, instructing it to generate whatever protein one wanted. But the idea was science fiction until several discoveries in the 1980s finally made it possible.

Of course, once scientists started experimenting with their own forms of mRNA they discovered a new roadblock. Immune systems are clever. They are well geared to detect foreign bodies trying to infiltrate the body, and early animal studies revealed synthetic mRNA triggered profoundly fatal inflammatory responses.

Across the 1990s mRNA technology sat on the fringes of science, with many researchers suspecting the immune problem was insurmountable, but in 2005 biochemist Katalin Karikó published an extraordinary breakthrough. After toiling for well over a decade, she and colleague Drew Weissman demonstrated a small molecular tweak to synthetic mRNA that could allow it to evade immune defenses, slip inside a cell and send its message to the protein factories.

This ground-breaking discovery ultimately led to the founding of a pair of now well-known biotech companies, Moderna and BioNTech. But the ongoing research continued to strike hurdles. Karikó’s innovative discovery seemed to avoid triggering immune responses in animals when delivering low doses of synthetic mRNA, but any kind of ongoing administration with larger doses still triggered dangerous inflammatory reactions.

So, many researchers pivoted to investigating synthetic mRNA as a novel vaccine technology, since vaccines generally require just one or two small doses. Vaccines were never the primary focus for many mRNA researchers, however, they did seem to be the most feasible and realistic clinical application.

Alongside all of these innovations, nanoparticle research was accelerating in the 2010s, and this introduced a perfect solution to another problem facing mRNA researchers. mRNA molecules are fundamentally built to be temporary. They get inside a cell, deliver the necessary message, and then quickly degrade.

So, synthetic mRNA needs to be encapsulated inside something else to remain protected while it moves from factory to fridge to human cell. The solution came with the development of novel lipid nanoparticles. These nanoparticles protect the mRNA from degradation while also effectively slipping through a cell’s wall, helping deliver the mRNA right to the door of the cell’s protein factory.

All of these innovations and discoveries helped pave the way for mRNA technology to be uniquely ready for what was going to strike the world last year.

The pandemic acceleration

Developing a new clinical therapy can be a frustratingly slow process. The path from initial discovery to market approval for a new medicine can take at least a decade, with the three-phases of human clinical trials alone taking up tens of millions of dollars and more than six years to complete.

By 2019 mRNA vaccine research was quietly chugging along, with a number of targets proving promising in early-stage clinical trials. However, no mRNA-based therapy had yet been approved for market use and few people around the world had ever been administered this experimental treatment.

Harry Al-Wassiti, a bioengineer from Monash University, has been working with mRNA technology for several years, and he describes the pace and scale of mRNA manufacturing and distribution across 2020 as remarkable.

“Many of the innovations currently used by COVID-19 vaccines were developed throughout the past 12 years – but when COVID-19 hit, the best of those innovations and knowledge were put together,” Al-Wassiti tells New Atlas. “This is what makes this field amazing: it requires different innovations and expertise to solve the puzzle.”

On January 10 last year Chinese researchers published the genetic sequence of a novel coronavirus that had recently appeared in Wuhan. This was all mRNA scientists needed to begin work on a potential vaccine. By mid-February Moderna was first out of the gate with an experimental vaccine being shipped out for early-stage human clinical trials.

A little over a year later hundreds of millions of people have been given this vaccine. And while other COVID-19 vaccines have been developed over the past year, none have rivaled both the efficacy and safety profile demonstrated by mRNA vaccines.

More than just a COVID-19 vaccine

Thomas Preiss, a professor of RNA biology from the Australian National University, has been working in the field for more than 25 years. It was perhaps little surprise to Preiss that mRNA technology was this close to reality, after so many years of prior research laying the groundwork for the 2020 acceleration. But he does view the last year as a real turning point for the technology.

“The pandemic has greatly accelerated the transfer of mRNA therapies into a clinical reality,” says Preiss in an email to New Atlas. “Given how strongly the mRNA vaccines are performing, I expect this to be a real watershed moment for the technology and we will see other vaccines but also therapies for other diseases becoming available in the near future.”

It is these other applications Preiss alludes to that really reveal the revolutionary potential of mRNA technology. More than introducing just a new kind of viral vaccine, this technology could hypothetically be applied to an incredibly broad assortment of applications.

Cancer is one application many mRNA researchers have been investigating for years, and the current acceleration in the field will certainly help speed up ongoing studies. Al-Wassiti says these mRNA cancer treatments can be called “therapeutic vaccines.”

“Those act in a similar fashion to the viral vaccine, to train the immune system to recognize 'existing' cancer by vaccinating against molecules present predominantly in cancer but not healthy cells,” explains Al-Wassiti. “Other approaches may use mRNA to make 'antibodies' that target cancer or stimulate the immune system to fight cancer. The current understanding is that those 'vaccines' will complement existing therapeutics to improve the chance of survival.”

Viral vaccines and new cancer therapeutics are just the tip of the iceberg when it comes to the potential for mRNA therapies. Al-Wassiti says these targets are “low-hanging fruit,” with pre-existing research easily built upon. Auto-immune diseases, metabolic diseases, and respiratory inflammatory diseases all present novel opportunities for mRNA interventions. Even gene editing therapies such as CRISPR could be improved using mRNA technology.

“… the CRISPR guide is already a (short) RNA,” Preiss explains, “[so] the requisite Cas protein could be co-delivered as mRNA and the cells then translate it to generate the CRISPR-Cas ‘gene scissors.’”

