How kisspeptin was discovered

Few hormones have a back story as roundabout as kisspeptin. It was found by cancer biologists who were not looking for a hormone at all, its receptor was identified by drug companies screening orphan receptors, and its true role came to light through families whose children never went through puberty.

1996: a metastasis suppressor in Hershey

At Penn State College of Medicine in Hershey, Pennsylvania, Danny Welch and his colleagues were studying why some melanoma cells spread and others do not. Transferring a copy of human chromosome 6 into aggressive melanoma cell lines cut their ability to metastasise by at least 95% without stopping them from forming tumours. By comparing the active genes of the two cell types, the team isolated a new sequence and called it KiSS-1. In their samples its messenger RNA was present only in melanoma cells that did not metastasise.

2001: an orphan receptor finds its ligand

For several years nobody knew what protein KiSS-1 produced or how it acted. In 2001 three research groups, working independently, answered the question at almost the same time:

• Takeda, Japan (Nature): purified a 54-residue amidated peptide from human placenta that activated the orphan receptor hOT7T175 and named it metastin; in mice it reduced lung metastasis of receptor-bearing melanoma cells.
• Brussels (J Biol Chem): isolated peptides of 54, 14 and 13 residues with a shared RF-amide end, showed that they bind GPR54, and coined the name kisspeptins.
• GlaxoSmithKline, UK (J Biol Chem): cloned the human receptor as AXOR12 and found that KiSS-1-derived peptides were its most potent activators.

2003: the link to puberty

The decisive turn came from clinical genetics. Two teams, one in France and one in Boston working with colleagues in Cambridge, studied families in which several members had isolated hypogonadotropic hypogonadism, a condition in which puberty does not start because the brain does not drive the pituitary. Both traced the condition to inactivating mutations in GPR54. The Boston and Cambridge group also produced mice lacking the receptor, and these animals did not mature sexually either.

Following the signal inwards

Over the next few years animal studies showed where kisspeptin acts. In 2005 researchers found receptor transcripts on GnRH neurons in mice and measured a surge of GnRH in the spinal fluid of sheep after kisspeptin was given into the brain. In juvenile monkeys, injections of kisspeptin-10 set off GnRH release long before the age of puberty, and KiSS-1 activity in the hypothalamus rose as the animals matured.

Confirmation from both sides

In 2008 a gain-of-function variant of the receptor was reported in a girl with early (central precocious) puberty, the mirror image of the 2003 findings. In 2012 the circle closed with an inactivating mutation in the KISS1 gene itself, found in a large family whose affected members did not progress through puberty.

Timeline

• 1996: KiSS-1 is described as a melanoma metastasis-suppressor gene in Hershey, Pennsylvania.
• 1999: researchers in Toronto clone GPR54 from rat brain, an orphan receptor resembling the galanin receptors.
• 2001: three groups identify KiSS-1 peptides as the natural ligands of GPR54; the terms metastin and kisspeptin appear.
• 2003: loss-of-function GPR54 mutations are linked to absent puberty in humans and mice.
• 2005: kisspeptin is shown to trigger GnRH release directly, and kisspeptin-10 advances GnRH activity in juvenile monkeys.
• 2011: the first published studies give kisspeptin-10 to healthy volunteers.
• 2012: an inactivating mutation in KISS1 itself is reported.
• 2023: the US FDA places kisspeptin-10 in its category of bulk substances that may present significant safety risks in compounding.
• 2024: receptor structures bound to kisspeptin-10 are published, and kisspeptin and its agonist analogues are added to the WADA Prohibited List.