Jeff Coller on mRNA, RNA Therapeutics, and the Future of Bespoke Medicine

RNA biologist Jeff Coller walks Sean Carroll from the central dogma of molecular biology through the COVID mRNA vaccines to the frontier now opening up: mRNA joined to gene editing to correct a person’s DNA inside their own body, one patient at a time.

Key ideas

1. mRNA is a disposable recipe card. DNA is the cell’s cookbook; a messenger RNA is a single recipe copied out and carried to the ribosome, which cooks the protein and then destroys the message so the same dish is not made endlessly. Because mRNA is a natural product the body clears within hours, and because we can design and manufacture it in a test tube rather than growing proteins in millions of chicken eggs, it can be produced far faster and more cheaply than a conventional protein vaccine.

2. The COVID vaccines were fast because the platform already existed. mRNA had been in human trials for over twenty years before 2020, mostly against cancer. When the SARS-CoV-2 genome was published in January 2020, Coller’s former graduate student — lead vaccine designer at Moderna — downloaded it and designed the vaccine within hours by dropping the virus’s spike-protein sequence into an mRNA. No eggs, no decade-long lead time.

3. The bottleneck is delivery, not design. Naked RNA is destroyed and not taken up, so mRNA is wrapped in a lipid nanoparticle — a fat bubble that fuses with the cell. Today this reliably reaches only immune cells at the injection site and the liver; the brain (behind the blood–brain barrier), lung (behind mucus), pancreas, heart, and kidney remain hard targets. Sequencing and editing are largely solved; getting the payload to the right tissue is the open problem.

4. mRNA plus CRISPR enables in-body gene correction. CRISPR is a GPS that finds one spot in three billion base pairs; a base editor fused to it rewrites the letter there. Delivered as a transient mRNA rather than as a permanent protein, the editor makes its correction and then vanishes — so it cannot wander the genome causing collateral damage. Baby KJ Muldoon, born with a one-in-a-million liver enzyme deficiency (CPS1), was treated this way in 2025 and is now thriving without the liver transplant that was his only prior option.

5. Personalised medicine breaks the blockbuster economic model. One in thirteen people carries some genetic disease; there are over 7,000 of them, each individually rare. A bespoke therapy still costs on the order of 8–10 million dollars to develop but serves a handful of patients, so the FDA framework — built for drugs sold to millions — does not fit. The same personalisation drives mRNA cancer vaccines: a pancreatic-cancer neoantigen trial saw half its patients still alive and cancer-free six years on, against a 95% one-year mortality baseline.

Summary

What mRNA is, and the central dogma

Coller sets the cast of characters. DNA is the blueprint held in the cell’s nucleus — ‘a giant recipe book that tells your body how to be you’, with roughly 25,000 genes. A messenger RNA is a single recipe copied out and carried to the ribosome, the cook that reads it and builds the protein. RNA differs from DNA by one oxygen atom and one letter (uracil for thymine), a small chemical change with large consequences: RNA is less stable but more versatile, able both to catalyse reactions and to fold into complex shapes, which is why most biologists now think RNA preceded DNA in the origin of life. The genetic code maps four letters, read three at a time (64 possible ‘words’), onto 20 amino acids — a redundant, ‘frozen accident’ in Crick’s phrase. Crucially, once read, an mRNA is actively destroyed; how fast it is read, set by the supply of the matching transfer RNAs, governs how long it survives.

How mRNA vaccines work, and why they were fast

A vaccine trains the immune system against a foreign protein. A conventional vaccine injects that protein directly, grown at great cost and slowness in bioreactors or eggs. An mRNA vaccine instead injects the instructions and lets the body build the foreign protein itself — here the coronavirus spike (S) protein, absent from humans and so recognised as an invader. Three properties make this powerful: the mRNA is a natural product, the body clears it within hours, and it can be designed in silico in hours and manufactured in weeks. Coller stresses the platform was not new in 2020 — over twenty years of in-human testing preceded it — which is precisely why Moderna could swap the influenza sequence it was already trialling for the published SARS-CoV-2 sequence and move within days. The manufacturing footprint collapses too: where a protein vaccine needs vats filling an aircraft hangar, some newer mRNA bioreactors ‘no bigger than like a 2 L of soda’ could hold enough to inoculate the planet.

RNA therapeutics beyond vaccines

Because mRNA is a general-purpose way to make the cell produce any protein, its uses run far past vaccines. Autoimmune disease and allergy — the immune system attacking self or over-reacting to pollen — might be treated by using mRNA to down-regulate immune responses. Cancer is the largest arena: a tumour rearranges its genome and makes unique proteins, and mRNA can present those neoantigen signatures to train the immune system to attack the tumour. Coller cites a 2022 Nature paper on personalised pancreatic-cancer vaccines — pairing an mRNA approach with the immunotherapy insight for which James Allison won a Nobel Prize — where half the treated patients remained cancer-free six years later, against a disease that kills 95% within a year.

Bespoke and personalised medicine — the n-of-1 case

The most striking frontier joins mRNA to gene editing. CRISPR, borrowed from a bacterial immune system, locates one precise region of the genome; a base editor developed in David Liu’s lab makes the correction. Delivering the editor as a transient mRNA — rather than a persistent protein — means it does its surgical work and then disappears, minimising off-target edits. The proof of concept is baby KJ Muldoon, born in 2024 with a one-in-1.3-million deficiency of the liver enzyme CPS1, which lets toxic ammonia build up. With unprecedented speed the FDA cleared a bespoke treatment; dosed three times into the liver (the one organ we can reliably reach), his DNA was corrected and he now walks and talks without needing a transplant. He is not cured — he can be re-dosed as his liver grows — but the template is set: sequence the mutation (now a few hundred dollars, down from the billion-dollar Human Genome Project), design the correction, deliver it. Coller notes even a 10–15% correction can meaningfully change a life.

Delivery, dual-use risk, and the regulatory bottleneck

The gating problem is delivery: every organ has its own barrier — the blood–brain barrier, the lung’s protective mucus — and Coller expects a 20-year toolbox of tissue-specific delivery to become the standard of care for genetic medicine. He is candid about dual use. AI trained on viral sequences has already designed novel bacteria-killing viruses that outperform natural ones; a bad actor could in principle design a human pathogen the same way, and mRNA vaccines are the only countermeasure fast enough to serve as ‘deterrence by denial’ — a reason, he argues, to protect rather than demonise the technology (China now develops roughly 46% of mRNA vaccines). Finally, the economics: an FDA built for blockbuster drugs sold to millions cannot accommodate an 8-million-dollar therapy made for a single child, and the framework must change to meet the moment.

Speakers

• Jeff Coller — RNA biologist; Bloomberg Distinguished Professor of RNA Biology and Therapeutics, Johns Hopkins University. Studies how the speed of mRNA translation governs message stability, and the therapeutic uses of RNA.
• Sean Carroll — host; theoretical physicist and author, Mindscape.

See also

• Sean Carroll — host