Dr. Lorents Gran

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The Observation in Congo

In the late 1960s, Dr. Lorents Gran was posted as a physician with the Norwegian Red Cross to what was then the Democratic Republic of the Congo. During his time there, he made a careful clinical observation: local women routinely drank a tea brewed from the leaves of a plant called Oldenlandia affinis — known locally as "kalata-kalata" — during labour. The tea appeared to dramatically accelerate and strengthen uterine contractions. Local midwives had relied upon it for generations.

Gran was both intrigued and scientifically troubled. The tea was prepared by boiling the leaves — yet its biological activity survived intact. Any protein he knew of would be denatured and inactivated by prolonged boiling. Whatever was in this tea was not behaving like a normal protein. The active compound was surviving conditions that should have destroyed it.

He collected plant material, returned to Norway, and began a painstaking biochemical investigation that would eventually yield one of the most consequential discoveries in peptide science — though it would take decades for the wider scientific world to recognise what he had found.

The Isolation of Kalata B1 (1973)

Gran spent years working to isolate and characterise the active component of the kalata-kalata extract. In 1973 he published two landmark papers identifying what he named kalata B1 — named directly after the local plant. He demonstrated it was a polypeptide of approximately 30 amino acids with potent uterotonic activity, capable of stimulating uterine contractions with a potency comparable to oxytocin.

The isolation itself was a significant technical achievement for the era. Gran used a series of precipitation, chromatographic, and biological assay steps to narrow down the active fraction — work that would have taken months with 1970s laboratory equipment. He was rigorous in documenting the molecule's unusual properties: it was heat-stable, acid-stable, and resisted protease digestion.

"The compound was heat-stable, acid-stable, and protease-resistant — properties entirely inconsistent with a normal polypeptide. We could not explain it."

But Gran could not explain why kalata B1 survived boiling, acid, or the digestive system. The analytical chemistry tools of 1973 — principally amino acid composition analysis and partial sequencing — could not reveal what we know today: that the peptide backbone was closed into a ring, and that ring was locked in place by three interlocking disulfide bonds creating a topological knot. The cyclic structure went undiscovered. Gran's papers were noted, filed, and largely forgotten by the scientific mainstream.

The 20-Year Gap

For over two decades, kalata B1 existed in the scientific literature as an anomaly. A small peptide with inexplicable stability. Potent biological activity at low concentrations. A structure that resisted every attempt at unfolding. Occasional papers referenced Gran's work, but no major research group took up the challenge of resolving the structural mystery.

The tools needed to solve it were being developed elsewhere. NMR spectroscopy was advancing rapidly throughout the 1980s, driven by applications in organic chemistry and structural biology. By the early 1990s, NMR had reached the point where small protein structures could be determined in solution at full three-dimensional resolution — exactly the capability needed to reveal kalata B1's secret.

Vindication: The 1995 NMR Structure

In 1995, a research team including members of what would become Prof. David Craik's group at the University of Queensland determined the three-dimensional structure of kalata B1 using NMR spectroscopy. The result was extraordinary: the peptide backbone was head-to-tail cyclic, with the N- and C-termini joined by a covalent peptide bond, creating an unbroken ring. Within that ring, three disulfide bonds connected six cysteine residues in an interlocking arrangement — a topological knot embedded within a cyclic molecule.

This was the Cyclic Cystine Knot (CCK) motif. In one structural revelation, the 22-year mystery of kalata B1's stability was solved. The molecule was indestructible not because of exotic chemistry, but because of topology: no enzyme could unfold it because unfolding would require breaking covalent bonds. Gran had been right all along — the compound simply could not be denatured by any means available to a biological system. His inexplicable observations in Norway were vindicated completely.

Legacy

Gran's contribution stands as the origin point of an entire field. Every cyclotide research programme — from Craik's drug-grafting platform at UQ, to Gruber's T20K clinical trial for multiple sclerosis, to the agricultural biopesticide Sero-X — traces its lineage directly to the kalata-kalata tea that Gran observed in the 1960s and the molecule he patiently isolated and named in 1973.

The fact that his work went unrecognised for two decades is a reminder of how scientific discovery actually works: not as a single eureka moment, but as an incremental process in which an observation waits for the technology needed to understand it. Gran provided the observation. It took the NMR revolution to reveal why it mattered.

Key Publications