The four-axis ranking
We rank humanity’s most important problems on four quantifiable dimensions — quantity of humans affected, severity per capita, current solution quality, and addressable market size — and package each as a proposal in the spirit of Musk’s Hyperloop Alpha. This document is the proposal for infectious disease (malaria, tb, hiv). Every number below is sourced and tagged with confidence. Every ranking is a conjecture, open to refutation.
Quantity · humans affected
2.5B
highSeverity · WTP / wealth
60%
medCurrent solutions
4.0 / 10
medMarket size · TAM
$200.0B
medWhat we are trying to solve
Malaria killed ~600,000 people in 2023, mostly children under 5. Tuberculosis kills ~1.3M per year. HIV kills ~630,000 per year despite proven suppression protocols. The Copenhagen Consensus ranks these interventions among the highest benefit-cost ratios in global development, $1 of intervention returns $20-$100 in economic and welfare gains. This is the baseline anyone claiming to rank humanity's problems has to include.
The gap between the world and the world that is physically possible
Today: ~1.3M deaths/yr from TB. ~600K from malaria. ~600K from HIV/AIDS. All preventable with known interventions but coverage gaps + drug resistance growing.
Current solution quality is rated 4.0 / 10 (med confidence) — meaning there is substantial unclaimed ground between what exists and what is possible. estimated — proven interventions (bednets, ARVs, DOTS) effective where deployed; coverage incomplete and resistance rising.
Who is already working on this
5 entities are currently working on this problem across public markets, private companies, and research orgs. Each is evidence the market is real; none has obviously solved it.
Gilead Sciences
public · USAHIV franchise leader (Biktarvy, Descovy, lenacapavir as twice-yearly PrEP). Also hep B/C, oncology.
$95.0B
GSK
public · UKGlobal pharma. Manufacturer of RTS, S and R21 malaria vaccines; major HIV and TB portfolios.
$72.0B
Moderna
public · USAmRNA platform company. Pandemic preparedness via rapid vaccine development, plus pipeline in malaria, HIV, and rare disease.
$10.5B
If we solve this, here is the world we get
After · 15 years
Malaria, TB, HIV mortality reduced 95%+ via single-dose curatives, gene-drive vector control, universal vaccines. Three of humanity’s oldest scourges effectively closed out.
Requests for startups · 3 concrete companies to build
Single-encounter curatives for TB
Tuberculosis kills 1.3M people a year and the cure requires 4–6 months of daily adherence most patients cannot sustain. Build the long-acting or single-dose regimen plus the delivery model.
- why now
- Long-acting injectable formulation science matured (proven in HIV PrEP); the same toolkit is unapplied to TB at scale.
- shape
- A drug-delivery company pairing a long-acting regimen with a field delivery and adherence model designed for high-burden, low-resource settings.
- success
- TB treatment becomes a single supervised encounter, and TB mortality falls like HIV mortality did after ART.
Safe, reversible gene-drive vector control
Bednets and spraying have plateaued; the mosquito is the delivery system for malaria. Build the safe, reversible, field-deployable gene-drive company for malaria vectors.
- why now
- Gene-drive and self-limiting designs reached field-trial readiness; the gating problems are now governance and reversibility, which are buildable.
- shape
- A vector-control company developing confinable/reversible drives plus the field-trial, regulatory, and community-consent apparatus to deploy them responsibly.
- success
- Malaria transmission collapses in deployment regions without ecological regret.
Point-of-care diagnostics under a dollar
You cannot treat what you cannot diagnose, and PCR needs a lab, cold chain, and a day. Build the paper or CRISPR diagnostic that returns an accurate result anywhere for pennies.
- why now
- CRISPR-based detection (SHERLOCK/DETECTR-class) moved from papers to manufacturable formats.
- shape
- A diagnostics company productizing instrument-free, ambient-stable tests for the high-burden infections, distributed through existing community-health rails.
- success
- Accurate infectious-disease diagnosis is available at the point of need anywhere on Earth for under a dollar.
full rubric + framing on the Requests for Startups page.
What the market can pay
The world is already paying $200.0B per year against this problem (global infectious-disease therapeutics + vaccines + diagnostics + delivery (WHO + IFPMA estimates); med confidence).
A successful solution does not need to capture more — it needs to redirect a meaningful slice of existing spend, plus the latent willingness-to-pay implied by the severity score above. The cost ceiling for a real solution is bounded by this number; everything cheaper is dominated, everything more expensive is a non-starter.
What could go wrong, and how we know we are not wrong
Section in progress
Failure modes, ethical considerations, and the conditions under which this whitepaper would be falsified are being authored as the weekly cadence ships. The Deutschian commitment: every claim above is a conjecture; we publish the conditions under which we would update. New whitepaper sections ship with each Monday newsletter drop. Subscribe to get the upgrade, or contribute on GitHub.
Who would back this
Capital allocators with a stated thesis or deployed portfolio in this domain. This is a starting list — Exa Websets enrichment will expand it to direct check-writers per company.
Deep Science Ventures
Outcome-first venture creation. Define the holy-grail outcome, then recruit founders.
Fifty Years
Every portfolio company must solve a UN SDG. Profit with purpose, no exceptions.
Rise Fund (TPG)
Growth-stage impact investing with rigorous Impact Multiple of Money scoring.
Where this is wrong, tell us
Every number on this page carries a source and a confidence tag. Every section open to refutation. If a citation is wrong, a number is stale, or a conjecture is unfounded — file a correction.
corrections → use the feedback widget in the nav · open issue at github.com/adamtpang/optimism.fun