mRNA's History- And Its Future

 BY DEREK LOWE

This is a really good article on the history of mRNA vaccines, and I recommend it. I and many others have been emphasizing that we've been very fortunate that so much work had already gone into this area before the pandemic hit - that and the experience we gained during the previous SARS and MERS outbreaks have been absolutely crucial to vaccine development (the latter not just for the mRNA vaccines), and without them we would be in far, far worse shape now. 

That Nature piece will also give non-scientists a realistic picture of what development of a new technology is like in this field. Everyone builds on everyone else's work, and when a big discovery is finally clear to everyone, you'll find that you can leaf back through the history, turning over page after page until you get to experiments from years (decades) before that in hindsight were the earliest signs of the Big Thing. You might wonder how come no one noticed these at the time, or put more resources behind them, but the truth is that at any given time there are a lot of experiments and ideas floating around that have the potential to turn into something big, some day. Looking back from the ones that finally worked out brings massive amounts of survivorship bias into your thinking. Most big things don't work out - every experienced scientist can look back and wonder at all the time they spent on various things that (in retrospect) bore no fruit and were (in retrospect!) never going to. But you don't see that at the time. When the first experiments were run that showed that mRNA could indeed be induced to enter cells and set off a bit of protein synthesis, it was clear that this could eventually be a therapeutic pathway. Emphasis on "could", because there were also a thousand issues that would have to be addressed along the way, and most any of them could (on closer inspection) turn out to sink the idea.

You'll also see that the earliest mRNA work was not directed at the idea of vaccines at all. It was going to be a laboratory tool to make cells produce whatever protein you coded the mRNA for, to run all sorts of experiments in what we would perhaps now call synthetic biology or chemical biology, or perhaps it was going to be a direct therapeutic to make people produce such proteins in their own bodies. The first attempts to use this technique to produce a protein antigen as a vaccine in the early 1990s were hard to reproduce, and the whole idea was still too expensive for the amount of risk it contained. As the article says, "In the 1990s and for most of the 2000s, nearly every vaccine company that considered working on mRNA opted to invest its resources elsewhere." RNA was considered too hard to work with, too unstable, and the whole idea too full of fresh problems that would have to be worked out along the way, compared to other options for the time and money.

And plenty of time and money did get spent in the intervening years. The RNA constructs did turn out to be too unstable in many cases - they fell apart in the blood, or they just landed in the liver on the first pass and were never seen again. Or they didn't get into cells very well, or didn't get translated into much protein when they did. A lot of the early attempts set off a general inflammatory response as well, because the body's innate immune system picked up on the sudden presence of foreign RNA and reacted as if this were a viral attack in itself. So there were a lot of stops and starts, with each failure leading to more refinement. This technique, like so many others, stands before you after spending years in the scientific equivalent of an expensive finishing school.

But now that many of the problems have been laboriously uncovered and dealt with, we do indeed have what looks like a really useful platform for vaccines (and for other uses as well). Here's where I break out the hose and turn it on some of the rowdier parts of the crowd, though. It's good to remember that the vaccine application is really the most straightforward of them all: for starters, you're depending on the huge amplification of the adaptive immune system working for you, so you don't need much of an mRNA dose. Your targets can (in the best cases) be pretty  clear: the earlier work on SARS strongly suggested that the Spike protein was the antigen of choice, and we have similar ideas for infectious diseases like RSV. Honestly, the development pathway for mRNA coronavirus vaccines was about as good as it can get.

There are plenty of other things in the works, and many of them are getting headlines. Keep in mind, though, that some of these have been in the works for years already; they're not just sudden turbocharged programs that have zipped into prominence since Covid-19. Moderna, for example, has been working on mRNA flu and RSV vaccines for years now - the recent headlines about their work on a combination of these two with their coronavirus vaccine (or booster) is good to hear, but it's not a gigantic leap from a standing start.

Similarly, talk of mRNA cancer vaccines takes you into an area that has had many, many years of effort put into it already (and so far, without much to show for it in human therapy). BioNTech had this as their story when they launched in 2008, for example. That Nature history link mentions a number of earlier attempts (and earlier companies) from the 1990s as well. The whole cancer vaccine idea was one of the first waves of immuno-oncology, and it is nowhere near as straightforward as coming up with a vaccine against a respiratory virus.

That's not to say it can't work - it's just going to be a longer time down a hard road before we can say that it does, though. mRNA is not magic. Using it does not address the biggest obstacle to the cancer vaccine idea, which is figuring out what to aim your neat technology at in the first place. What protein on a cancer cell should you be raising an immune response to? You need one that is going to set off a robust attack on those cells, for sure, but at the same time one that will not set off a similarly robust attack on the linings of your kidneys or the valves of your heart. This is a far, far easier problem when you have some completely non-human viral protein to aim at, as you can appreciate. And as we've seen with viral vaccine side effects (Guillain-Barré, myocarditis), the human population varies enough that in small numbers of people you're going to see misfires even when you target a virus.

I like mRNA therapeutics and vaccines, and I'm really glad that they're getting the chance to prove their worth. We're going to get a lot of useful things out of this platform. But the platform itself does not guarantee success, especially in those areas where the problems that it can fix are not the ones holding things back.

https://www.science.org/content/blog-post/mrna-s-history--and-its-future