As the sun rose on December 13 1964, the HMCS Cape Scott dropped anchor in Cook Bay, Easter Island. Its crew were there to collate medical data from the 1000 inhabitants of this remote island and collect bacterial samples from the soil and the water, before an airport was built and the modern world ruined the island forever. However, what was inadvertently unearthed on this trip was one of the most fascinating longevity secrets of all time.
A trip to this idyllic Polynesian island renowned for its Maoi statues, and made famous with the Kon-Tiki raft expedition, lists as one of my bucket-list destinations. However, for the Canadian leaders Dr. Stanley Skoryna and Dr. Georges Nogrady, this was an important medical research trip that became a logistical nightmare and almost never happened at all.
Rapa Nui, as the island is colloquially called, is situated 3500km off its mother country Chile, dotted about one-third of the way between South America and New Zealand. In 1964, a year before the landing strip was due to be built, there was only one boat per month that visited the island, bringing supplies to the locals and taking wool back to Chile. The island was quite remote, and so just getting there was the first logistical headache.
Next, this was not a couple of doctors heading off on a vocational jolly, this was a team of 38 scientists being transported from Canada, through the Suez Canal and deep into the Pacific Ocean. They were travelling on a naval vessel accompanied by one hundred tons of accommodation, food and medical testing equipment. Once there, this entire medical village (complete with a laboratory, radio station, X-ray machines and a truck) had to be delivered onto the island, that had no harbour.
In addition, the expedition needed a stamp of approval from the Canadian government, permission from the Chilean government and the blessing of the World Health Organization (WHO), each of which presented significant challenges.
Lastly, and most importantly, they needed money. Funding that a scant twenty years after the Second World War, most people couldn’t give them, but funding that Skoryna managed to secure from the WHO, the Medical Research Council, the Canadian government and multiple private donors.
You may think that the surnames Skoryna and Nogrady do not sound particularly Canadian, and you would be absolutely correct. Skoryna grew up in Poland, and Nogrady in Hungary, and both had fled Europe for a more peaceful place to call home. Both had seen death and hardship and as a result, both were driven to succeed in their careers in their new-found country. Skoryna was an accomplished gastrointestinal surgeon and researcher who had done a huge amount of work on cancer, sending his research to Peyton Rous, the 1966 Nobel laureate whom we met at the start of this book. It was the determination of Stanley Skoryna that drove the process of raising money, getting the governmental approval, securing the navy ship and enthusing the 38 medical scientists to leave their day jobs and join him on this remote adventure.
However, it was Georges Nogrady who stumbled across the golden ticket on this expedition. Whilst other doctors were performing the honourable duties of blood pressure readings and mental health tests, Georges was somewhat ridiculed for his passion for collecting soil and water samples from the island.
In 1964, antibiotics were still a fairly new type of drug, and post-war there was a gold rush by the pharmaceutical companies to extract bacterial samples from distant lands and discover some of nature’s best-kept antimicrobial secrets. For example, during the Second World War, it was soil bacteria that had produced streptomycin, the first known drug to have specific activity against tuberculosis. Then in 1957, Eli Lilly had famously made a fortune by extracting the antibiotic, vancomycin from soil collected by a missionary in the jungles of Borneo.
So, the remote location of Easter Island was an exciting prospect for discovering unique bacteria, carrying novel chemicals that might fight off fungi or other bacteria. This inspired Nogrady to ignore the sniggers and divide the 24km by 12km island into a grid pattern. With that system, he collected mouth swabs from the 1000 local inhabitants, and soil and water samples from the top of the mountains and the depths of the caves.
The hard work really started when Nogrady returned to Montreal. There he grew and studied the bacterial samples from the mouth swabs, and sent the soil samples to multiple pharmaceutical companies, in the hope that they would discover a novel wonder drug and perhaps gain some recognition for his work.
However, it was all uphill work and it took another 5 years before Claude Vezina, a friend and scientist from Ayerst Pharmaceuticals, presented a paper on some of Nogrady’s soil samples. He described the exciting news that he had isolated over 30 microbes displaying anti-bacterial and anti-fungal activity, hinting at the possibility of future new drugs. One of them, Streptomyces hygroscopicus was a novel bacterium and from it, they would extract rapamycin which would eventually yield the pharmaceutical company billions. The name rapamycin would be a nod to Rapa Nui, its country of origin, but the work of Nogrady would never get a mention.
