Posted 21 August 2024
Professor Jack Martin’s research began a discovery cascade that led to the identification of a revolutionary new protein and the development of a novel and effective drug therapy that is now used worldwide to treat osteoporosis, cancer and other diseases, according to a book by Professor David Findlay.
Bones are essential for the overall structure and function of the human body, impacting everything from movement and protection to blood cell production, endocrine regulation and mineral storage.
Bone is made by the combined action of cells called osteoblasts (bone forming cells) and osteoclasts (cells that remove bone). To understand anything about bone it is important to find out what makes these two cell types do what they do.
In the 1970s, not a lot was known about bone. Jack wanted to make a bone tumour in the laboratory that would respond to the newly discovered hormone, calcitonin. This was despite the fact that no-one had previously done this.
When former colleague, David Findlay, asked him what the rationale was for making these osteogenic sarcomas, Professor Martin, now SVI’s John Holt Fellow, described it as ‘an idiotic rationale’.
Today, researchers need a well-thought-out strategy to do experiments said Professor Findlay.
“There is no possibility of getting funding unless ideas are based on previous excellent research, and there needs to be a very compelling reason to perform the work. Even with that, there is only around a 1/10 chance of getting funding, certainly in Australia.
“Jack did successfully produce tumours whose cells had features of osteoblasts. He then saw that the response of these cells to molecules such as parathyroid hormone (PTH) and prostaglandins was spookily similar to the levels that caused calcium to be released from mouse bones in organ culture.
“This was hard to understand because the release of calcium from bone implied that the bone was being broken down, but osteoblasts were the cells responding, and they are the cells that make bone. The process of breaking down (or resorbing) bones is performed by osteoclasts,” said Findlay.
Why then would bone-forming cells respond to molecules like PTH and various prostaglandins to the same extent as the bone resorbing process? Jack wrestled with this puzzle long and hard and presented his observations at a meeting in London in 1979.
In the manuscript of his presentation at the meeting, and then in a paper published in the journal ‘Endocrinology’ in 1981, he made what turned out to be – according to Findlay – an amazingly prophetic proposal:
“that the osteoblast may be a primary site of action of PTH and prostaglandins, which may cause this cell to produce some other substance which would then act on the osteoclast to elicit bone resorption”.
In other words, Jack proposed that PTH and prostaglandins acted first on osteoblasts, and that osteoblasts responded by producing something that then caused osteoclasts to resorb bone.
Jack’s ‘idiotic rationale’ and his presentation at the 1979 London meeting began a chain of events, stimulating research which was to continue for two decades, and resulting in the eventual discovery of RANK Ligand (RANKL), an osteoblast product that is essential for osteoclast formation and activity. An antibody against RANKL is now the most used drug in the treatment of osteoporosis.
SVI Deputy Director Professor Natalie Sims said the way that Jack interpreted his findings is a great example of SVI’s motto ‘Inspired by discovery, driven by purpose.’
“By careful study of how the cells in the body work, scientists can develop entirely new ways of thinking, which can go on to provide cures,” Natalie said.
Jack’s work had a big impact on the treatment of osteoporosis and the inhibition of cancer-caused bone loss – changing the way people see bone, and saving thousands of lives.
To learn about daring scientists and their contributions, read
‘Good Science, Strong Bones, and the Case for Supporting Discovery’
by David M Findlay, Cambridge Scholars Publishing