The Millennium Problems for Biology
4 hours ago
- Demonstrate unassisted emergence of self-replicating RNA/protein cells from primordial soup, with a 10-fold abundance increase, indefinite division, and heritable genetic information encoded in polymers.
- Achieve reversible whole-body cryopreservation of adult wild-type mice, with >99% viability after 24 hours frozen, no permanent damage, and ethics approval.
- Create an enzyme that reverse translates arbitrary peptides into RNA/DNA without a template, achieving ≥90% accuracy over ≥25 residue reads on ≥100 random 50+ amino acid sequences.
- Produce a Rubisco enzyme with specificity (Sc/o) ≥ G. Partita and turnover (kcat) ≥ maize Rubisco, validated via paired assays.
- Engineer a living cell using a quadruplet codon code for all proteins, with non-synonymous mutation probability independent of codon position and no triplet decoding.
- Regrow amputated limbs in adult wild-type mice with full motor and sensory recovery, indistinguishable from controls by blinded observers, with ethics approval.
- Produce infectious replication-incompetent AAV and lentivirus in bacteria, with similar capsid-to-genome and infectious unit ratios as mammalian cell culture.
- Design site-specific proteases that cleave blinded sites in endogenous folded proteins with high efficiency and low off-target effects, achieving >80% success on 20 preregistered sites within 24 hours.
- Design zero-shot protein binders (preferably antibody-like) that enter cells and target intracellular proteins, with 80% success on 20 preregistered targets, without transfection or evolution.
- Achieve exponential amplification of arbitrary peptide substrates (100 preregistered, 50+ residues) with ≥1000x enrichment and ≥90% per-residue accuracy, without nucleic acid intermediates.
- Develop a complete set of 3′→5′ polymerases (DNA, RNA, reverse transcriptase, RDRP) with processivity and error rates comparable to standard 5′→3′ enzymes.
- Create a nitrogenase that converts N₂ to ammonia at similar rates to natural ones but with no sequence or structural homology to known nitrogenases.