Sometimes a seemingly minor discovery in science can snowball into something huge. So it was with Professor Michael Hall’s investigations into a compound called rapamycin, originally discovered in a handful of soil from Easter Island in the southern Pacific.
In 2024, he was awarded the Balzan Prize for “groundbreaking contributions” to our understanding of the molecular mechanisms that regulate cell growth and ageing. Based in Italy, the Balzan Prize is an annual international award set up to recognise outstanding achievements in various fields, including science.
Hall is an American-Swiss scientist based at the Biozentrum, the Center for Molecular Life Sciences at the University of Basel, Switzerland. What he has unearthed over the past 30 years has transformed our knowledge of the cellular processes linked to ageing and age-related diseases such as cancer, diabetes and cardiovascular diseases.
Part of this research was supported by EU funding. The global recognition of Hall’s work and its resounding impact in medical fields today has a long and interesting back story.
Antifungal agent
Rapamycin was first discovered in soil samples from Easter Island – locally known as Rapa Nui – isolated from a bacterium called Streptomyces hygroscopicus.
Initially developed as an antifungal agent, it was named rapamycin in reference to its origins. However, it was found to be able to suppress the body’s immune response, which led to it being redirected for use in treating certain forms of cancer and for preventing organ transplant rejection.
“
This research got the attention of essentially every pharma company in the world.
When Hall first began his studies on rapamycin in the 1980s, he was simply curious to know how the compound worked. A researcher in his lab – a medical doctor named Joe Heitman – took the bold step of giving rapamycin to yeast cells to see what happened.
The bacterial compound brought back from the South Pacific was found to interfere with an enzyme dubbed “target of rapamycin” or TOR (referred to as mTOR in mammals).
Cell growth
Experiments in Basel in the early 1990s initially suggested that the enzyme controlled cell division – the process by which a parent cell divides into two or more cells, ensuring the reproduction, growth and repair of tissues.
However, further research revealed that mTOR actually orchestrates cell growth – the increase in cell size or mass.
“This was surprising because in those days, nobody thought cell growth was controlled, actively controlled. It was considered just a spontaneous process that happened when nutrients became available,” said Hall.
The researchers then found that the TOR protein combines with other proteins to form a complex structure which acts like a “molecular machine” inside cells. This machine regulates important processes such as cell growth and metabolism.
What is remarkable is that this machine is found not only in humans, but also in a wide range of other multicellular organisms, including insects, plants and yeast. This widespread presence suggests that it plays a vital and fundamental role in the biology of all complex life forms.
Life extending
Another key development was the discovery of a link between TOR and nutrient intake.
“We showed that TOR controls growth and metabolism in response to nutrients,” said Hall.
In fact, TOR acts like a “nutrient sensor”. When TOR is active, cells focus on growth rather than maintenance in response to food.
With dietary restriction – when calorie intake is reduced without causing malnutrition – TOR activity decreases and cells shift to “maintenance mode” instead of growth mode. This allows the cells to focus on repair processes, cleaning up damaged components and conserving resources.
Ageing is often associated with the buildup of cellular damage over time. Reduced TOR activity due to dietary restriction enhances cell repair mechanisms and reduces stress on the cell from excessive growth demands. This slows down processes that contribute to ageing, such as inflammation.
Hall’s studies showed that rapamycin can mimic the effects of dietary restriction by restricting TOR activity. This led others to show that rapamycin extends the lifespan of animals like mice and flies.
“When you inhibit TOR with rapamycin, you mimic the effect of restricting calories,” said Hall.
This slows the ageing process and delays the onset of age-related diseases such as cancer and neurodegenerative disorders.
“Now we know that rapamycin is the most robust and reproducible intervention that extends lifespan in eukaryotes,” said Hall. All animals, plants, fungi and many single-celled organisms are eukaryotes.
Slowing cancer growth
This connection is a key focus of ageing research today. It is also an important avenue of research for the treatment of cancer.
Given that the TOR complex evolved to direct cell growth, it is perhaps not surprising that TOR activity is implicated in the abnormal growth seen in cancer.
“
It was a tremendous breath of fresh air for European science when the European Research Council came into existence.
“It has been calculated that the TOR complexes are upregulated and contribute to tumorigenicity in, let’s say, 70% of all cancers,” said Hall.
The research funded by the EU focused on how restricting TOR activity through the use of rapamycin could help slow the growth of cancer cells and make them more susceptible to treatments like chemotherapy and radiation.
“This research got the attention of essentially every pharma company in the world,” said Hall.
While TOR inhibition shows promise, however, it can also affect normal cell functions and lead to side effects such as immunosuppression and metabolic issues. Research is ongoing to refine these therapies and target TOR more selectively in cancer cells.
Curiosity-driven research
From a seemingly simple probe into how this antifungal agent works, Hall discovered a master controller of cell growth, a potential way to slow down the ageing process and a promising avenue for cancer treatment.
“This is a wonderful example of the value of curiosity-driven research,” said Hall.
According to Hall, this is what EU funding allowed him to do – ask questions and then more questions, following a path of discovery that was completely hidden at the starting point.
“It was a tremendous breath of fresh air for European science when the European Research Council came into existence,” he said.
The European Research Council (ERC) was set up by the EU in 2007 to support excellent frontier research across all fields of science, engineering and the humanities. ERC grantees have been awarded several important prizes in the field of science, including nine of the more than 30 Nobel Prizes won by EU-funded researchers, four Fields Medals, 11 Wolf Prizes and more.
This is also not the first time that Hall has garnered awards for his work.
“I’ve been fortunate to win many prizes. It never gets old, it’s a wonderful feeling,” he said. “It’s like being paid a huge compliment. Everyone loves a compliment, and it’s also a wonderful validation of one’s life work as a scientist.”
Research in this article was funded by the European Research Council (ERC). The views of the interviewees don’t necessarily reflect those of the European Commission. If you liked this article, please consider sharing it on social media.
