The Millennium Problems for Biology

This presents twelve concrete biological grand challenges framed as experimentally testable millennium problems with strict, quantitative success criteria. Each challenge specifies what must be built or demonstrated, including preregistration, controls, replication thresholds, and ethical oversight, and rules out shortcut strategies (database lookup, indirect templates) so accomplishments are unambiguous. The problems prioritize methods that are scalable, compatible with standard molecular tools, and measurable against explicit benchmarks such as fold-increase, percent viability, sequence accuracy, and catalytic rates.

The list includes precise targets: origins of life - generate self-replicating RNA- and protein-based compartments that expand by ≥10^6 and encode heritable polymers; whole-body cryopreservation - freeze and revive adult wild-type mice with >99% viability and no permanent organ damage; a reverse-translatase - a protein catalyst that converts arbitrary peptides into nucleic acids for 100 preregistered 50-residue sequences with ≥90% accuracy; Rubisco improvement - an enzyme exceeding natural specificity and kcat against specified controls; a living cell using only quadruplet codons; adult mouse limb regeneration with indistinguishable function; bacterial production of AAV/lentivirus matching capsid/genome and infectivity ratios; programmable zero-shot proteases and cell-penetrating binders with defined success rates; protein-only exponential peptide amplification; novel 3′→5′ polymerases; and de novo nitrogenases with comparable activity but no homology to known families.