Karikó. Remember that name.

There are three basic types of RNA in the cells of eukaryotic organisms: mRNA, rRNA, and tRNA. mRNA, famously, serves as a transcript of DNA. When mRNA encounters a ribosome (which is composed mostly of rRNA) just outside of the cell nucleus, tRNA delivers raw amino acids to the ribosome, and the ribosome assembles those amino acids into the protein that was specified by the mRNA blueprint.

This process (called "translation" or "protein synthesis") is responsible for all life on earth. Every living thing is composed of water, a handful of minerals (calcium is common), and a giant stack of proteins. Universally, mRNA is the blue-print for those proteins, and by this mechanism all known life exists.

In 1969 Lockard and Lingrel were the first to demonstrate that cells could be induced to synthesize (i.e, generate proteins from) an arbitrary mRNA sequence. In their experiment, they (in vitro) injected rabbit cells with the mRNA that encodes mouse hemoglobin, and proved that the rabbit cells happily synthesized the resulting mouse hemoglobin protein.

Over the course of years, many such experiments were carried out: injecting cells (in vitro) with various types of mRNA and observing that the mRNA was synthesized into the appropriate protein. It was clear that it was possible to use cells to crank out arbitrary proteins.

All of the experiments described above were "in vitro", in the proverbial petri dish. ("In vitro" is Latin for "in glass"). The natural question arises: if this works in vitro, can we persuade the cells of a living organism to translate arbitrary mRNA into proteins?

In 1990 molecular biologist John Wolff (at University of Wisconsin) decided to find out. He and his partners generated the mRNA that encodes luciferase, the enzyme that makes firefly butts glow. mRNA is extraordinarily fragile, but with careful handling Wolff and team were able to inject this mRNA into the thigh of a mouse. After waiting a couple of hours, they put the mouse under a bioluminescent imager and looked for the telltale optical signal that would indicate the living mouse was generating luciferase proteins.

The historian Herodotus is said to have written "Very few things happen at the right time, and the rest do not happen at all. The conscientious historian will correct these defects."

In the spirit of Herodotus then, let history record that upon looking in the instrument, Wolff exclaimed "Thar she glows!"

From the vantage point of history, let us look upon Wolff in his lab in 1990, glance at our watches, and realize that three decades hence a deadly pandemic will sweep the globe. While we can celebrate Wolff's glowing mouse and the hard proof that the cells of a living organism can be programmed to pump out an arbitrary protein, there is an enormous practical problem that makes any hope of mRNA vaccines virtually impossible: mRNA is extraordinarily fragile, and the innate immune systems of virtually all mammals are "programmed" to attack and destroy foreign mRNA. Wolff's mouse glowed, but not much and not for long.

Readers should note that this brief overview skips over so many names, and so many experiments. So many people deserve credit... but that credit is for naught if we can't figure out how to inject mRNA into a living organism without that organism's immune system destroying it almost immediately. Immunobiology, like the moon, is a harsh mistress.

Let's rewind the clock a little.

It's 1985 and Kati Karikó is an immunobiologist with a foundering career living in Hungary. With little to tie her family to her homeland, she and husband decide to move their young family (they had a toddler daughter, Susan) to the United State to take a job at Temple University. Hungary would only allow them to leave the country with $100, so she sold the family car, sewed the $1246 in proceeds into her daughter's teddy bear, and the Karikó family landed in the United States.

Katalin (Kati to her friends) Karikó moved from lab to lab for awhile, making occasional discoveries, but rarely having enough funding or resources to pursue them. Karikó eventually landed at University of Pennsylvania, again bouncing from lab to lab until a chance meeting at a photocopier with immunologist Drew Weissman. Weissman shared Karikó's fascination with the promise of mRNA, he invited her to share his lab, and they became research partners.

All of their early experiments were failures. Repeatedly Karikó would inject various mRNA transcripts into various organisms, and repeatedly the immune inflammatory response would destroy the mRNA and sicken the test animal. Variations on these experiments went on for years, with Karikó and Weissman making minor discoveries but never solving the final problem that would open the way for mRNA vaccines.

In 2005, Karikó hit upon an idea. Weismann and Karikó knew that tRNAs, injected into a test animal, didn't elicit the sort of immunogenic response that mRNAs did. What could be the difference?

Most readers know that DNA is made of 4 types of nucleotides: adenine, cytosine, guanine, thymine. The first letters of those four nucleotides give us the famous letters of the genetic code: A, T, G, and C. RNA is constructed similarly, except that in place of thymine (T), RNA has uracil (U). You've probably seen pictures of DNA as a "double helix", which is basically a twisted up ladder. The "rungs" of that ladder are made up of pairs of nucleotides, and the sides (or "backbone") of that ladder is composed of interconnected phosphate groups. RNA is the same, except there is only one side of the "ladder".

A vocabulary note: we are about to discuss "nucleosides". A nucleoside is composed of one of four bases plus a sugar. A nucleotide is composed of a nucleoside, plus a phosphate that forms the backbone of the DNA or RNA molecule. For the purposes of this discussion, you may think of nucleotides and nucleosides identically, though we are going to use the word "nucleoside" to describe the collection of atoms we are talking about.

Where we we? Oh yes... RNA has uracil in place of DNA's thymine. The uracil nucleotide is composed of a sugar, the base uridine, and the phosphate backbone. Now back to the lab!

Karikó spent time carefully examining the uridine in tRNA (recall that tRNA rarely elicits an immunogenic response), and took note of the fact that the uridine nucleoside in most tRNA is very slightly different than the uridine present in most mRNA. In mRNA, uridine connects to the phosphate backbone (the side of the "ladder") via a bond composed of a carbon atom and a nitrogen atom. In tRNA, the uridine connects to the phosphate backbone via a bond composed of two carbon atoms. (In this configuration it's usually called "psuedouridine", pronounced "psuedo-uridine".)

Karikó wondered: if mRNA could be created in such a way that psuedouridine was substituted in the places where mRNA usually has uridine, might that allow mRNA to slip past the innate immune system in the way tRNA does?

Karikó and Weissman's efforts were then poured into the novel biochemistry of creating mRNA molecules that contained psudeouridine instead of uridine.

The rest, of course, is history. This nucleoside-modified mRNA was one of the primary keys to saving millions of lives during the SARS-CoV-2 pandemics... and in epidemics and pandemics to come.

It is a near certainty that almost everyone reading these words knows someone that is alive because Katalin Karikó was too stubborn to quit. She failed over, and over, and over.

What's that phrase? Oh, yes:

"Nevertheless, she persisted."

Oh, I almost forgot: the little Karikó girl, the one with the teddy bear? She grew up to be Olympic athlete Susan Francia, and has brought gold medals in rowing home to the US in two separate Olympics.