The incredible origins of the immunosuppressant and anti-aging drug rapamycin

The process of discovering a new drug is a complex undertaking that involves the identification of candidates, synthesis, characterizations, validation, optimization, screening, and more. Scientists usually take at least 10 years and spend an average of $2.6 billion for each successful drug that hits the market. Out of the thousands of drugs that have been discovered over the last 50 years, rapamycin (arguably) has the most fascinating discovery story. About 1000 AD, the spiritual leader at an island in the Pacific had a vision in his sleep. He envisioned himself flying like a bird over the ocean and witnessing a beautiful island with cliffs and volcanic craters. Shortly thereafter, about 100 inhabitants representing all facets of society set out on two wooden boats and weathered waves and storms to find the new island. The immigrants created a flourishing settlement in Rapa Nui (now known as the Easter Island). However, it wasn’t long before the entire society collapsed. Hundreds of years later in 1964, the Canadian government sent a medical expedition to document and study the isolated community about 2000 miles off the coast of South America. Among other activities, the team took dozens of samples from soil on the island. These would then be sent to scientists all over Canada. Dr. Surendra Nath Sehgal, fondly referred to as Dr. Suren by family and colleagues, had immigrated from Delhi to Canada after completing his Ph.D. He would then secure a drug research job for a pharmaceutical company known as Ayerst, McKenna & Harrison. Dr. Suren was among the many scientists in Canada who received a sample of the dirt retrieved from Easter Island by the government-flagged expedition. Suren and his team immediately got to work, isolating from the dirt a compound that was never seen before and that had a very interesting molecular structure. It was a clear, white, and crystalline-type of powder-looking thing. At his employer’s lab in Montreal, Dr. Suren put the compound in different petri dishes and exposed certain fungi and bacteria to it in an attempt to find out more about it. An interesting discovery was made; any fungi that came into contact with this white substance just froze and stopped growing. Inspired by the idea that he may have landed on a potentially new anti-fungal drug, Dr. Suren conducted further experiments with mice, dogs, and even a friend’s wife who had a fungal infection on the arm. The results were consistent. The motivated researcher gave the compound the name ‘rapamycin’, filed a patent for the drug, and published his first paper in 1975. But it wasn’t long before there was a problem. Rapamycin seemed to have very strong immunosuppressant properties. That means it stopped the growth of immune cells just like it did with fungi — which was bad because immune cells need to grow quickly when there’s an infection. Disappointed by this unexpected development, Dr. Suren’s employer decided to shut down the Montreal lab and relocate to New Jersey. Add samples were ordered destroyed but Dr. Suren could not bring himself to throw out Rapamycin. He felt like he was just getting started with this wonder compound. Five years later, Dr. Suren was working in the US and had new bosses. In the world of medicine, organ transplantation was still sort of science fiction. It was confined to the tiny world of identical twins. One of the biggest hurdles facing this emerging area of medicine was the immune system. Patients sometimes died of rejection as doctors hadn’t perfected how to stop the immune system from attacking the new organs. Sometimes, the powerful drugs given to stop rejection left patients susceptible to infections. Reliving the earlier discovered immunosuppressant properties of rapamycin, Dr. Suren pitched the idea to his bosses. Luckily, the samples he had stashed away when the Montreal lab was closed were still as active as they had been 5 years ago. The researcher went back to work at his employer’s lab, while also sending samples to scientists all over the place. At around the same time in 1992, David Sabatini was studying to become a doctor and scientist at the same time – but couldn’t figure out what to do for his dissertation. He was walking around the lab one day when saw a notebook written ‘rapamycin bibliography’ along with vials and a note from Dr. Suren. He decided to figure out how the drug worked and made it his Ph. D project. Experimenting with hundreds of lab rats over a lengthy duration of time, Mr. Sabatini discovered that rapamycin worked by binding with a previously unknown protein. This was later named mTOR (mechanistic target of rapamycin). By the time he was done with the research, a couple of other labs were also revealing their findings. It was evident that mTOR was present in each cell within every multicellular species, not just mice. After nearly 10 years of research work, Dr. Sabatini had managed to figure out that mTOR was really a sensor. It sensed the availability of nutrients and told cells whether or not to grow. If nutrients weren’t available, it told the cell not to grow. Rapamycin worked like a blindfold — tricking cells into thinking that there was a low nutrient supply even when there was an abundant supply. While Dr. Sabatini was figuring out all this, Dr. Suren had been sending out rapamycin to countless transplant doctors. It worked so well that it attained FDA approval for immune suppression in 1999. Some doctors also found an interesting way to use it to prevent rejection (by the body’s immune system) of stents. These were little tubes that were inserted in arteries to keep the heart open for patients who were at risk of a heart attack. Dr. Suren was eventually diagnosed with stage 4 metastatic colon cancer after a routine colonoscopy in 1998. The attending oncologist gave him 6 months to live. Ever the scientist – and determined to carry on with his work – Dr. Suren decided to take rapamycin and figure out whether it had any effect on cancer cells. Surprisingly, the cancer was gone in a few years. It only came back as lung cancer (killing him in months) five years later after he stopped taking rapamycin and decided to let nature take its course. After all, he had proved his oncologist wrong, published papers, and traveled the world. Scientists have just recently comprehended that in addition to freezing growth, mTOR has a secondary starvation protocol. The buildup of junk inside our cells makes us less efficient, sick, and eventually dead. The starvation protocol – which is activated when nutrients are deficient or rapamycin is administered — prompts cells to clean out the junk. Research completed by Matt Kaeberlein, a professor of laboratory medicine and pathology at the University of Washington, shows that rapamycin reduces cognitive decline and other markers of aging in mice. This has massive implications for healthspan and lifespan. In the end, the mysterious white compound that was retrieved from an island in the middle of the Pacific Ocean half a century earlier would go on to save millions of lives. Rapamycin had been approved for immune suppression and stents during Suren’s lifetime. It got approved for rare cancers in the years after his death. And on top of that, there are dozens of studies going on to see if rapamycin can maybe one day prevent or reverse aging in humans.