mRNA has been much in the news of late, for good reason, but its potential goes far beyond restoring the world to a state where we can have friends over without risking death.
It has the potential to cure a wide range of diseases, from malaria to--maybe--cancer.
All this potential exists because mRNA provides programmable solutions to a wide range of biological problems. mRNA fragments are literally programs that run on the hardware of our cells to produce anything that can be made of peptides, which are the basic building blocks of proteins.
Biological systems are an incredible example of the power of building blocks: they start with atoms that have almost no properties--mass, charge, spin, and a few quantum numbers that govern how they bind with each other--and end up with organisms like us, who have more properties than we know what to do with.
There's no magic in this process: just accumulation of complexity that builds up across multiple levels of organization, from atoms to molecules to meta-molecules (molecules made of molecules) to cellular pathways formed by groups of meta-molecules working together, and beyond that to cells, whole organisms, groups of organisms, even ecosystems.
Atoms bind together to form molecules. Hydrogen, carbon, oxygen, and nitrogen are especially important atoms for life in this regard, with carbon in particular being able to bind with itself and others in a rich variety of ways. Organic chemistry is the chemistry of carbon.
Thanks to the structural promiscuity of carbon, which can form long chains and linked loops, organic molecules can grow to enormous size. Non-carbon ("inorganic") molecules are typically made up of a few atoms: Fe2O4 (rust) has six. Many minerals have more--talc, for example, is Mg3Si4O10(OH)2--but even "small" organic molecules can be made of hundreds of atoms.
The whole trick of life is that these large organic molecules are capable of acting on each other and their environment in ways that result in their preservation and reproduction, with a different type of molecule being responsible for each function. Reproduction is the domain of long chains of nucleic acids, which form DNA and RNA. Preservation--which includes metabolism and the general working of our cellular machinery--is the domain of long chains of amino acids, which form proteins and enzymes. These two functions work together, as DNA produces RNA which results in protein and enzyme production, which ultimately result in the production of more DNA when cells divide.
Human life at the cellular level is a process of proteins and enzymes helping DNA produce mRNA which is used by the cell as a template to create more (and different) proteins and enzymes, which are sometimes simply called "poly-peptides." Our cells contain machinery that can make almost any poly-peptide. mRNA is the programming language for that machinery.
A "peptide" is a short chain of amino acids--anywhere from a few to about 50 molecules long--that can be linked together to form proteins. Like any good system of building blocks, when making something complex from the basic blocks (the 20 amino acids that humans use) it is a great savings to create an intermediate set of more complex forms (the peptides) so that the machinery for dealing with them doesn't have to handle literally any arbitrary collection of amino acids, but "just" a large (but finite!) number of peptides.
The thing that makes polypeptides fundamentally useful to life is that they are a) rich in chemically active sites and b) mechanically active as well. By "mechanically active" I mean they can be thought of as springs that have been folded up into some complex configuration that can be changed when they encounter some other molecule that binds with their chemically active sites. This is what gives polypeptides the ability to move stuff around in the cell, which is critical to life.
How various polypeptides work together to make life happen is outrageously complicated because it is evolved, not engineered. Evolution works by opportunistic elaboration iterated over a ridiculously large number of trials and an only slightly smaller number of errors. But the difference matters: the non-errors are--by definition--conserved. That is, they are non-errors precisely because they act to encourage their own replication. That's the sole criteria by which an elaboration is judged.
But the initial source of elaboration is randomness. At every step of any biochemical process, there is an opportunity for things to go differently. If a difference happens to increase the odds of that difference being replicated... it is more likely it will be replicated! The progressive accumulation of such differences results in the increasing complexity over time, but it is still the result of random changes, and as a consequence living organisms are essentially Rube Goldberg machines made of tiny programmable molecular springs.
The programmability is key to mRNA's power, as it acts as a hack into the biological machinery to reprogram it to our purposes. Old-style vaccines were like sending a whole complete, edited, video around: a large file that took ages to make. mRNA vaccines are like sending a script for one essential scene to a sketch comedy troupe and having them post the result to YouTube the next day.
mRNA turns the cell into a programmable machine for making... anything.
In the case of malaria, the parasite that causes it produces an enzyme that makes memory T-cells forget about it, so the next time someone encounters it the body is like, "Sorry, I don't think we've met" and lets it in. The RNA vaccine for malaria is a program that teaches the body to respond to this enzyme, allowing it to remember malaria and kill it. The specific form of RNA is even more clever than mRNA: it is "self-amplifying" RNA that can create copies of itself, meaning that the long, complex, and slow supply chain of conventional mRNA is bypassed after the first batch.
We have a ways yet to go with this, but we're taking ever-longer steps.
Good explanation. The paragraph about polypeptides being “springs” was particularly helpful. I often read of how important folding of proteins can be, and how the sequential exposure of chemical faces may govern the order in which biological processes occur. But thinking of a polypeptide as a “spring” clarifies for me how this might all work mechanically. (The new bio of Jennifer Doudna has quite a bit about folding, but manages to be unclear about the mechanics of CRISPR reactions).
You mentioned mRNA and cancers at the top, and that’s a topic that interests me. The fellow who first argued in biological detail that viruses might cause cancer was a really amazing Soviet scientist, Lev Zilber. I am not capable of untangling who exactly deserves a Nobel Prize, but Zilber spent 8 years in the gulag and his discoveries were falsely attributed to anonymous NKVD scientists. Zilber himself got in trouble because he claimed that a plague in So jet Azerbaijan was due to poor sanitation practices, when Stalin had already made clear that it was because of hostile intelligence services digging up the bodies of deceased people at night.
Anyway, if you have any detailed insight into how viruses associated with cancer might be eradicated with mNRA, that would be an interesting topic. I’ve seen the claim that it would certainly work, but it seems it’s not quite so simple as was first thought.
Good explanation. The paragraph about folding and “springs” is particularly vivid; I often read about how proteins are folded, how the surface outwardly presented controls the chemical interactions, etc, but I think the idea of a slowly-opening spring makes the mechanics clearer.
I’m interested in viruses that cause, or contribute to, cancers, such as hpv or hep C. It seems that mRNA technology should be usable to prevent those viral infections, too, though I don’t fully understand the practical problems in applying it for precancerous viruses.