“If you start to take Vienna, take Vienna”— Napoleon (reportedly)
What’s the fuss? BioX won the Nobel Prize….er rather it was the mRNA vaccine that won. Correction—it was the scientists, Katalin Karikó and Drew Weissman of the University of Pennsylvania, who developed the RNA technology that went into the novel vaccine who won the prize. But their work directly led to the vaccine, a first fruit of BioX.
Readers of these blog pages might remember that about this time in 2020, that year’s Nobel award for Medicine or Physiology went to three scientists for their decades-long search to discover what caused hepatitis type non-A, non-B. It turned out to be a whole new virus, the hepatitis C virus (or HCV) that took four decades to identify. Even though it still remains a huge health problem, there still is no vaccine for it. I compared that four decade slog just to find the pathogen to how fast the novel viral cause of COVID-19 was found and a vaccine developed—all done in less than a year! I anointed the new biology that did that amazing feat, ‘BioX.’ That was rather prescient of me, since three years later, the co-founders of the COVID vaccine using BioX too were awarded the Nobel Prize.
I dubbed the new amazing post-molecular biology science that enabled such a quick identification of the novel coronavirus and development of a vaccine against it, ‘BioX’ after SpaceX. SpaceX, of course, is the name for the new way space travel is now being done. Shortly before the Nobel award for the discovery of HCV, Elon Musk’s SpaceX took astronauts in an unpiloted vehicle to the International Space Station. Then the launch vehicle, rather than being discarded as usual, was landed, upright, in the center of a bullseye on a barge off the coast of Ireland, to be reused on a future space flight--maybe to Mars? The whole thing was developed in a fraction of the time at a fraction of the cost of what NASA had historically been doing. NASA’s technology was rendered archaic by SpaceX, which introduced us to a new era of space travel.
The breathtaking speed with which a new biology discovered the SARS-CoV-2 virus and then developed a safe and effective vaccine against it ushered in a new post-molecular biology world I dubbed ‘BioX’.
Now the details. But as breathtaking as SpaceX is, it was not developed overnight in a vacuum. It arose on the back of decades of NASA engineering R&D, which included some spectacular failures and even a few tragic deaths. Similarly, as breathtaking as BioX was with the rapid identification of a novel virus and development of the new mRNA vaccines to a wholly new disease, that technology too was built on the back of decades of hard work, punctuated with many failures, but also flavored with impressive perseverance on the part of a few individuals.
There are two major components to the novel COVID vaccines—the mRNA which generates the viral protein to which the immune response is made, and the lipid nanoparticles that encapsulate and protects the fragile mRNA from a world that is hostile to mRNA. Both components took very separate, decades long, twisting, uphill roads to develop. Both nearly met with failure. And both came together with spectacular success. BioX!
- The mRNA. Weissman, and especially Karikó, languished for years on the fringes of science with a, then, very weird idea of using mRNA to produce drugs or vaccines. Their collaboration began with a chance encounter at a UPenn copy machine in the 90s and went downhill from there as recently told in the Wall Street Jounal. Funding for their work was hard to come by. Karikó was banished to an office on the outskirts of the campus and languished in a non-faculty position for years. At one point, she had to take a demotion to simply keep a job at Penn.
They just could not get their idea to work. The mRNA was too fragile and too short-lived to work with and produce the desired proteins when they tried to express it in cells or animals. The fact is that there are ubiquitous enzymes all around us called RNases that have a ravenous appetite for mRNA. RNA molecules, especially mRNA disappear almost as fast as one can purify or make them, let alone then try to get them into cells in tissue culture or into bodies. On top of that, when naked mRNA is injected into a body, it elicits a powerful immune response that further quickly degrades it. Note that there are several different types of RNA, and mRNA is the most fragile and hardest to work with, but it is the type that provides the message that turns a genetic code into a protein molecule like a spike protein, which is why it is used in the vaccine.
