The story in six moments

Every entry in this Atlas traces back to a real paper. These six built the field, from a soil sample on a Pacific island to a large clinical trial that missed its primary endpoint. They are a curator's selection, not a consensus list.

How we got here

Every entry in this Atlas traces back to a real paper. Here are six moments that built the field – from a soil sample on a Pacific island to a large clinical trial that missed its primary endpoint. These six are a curator's selection, not a consensus list.

Moai at Rano Raraku, Rapa Nui — the island the soil sample came from — Moai at Rano Raraku, Rapa Nui. Photo Aurbina, Wikimedia Commons, public domain.

1975

A molecule from Rapa Nui

Vézina and colleagues isolate a compound from Streptomyces bacteria in a soil sample from Rapa Nui (Easter Island), with antifungal activity nobody can yet explain. They name it after the island: rapamycin. DOI: 10.7164/antibiotics.28.721 Where it sits in the timeline →

Rapamycin (green) held between FKBP12 and the FRB domain of mTOR, PDB 1FAP — FKBP12–rapamycin–FRB complex (PDB 1FAP). Image J. Swaminathan and MSD staff, EMBL-EBI, via Wikimedia Commons, public domain.

1994

The target gets a name

Sabatini and colleagues purify a rapamycin-binding protein from rat brain and propose it as the mammalian TOR homolog – they name it RAFT1. Brown and colleagues independently report the same protein as FRAP in Nature that same year. The name "mTOR" itself comes a year later, from Sabers and colleagues in 1995. Two decades of "what does this drug even do?" finally has a molecular answer. DOI: 10.1016/0092-8674(94)90570-3 Where it sits in the timeline →

Subunit composition of mTORC1 and mTORC2 — Subunits of mTORC1 and mTORC2. Diagram Lybbar12, Wikimedia Commons, CC BY-SA 3.0.

2002–2004

One protein, two complexes

Kim et al. and, independently and simultaneously, Hara et al. discover Raptor, the partner protein that defines mTOR Complex 1 – this Atlas's own RAPTOR-MTORC1 edge cites both. Loewith and colleagues define the TORC1/TORC2 split in yeast the same year. Two years later, Sarbassov et al. discover Rictor in mammalian cells – defining a second, rapamycin-resistant complex, mTORC2. mTOR turns out to have two faces at the molecular level too. DOI: 10.1016/s0092-8674(02)00808-5 Where it sits in the timeline → · DOI: 10.1016/j.cub.2004.06.054 Where it sits in the timeline →

A laboratory mouse — Laboratory mouse — illustrative, not an ITP animal. Photo Rama, Wikimedia Commons, CC BY-SA 2.0 FR.

2009

The first drug shown to extend mammalian lifespan

The NIA Interventions Testing Program, led by Harrison and colleagues, shows rapamycin extends lifespan in genetically heterogeneous mice – even when treatment starts late in life. First pharmacological intervention ever shown to do this in a mammal. DOI: 10.1038/nature08221 Where it sits in the timeline →

Influenza A/H1N1 virus particles, colourised transmission electron micrograph — Influenza A/H1N1 particles, colourised TEM. NIH Image Gallery, public domain.

2018

From mice to people

Mannick and colleagues show low-dose mTOR inhibition reduces respiratory tract infections and upregulates antiviral interferon-response genes in elderly volunteers – building on their 2014 finding that a similar regimen improved influenza-vaccine response. Together, the first hints the mouse result might translate to humans. DOI: 10.1126/scitranslmed.aaq1564 Where it sits in the timeline →

Bottles of Cebocap placebo capsules — Cebocap placebo capsules, NIH collection, via Wikimedia Commons, public domain.

2021

The reality check

The follow-up phase 3 trial – 1,024 participants – misses its primary endpoint. The drug still switched on the right antiviral genes; it just didn't reduce clinically symptomatic illness. This Atlas keeps that result next to the success that came before it, because a database that only remembers the wins isn't science. DOI: 10.1016/S2666-7568(21)00062-3 Where it sits in the timeline →

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