Jeff Coller on mRNA, Vaccines, and Bespoke Therapeutics | Mindscape 357

mRNA vaccines, like those for COVID-19, are designed in hours and manufactured at scale in weeks. This speed is due to their synthetic nature, bypassing the lengthy processes of growing proteins in biological systems (e.g., chicken eggs) required for traditional vaccines. This rapid response capability was crucial during the pandemic and stems from decades of prior research.

The Chinese researchers released the SARS-CoV-2 genome in early January 2020. The very next day, a Moderna graduate student designed the COVID vaccine sequence in hours, leveraging existing influenza vaccine infrastructure. Traditional vaccines can take 10-15 years to develop.

A groundbreaking therapeutic approach combines mRNA technology with CRISPR-based gene editing to correct specific genetic mutations directly within the human body. mRNA delivers the transient instructions for the CRISPR 'surgical instrument,' which makes the precise genetic correction, then the mRNA is destroyed, preventing off-target effects.

This was demonstrated in baby KJ Maldun, born with a rare CPS1 enzyme deficiency in his liver. Researchers used mRNA-delivered CRISPR base editors to correct the mutation in his liver cells, allowing him to metabolize proteins normally and avoid a liver transplant. The mRNA's transient nature allows for potential redosing.

mRNA vaccines and therapies can be manufactured in significantly smaller and less expensive bioreactors compared to traditional protein-based vaccines. This dramatically reduces production costs and increases scalability, making it feasible to produce doses for the entire planet in a bioreactor the size of a 2-liter soda bottle.

Traditional protein vaccine bioreactors can fill half an aircraft hanger, requiring thousands of liters. mRNA bioreactors can be as small as a human body, or even a 2-liter soda bottle, to inoculate the entire planet.

mRNA technology is being used to create personalized cancer therapies. By identifying unique protein signatures (neoantigens) on a patient's cancer cells, an mRNA can be designed to instruct the body to produce these proteins, thereby training the immune system to recognize and attack the tumor.

A 2022 Nature paper from Slocketarine detailed a small clinical trial for pancreatic cancer patients using personalized mRNA neoantigen therapy. 50% of patients responded and were cancer-free six years later, a significant improvement over the typical 95% mortality rate within a year for this aggressive cancer.

Despite the immense potential, the main limitations for widespread mRNA therapeutic application are targeted delivery to specific organs beyond the liver and the current regulatory framework. Each organ presents unique delivery challenges (e.g., the blood-brain barrier, lung mucus), and the FDA's 'blockbuster drug' mentality struggles with the economics and approval processes for highly personalized, ultra-rare disease treatments.

Current lipid nanoparticle delivery is effective for immune cells and the liver, but targeting organs like the brain, pancreas, or lungs requires new mechanisms. The FDA's system is designed for drugs used by millions, not individualized therapies costing millions for a handful of patients, creating an economic and approval hurdle.