How mRNA vaccines work
How mRNA vaccines work

The challenges ahead

Despite the extraordinary success of the COVID-19 mRNA vaccines over recent months, there are still big problems that need solving before this technology can be broadly applied to other diseases.

“As always with genetic medicines, the key hurdles are to solve effective and tissue-targeted delivery,” notes Preiss. “This is a comparatively minor issue with vaccines, but increasingly more important when the goal is to engender sustained therapeutic protein expression to treat non-infectious disease.”

Researchers now know mRNA technology works in the context of viral vaccines. But how to deliver these manufacturing blueprints to specific cells or organs is a whole new challenge.

“There is a common saying in gene and mRNA therapy: 'delivery, delivery, delivery,' this is because mRNA need not only [provide] protection but also delivery to specific organs,” says Al-Wassiti. “Delivery technologies will be a major development that will improve the technology further.”

It’s difficult to predict exactly how influential mRNA technology will be on medical science over the coming decade. What is undeniably clear though is how quickly this technology has moved from the experimental fringes into the mainstream.

Along with this greater attention comes increased funding for research and manufacturing. In the past it hasn't been cheap to manufacture mRNA products, but that is rapidly changing. As the technology rapidly scales up and new researchers are attracted to the field it is fair to suggest the mRNA boom has begun.

Eighteen months ago the amount of humans administered with synthetic mRNA therapies numbered in the thousands. Now, that number is in the hundreds of millions. The technology has presented humanity with a pathway out of the worst pandemic in a century, and potentially this is only just the beginning of the mRNA therapy story.

I am so glad this worked as quickly as it did. We dodged a bullet, this virus could have been much deadlier and more contagious. We need to get off our lazy butts and move more experimental treatments along more quickly by allowing people with fatal diseases to sign away any rights to sue in exchange for treatments that might give them a chance!
Nice Article - well developed! As a recipient of the Moderna vaccine recently, I was very interested in the history of this science.
Brian M
We dodged a bullet - Indeed, but I'm worried about the ricochet!
Well written article Rich Those of us who protested and cried out when "W" cut the research budgets knew we needed to keep researching - we knew the many genetic research breakthroughs at that time needed more work. Despite the severe cuts of "W", and then despite the draconian cuts of the orange administration, over 60 years of research have come together in a successful therapeutic intervention. When I was in grad school, pre-Crispr technology had proven fatal, mRNA technology had proven fatal, and even DNA analysis wasn't to the level of "23_me" - we were hoping to maybe sequence mitochondrial DNA for determining matriarchal lineage. Now today we have research that has moved us 'quickly' to our current vaccination drive. Yes, 60+ years of research has quickly produced results. And are we setting ourselves up for an immune reaction by the 20th vaccine of this type? 15th vaccine of this type? As all breakthroughs, we have to stay vigilant to any untoward outcomes.

Thank you for explaining how slow and arduous this research has been, and how administrations who cut anything that "didn't give them any results now" blocked the scientific research. This miracle took 60 years of failures to yield human results. The previous 50 years always resulted in wholesale failure. It seems miraculous today, likely as miraculous as electric light would seem to Neanderthals - no offense intended to the Neanderthal rich genomed.

You should look into epidemiology of wastewater analysis - or have you already? This is another breakthrough that has been shut out of government funded labs and the EPA because of "Tea Party" Privacy views. Knowing how much estrogen or penicillin or Cocaine metabolites are in our wastewater would violate self incrimination protections of the 5th amendment. Even in a small town of 100,000 people, wastewater analysis could not name anyone as the source - especially if one sewage feed came from a highway restaurant and truck stop!

Sorry Rich, too many words. But thank you for explaining the most serious issues with this mRNA development over the past 60-odd years. A very thorough article, and it almost pointed out where our 'libertarian' and 'self-interest' tendencies worked against our necessary medical research. I'm with T. Hobbes on the Social Contract. If you agree to the vaccine, you should also understand you have agreed to the past and future development of science no matter how much you deny all of science's findings.
I’m no bioengineer so it would have been nice to see a contrast between mRNA technology and traditional vaccines. From my admittedly limited knowledge, how different would the diagram showing how mRNA attacks COVID be from traditional technologies like in the J&J vaccine?
Excellent introductory article, but would like to see references to more detail literature. Also, I think there is an error in the diagram. It shows the constant region of the antibody - the tail of the 'Y' - attaching to the spike protein. Shouldn't it be one of the variable regions, one of the arms of the 'Y'? A minor point to a very good and important article. Thank you.
Are all of the vaccines mRNA? What about the Sputnik and Sinovac or Sinopharm?
Ralf Biernacki
@ BlueOak: In an actual infection, a virus enters a cell and programs it to produce new viruses---the spike protein as well as other virus parts, including the capsule and its reproductive genetic code.

A vaccine delivers a virus that is somehow crippled; it still does its thing, but slowly and awkwardly. Most of the time it is the spike protein---the most visible part of the virus---that is malformed, to make it difficult for the virus to infect cells.

A mRNA vaccine enters the cell and programs it to produce proteins, just like a virus---but it only makes one part, the spike protein. Most importantly, it does not have the reproductive parts, so chain-reaction infecting of other cells just doesn't happen---instead of churning out live chickens, the cell just makes chicken legs, and puts them out for the immune system to fuss over. The immune system recognizes the spike protein as an invader, and gears up to fight it. It just so happens that this is the most visible part of the actual virus, so when a real infection happens, it is immediately recognized and attacked.