However, this was all to come, and not having the equipment to extract the chemicals from the bacteria, Vezina forwarded some soil samples to Surenda Sehgal, a friend and colleague at Ayerst. It was Sehgal who managed to isolate rapamycin, and by 1972 had produced the first paper on it, describing its anti-fungal properties. In 1978 Ayerst released a paper showing how they had identified rapamycin as being a brand-new macrolide type of antibiotic.
Nogrady seemed to be kept in the dark about all of this, while he continued to promote the Easter Island trip at multiple conferences, wrote a book on it and tirelessly enthused his friends from the trip with letters and newspaper cuttings about their trip. He seemed frustrated by the lack of progress on his soil samples, to the extent that his wife ‘feared that he would have a heart attack from the enormous stress of it all’.
Meanwhile, by 1982 rapamycin was shown to have immunosuppressive effects, that could be useful for autoimmune diseases like rheumatoid arthritis, organ transplantation and was also found to have wonderful new abilities in preventing cancer growth. However, in the early 1980s, the most severe recession since the Second World War had hit, and Ayerst laboratories closed down any research that had not proven itself. Vezina was laid off and all work on rapamycin was halted. If it wasn’t for the vision of Sehgal, who illegally smuggled vials of the streptomyces bacteria to store in his fridge at home, rapamycin would have been lost to the world forever.
Finally, in 1987, 23 years after Nogrady had collected his soil samples, a large, successful pharmaceutical company called Wyeth bought out Ayerst, and Sehgal was able to bring his vials back to the laboratory and continue his study of the amazing rapamycin. Over the next ten years, this compound generated an impressive 1500 papers.
Sadly, in 2003, Sehgal died from colon cancer. However, during the previous five years, he had been treating himself with rapamycin and buying himself a little more time to continue his work. Having spent most of his career working on Rapamycin, Sehgal was convinced of its importance. Once he knew that he had terminal cancer, he knew that someone else would need to carry on the work of exploring this amazing molecule. Because of this, he sent samples of Rapamycin to multiple laboratories, accompanied by a small booklet explaining its history, with the hope that someone else might take the fight further.
One such sample made its way to the Johns Hopkins University where a young undergraduate called David Sabatini was looking for a topic to study for his PhD. He was intrigued by what he read about rapamycin and set out to discover how it attached to the cell. Miraculously, this young student discovered a novel receptor that rapamycin attached to. Not knowing what else to call it, the laboratory decided on the laboriously descriptive name ‘mechanistic Target Of Rapamycin’, or as it has more affectionately been termed, mTOR.
The rest as they say is history and mTOR has proven to be the receptor that oversees autophagy, or cell-cleaning, which is arguably the world’s most important health and longevity pathway. As a result, rapamycin has been shown to extend life in yeast, flies, worms and rats, and is proving to be probably our most useful longevity drug, but that is a story for another day.
If it were not for Dr. Stanley Skorenya’s dedication to making the trip to Easter Island happen, Dr. George’s Nogrady’s attention to detail in finding samples on the island and his lifelong dedication to promoting those samples, Sehgal’s work in identifying rapamycin and then storing bacterial samples in his home fridge for several years, and lastly Dr. David Sabatini’s picking up a leaflet on his desk and becoming intrigued about this new molecule that they had been sampled, we would probably not have the drug rapamycin today, and we may not have the understanding that we do have of the mTOR pathway.
The amount of labour, stubbornness, bravery and good luck that was needed by so many people for the secrets of Rapamycin to be revealed, is quite remarkable.
References
- Griffith RS. Introduction to Vancomycin. Clin Trial. 1981: 3: S200-4.
- Swindells DCN et al. The x-ray crystal structure of rapamycin C51 H79 NO13. 1978. https://cdnsciencepub.com/doi/pdf/10.1139/v78-407
- Jacalyn Duffin. Stanley’s Dream. McGill Queen’s University Press. 2019. 341-342.
- Blagosklonny MRapamycin for longevity: opinion article. Aging. 2019: 11: 8048-67.
