Rapamycin is a paradoxical drug. It improves anticancer immunity, but it can also cause cancer. It protects against bacterial infections and stops viral replication, but it also suppresses the immune system. It improves metabolic function, but it also causes type 2 diabetes. This list of contradictions goes on and on. But there is one thing about rapamycin that scientists tend to agree on. Unfortunately, rapamycin was out of luck.
Rapamycin as an antifungal agent
In the 1960s, the Chilean government Scheduled construction An international airport on Easter Island, one of the most popular territories. Two Canadian scientists, Stanley Skoryna and Georges Nogrady, saw the perfect opportunity to study the island and its people before and after the construction of the airport. In addition to performing extensive physical examinations on most of the island’s population of about 1,000, Skoryna and Nogrady collected soil samples from various locations on the island to characterize microbial diversity. Ultimately, Skolina and Nogradi’s undertaking brought little academic reward. But their soil samples somehow ended up in the hands of Surendra Sehgal, a senior researcher at his Ayerst Pharmaceuticals, now at Pfizer.
In 1972, the Ayerst team led by Sehgal new antifungal compound in soil samples. The compound was named rapamycin in honor of Rapa Nui, the Polynesian name for Easter Island.
Unfortunately, rapamycin’s antifungal potential was short-lived. blocked the production of immune cells, an undesirable feature for patients trying to fight off infection. The drug was labeled an immunosuppressant, putting an end to antifungal adventures.
Rapamycin as an anticancer agent
Sehgal wasn’t ready to give up rapamycin. On a hunch, he sent a sample of it to the National Cancer Institute (NCI), where it was screened for anticancer effects. Immunosuppressants are usually not good cancer treatments. In fact, the FDA requires most immunosuppressants to carry a warning that they increase cancer risk. The immune system is responsible for killing cancer cells. Therefore, suppressing the immune system increases the risk of cancer. Nevertheless, Seghal’s hunch paid off. During the screening process, it was revealed that rapamycin stopped cancer cell lines from growing in a way that no other cancer treatment had ever done before.
Prior to the 1980s, all chemotherapy was cytotoxic. In other words, it kills living cells. This causes severe side effects as healthy cells die as collateral damage. However, based on NCI screening, rapamycin was cytostatic. In other words, it stopped the cells from dividing, but didn’t kill them. This discovery had the potential to fundamentally change the way cancer is treated. The NCI has rapidly advanced rapamycin as the drug of choice. Unfortunately, the drug had more bad luck.
Ayerst laid off 95% of its employees because Ayerst researchers and academic scientists planned a clinical trial of rapamycin. Despite its potential, the rapamycin program was discontinued. But once again Sehgal wasn’t ready to give up. He took home a sample of the rapamycin-producing bacteria, put them in his freezerthey stayed for six years.
revival
In 1987 Ayerst merged with Wyeth and was taken over by a new management team. Sehgal persuaded them to revive research on the drug and its anti-cancer effects. Following its resurgence, numerous reports confirmed the inhibitory effects of rapamycin on cell proliferation. fungi To plant To animalThese inhibitory effects vary by organism. However, the observation that rapamycin targets such a broad range of cells suggested that it acts via evolutionarily important master regulators.This paved the way for pioneering 1990s research It identified mTOR, a highly conserved mechanistic target of rapamycin, a protein important for cell division.
Following the discovery of mTOR, scientists discovered that this enzyme governs a complex signaling network that controls nearly every aspect of growth and metabolism. mTOR determines whether cells proliferate Based on amino acid, glucose, insulin, leptin, and oxygen levelsThis evaluation is important. For example, when a cell doesn’t get enough nutrients and begins to multiply, it dies trying to carry out its process.
The discovery of mTOR gave the FDA peace of mind in 1999 to approve rapamycin for organ transplant patients, and it has been used by millions of patients ever since. Its immunosuppressive activity prevents the immune system from attacking the transplanted organ, and it is much more tolerable to patients, as side effects are relatively few. , found that they were less likely to develop cancer than other patients. Unfortunately, Rapamycin had bad luck with the final blow.
A scientist who has never lost faith in rapamycin, Surendra Segal was diagnosed with stage 4 colon cancer in 1998. At that time, the median survival time for colon cancer was 14.4 months for him. His doctors started treating him with a rapamycin analogue when the cancer metastasized to his liver and no tumor in his liver grew. He died in 2003, five years after his diagnosis. In 2004, an analogue of rapamycin was approved for the treatment of kidney cancer.
Rapamycin as an anti-aging
As more research groups experimented with rapamycin and its analogues to suppress mTOR activity, they found that the drug extended lifespan in fungi and animals. As part of the National Institute on Aging’s interventional trial program, researchers gave rapamycin to mice to study how it changed the lifespan of the mice. result, Reported in 2009made headlines: Rapamycin-fed mice lived an extra six months (about 20 years in humans).
After the mouse studies, scientists began investigating rapamycin’s antiaging effects in other mammals, including humans. 2014 Novartis reported results From a trial in which 200 older adults took placebo or tablets containing one of three doses of a rapamycin analogue (everolimus) for six weeks. I didn’t want to wait decades to get rid of it, so I took a different approach to determine if rapamycin would make older people healthier.
Overactive mTOR As we age, the immune system (and possibly other systems) functions harder, but not necessarily better. I thought it would be strengthened. After six weeks of treatment, the researchers gave all study participants an influenza vaccine and assessed how well the participants’ immune systems responded. had the most influenza antibodies in This suggests that low doses improved immune system function.
rejuvenation of the immune system
It may seem paradoxical that the immunosuppressive drug rapamycin can boost immune function. At low doses, rapamycin “rejuvenates the immune system,” calming hyperimmunity rather than suppressing healthy immunity. It would have sounded much more appealing if it had been labeled as a drug or anti-inflammatory.
Because rapamycin was lumped with other immunosuppressants, it has an unfair reputation for increasing the risk of cancer and infections. Rapamycin prevents lymphoma and some types of cancer in transplant patients and Improves resilience against pathogensOne important reason why rapamycin side effects are exaggerated is that the frequency of rapamycin side effects is often extrapolated from studies lacking a healthy placebo group. Thankfully, this is starting to change.and Placebo-controlled study No side effects were seen compared to placebo in healthy older adults. In 2020, UCLA scientists will 3 years of research Long-term safety and anti-aging effects of rapamycin in healthy older adults.