The researchers had great difficulty getting grant funding for their research because no one believed it would go anywhere. When they could produce some data, they had a very hard time finding journals to publish it. No one was interested because no one believe that there was any utility in the whole premise of using mRNA as a therapeutic tool. In the publish-or-perish world of academia, such negative peer pressure usually is the kiss of death. They should have seen the writing on the wall and been teaching high school biology. But for some reason, Karikó continued to have faith in her idea even though no one else did. For some reason, she persevered.
After dogged determination and ignoring all the naysayers, she eventually had a major breakthrough after a doing a simple experiment. They found a simple way to protect the mRNA from the immune response and published this in 2005. It opened the field and colleagues minds about using mRNA as a possible therapeutic tool. But there still was the problem that mRNA was exquisitely sensitive to RNase enzymes that were everywhere—on your fingers, in your breath and blood, even on sterilized surfaces—the enzymes are incredibly stable molecules and very hard to destroy. Life intended mRNA to be short lived molecules, not to be used in vaccines.
It wasn’t until folks paired the immune-stable mRNA of Karikó and Weissman with a way to protect the molecules from RNase enzymes that mRNA vaccines became possible so they could win the Nobel Prize. Lipid nanoparticles did the trick.
- The lipid nanoparticles. The story behind the development of the lipid nanoparticles used to deliver the CoV-2 viral spike mRNA sequence to cells so they could use their normal gene expression machinery to put the spike protein on their surface and generate an immune response is a long one. In that regard it is quite similar to the long, arduous story behind the development of the therapeutic mRNA. Early on, neither technology was believed possible or useful by the scientists’ peers. Both groups had very hard times getting their scientific feet on the ground. Both nearly failed. I described Karikó’s struggle above and in March 2021 I wrote in these pages about the professional plight of Bob Langer who, in the 70s, had a vision for using liposomes (short for lipid nanoparticles) for delivering fragile bio-molecules and drugs to cells (you can read that post here). Briefly, his idea was to create mini-cells in which to package and protect fragile therapeutic molecules and then deliver them to cells and tissues in the body. The liposomes containing the fragile therapeutic molecules would fuse with the lipid membranes of cells and disgorge their contents into the cells. Many people told him it was not possible and he had his first nine grant applications rejected—and this was a time when medical science research grants were easy to get (when I was in graduate school in the early 80s, NIH grant applications had a 50% success rate. By the time I became a faculty member in the late 80s that dropped to 10%). Langer, like Karikó, also could not get a faculty position because people did not believe in his research. Also like Karikó, for some reason Langer persevered.
Also like Karikó, Langer too succeeded—eventually. It took a long time. The technology he successfully developed was first used to package a drug used to treat a rare genetic disease that causes nerve and heart damage. It also was used to package mRNA for an Ebola vaccine. From an ignominious beginning, Bob Langer became a professor at MIT where there now is a bioengineering lab named after him. That is not quite as nice as winning a Nobel prize, but high recognition still.
Along the way, he also co-founded a small biotech company named Moderna that was focused on developing mRNA vaccines for infectious diseases, cancer and other diseases. Then COVID came calling and Moderna immediately pivoted, and along with BioNTech, NIH, and Pfizer, quickly gave us mRNA vaccines delivered in liposomes that saved millions of lives from COVID.
That is how BioX technology led to the Nobel prize this year.
The bottom line. BioX, like SpaceX, was built on decades of hard research that was punctuated by painful failures, but highlighted by dogged determination. Both technologies, BioX and SpaceX, are here to stay at least until the next amazing thing replaces them. You can bet that that next amazing thing will have been developed on the back of determined researchers who very possibly will be working at the fringe of their professions and may flirt with professional failure early on. You can also bet that the next amazing things will be built on the backbone of SpaceX and BioX. That is how science and engineering painfully progresses.
So, when you hear someone say that the mRNA vaccines are experimental like I very often do, tell them the truth. They were built on decades of hard research going back to the 70s.
Stay tuned for a coming post on the future of BioX, which is here to stay for a while. New mRNA vaccines are being developed for previously vaccine-impossible diseases including HIV, cancer, and various animal diseases. Work also is underway for a universal flu vaccine.
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