On Mar. 10, 2022, Howard Hughes Medical Institute announced that after more than two decades of effort researchers revealed the structure of a crucial signaling molecule, opening the door to new and better drugs for some cancers. The paper which revealed the complete structure of the protein, known as Janus kinase, was published in the journal Science.

Janus kinases are one of the communication whizzes of the animal kingdom. They take signals that come from outside cells and pass the info along to molecules inside. Scientists have known for years that malfunctioning Janus kinases can cause disease. Some mutations that impair Janus kinases can severely curtail the body’s ability to fight off infection, causing a condition virtually identical to “bubble boy disease.” And when genetic glitches and exaggerated signals rev up the kinases too much, the result can be blood cancers like leukemia, and allergic or autoimmune diseases.

Researchers knew the shape of parts of the proteins, including related enzyme and regulatory regions at the end of the molecule, which earned them the name Janus kinases, after the two-faced mythological Roman god. And sophisticated drug screens have unearthed molecules that inhibit these proteins, giving doctors a way to treat some cancers and disorders like rheumatoid arthritis.

But scientists developed the drugs without knowing the molecules’ full structure or how they become activated. So most of the current arsenal of nearly a dozen drugs, plus more in clinical trials, are relatively blunt instruments, blocking both healthy and mutated Janus kinases. They can still treat many diseases, from eczema to COVID-19, but also can cause a range of side effects.

The structure also reveals how the cancer-causing mutation short-circuits this messaging chain – by gluing two parts of the Janus kinase together. That causes the two active regions to stay switched on even when there are no outside cytokines, sparking uncontrolled activity that can trigger cancers.