Man of Culture
A bacterium found on a remote Pacific island first became the obsession of a Punjabi microbiologist. It then became a wonder drug that gave hope to millions around the world.
The sky is clear, the sea a deep blue. A patch of sand separates the water from a hill. Palm trees stud the landscape. A moai statue appears to be saying something to five other figures. In the middle of this idyll, seemingly incongruous, is the honeycomb structure of a molecule.
We are in a painting by Sir Roy Calne, a British surgeon and a pioneer of organ transplantation. The scene is from Easter Island or Rapa Nui, one of the world’s most remote inhabited islands. Its nearest mainland neighbour is the country of Chile, more than 3,500km away. The moai statue expounding to the others is meant to represent Surendra Sehgal, an Indian scientist born in undivided Punjab. The molecule is a compound called rapamycin, found in the soil of the island.
Rapamycin, also called sirolimus, is now a life-saving wonder drug. It’s used for immunosuppression in organ transplant patients and coronary artery stents after balloon angioplasties. Trials are underway to test its efficacy in treating ALS, Crohn’s disease, and metastatic and advanced cancers. Some studies suggest that rapamycin could increase lifespan.
But all these bounties were unimagined when soil samples from Easter Island arrived on the desk of a 37-year-old microbiologist in Montreal in the year of the moon landing. Calne’s painting takes some creative licence. Sehgal himself never visited Rapa Nui, but the man and his molecule are forever tied to the island. This is their story.
Island In The Stream
n 1963, the Cold War appeared to have pushed humans not only towards the moon, but also to the brink of self-annihilating madness. Nuclear arms testing had raised fears of radioactive fallout. Overpopulation added a tremendous strain on resources. With the world on boil, scientific communities wondered: how do we adapt?
This churn of events led to the genesis of the International Biological Programme in Europe. The IBP would conduct a series of environmental studies to attempt to piece together the path ahead for humanity.
In Canada, two colleagues, both immigrants from war-torn Europe, were following the developments of the programme. Polish surgeon and researcher Stanley Skoryna and Hungarian microbiologist Georges Nógrády had just learned that an airport was going to be built on the distant isle of Rapa Nui, where hundreds of years earlier, islanders had carved out 800-odd large monolithic statues from volcanic stone to honour their ancestors.
There’s a theory that the islanders cut down all the giant palm trees that dotted the island: for agriculture, to build fires or to transport the massive statues. Whether or not the tree-cutting was the cause, their robust civilisation ultimately collapsed.
The painting by Sir Roy Calne. It now hangs on a wall in Neel Sehgal's home. Credit: Courtesy Sehgal Family
The Rapa Nui mystery had long captured the imagination of archaeologists and ethnographers. Now, it caught the fancy of these two scientists. Skoryna wanted to study what the coming of the airport would mean for one of the most sequestered communities in the world. As part of the IBP, his team put together an ambitious plan to study the biosphere before and after the airport was constructed.
One chilly November morning in 1964, the Medical Expedition to Easter Island set out from Halifax on a Canadian Navy vessel. On board were microbiologists, virologists, parasitologists, medical doctors and 200 sailors. Once they reached, they stayed at their destination for the next two months, gathering swabs, collecting urine samples and X-raying the island’s 1,000-odd inhabitants. The earth, too, was thought to yield unanticipated treasures. [1] Nógrády divided the island into dozens of strips of land and dug out soil from each of them. [2]
Back in Canada, the team disseminated their Easter Island riches to laboratories around the world. But the team never went back as planned, and Skoryna didn’t publish a single report. Still, the expedition was not in vain. In 1969, some of these soil samples made their way to the Ayerst Research Lab in Montreal.
urendra Nath Sehgal was born in 1932 in Khushab village in western Punjab, in an India still undivided. The family moved to Delhi before Partition, where Sehgal’s father continued the family business of manufacturing medicines and medical equipment. Business wasn’t easy, but the firm survived.
Sehgal, whose childhood was punctuated by regular visits to his father’s factory, developed a keen curiosity for how medicines worked on the body. He earned undergraduate and master’s degrees in pharmacy at the Banaras Hindu University. For a year after that, he taught at BITS, Pilani. But he was itching to do more. When he got a scholarship to work towards a PhD in microbiology at Bristol University in the United Kingdom, his family was thrilled. Nobody in their circle had journeyed beyond the subcontinent.
“Suren complained to Air India saying, ‘My parents and siblings are here because of you. You must give them breakfast.’”
Sehgal’s departure in 1954 was a delightful family event, with the entire battalion accompanying him to the airport with garlands and blessings. “The plane was delayed by a few hours, and we all waited till morning,” Swadesh, his now 88-year-old younger brother, told me from Delhi. “Suren complained to Air India saying, ‘My parents and siblings are here because of you. You must give them breakfast.’ This is how my brother got things done. Firmly but politely.”
He would deploy a similar brand of single-mindedness when it came to convincing his employers to take a chance on rapamycin. By the time the samples arrived at his desk, he had spent ten years as a researcher in the microbiology section of Ayerst, working on medicinal compounds made by bacteria. Together with his colleague Claude Vézina, he already had five patents to his name.
The Petri Dish
yerst had received nearly 70 soil samples from Easter Island. Sehgal and his team isolated the microorganisms from the soil, grew them in the lab and examined the chemicals the culture produced. An as-yet unknown compound secreted by a bacterium called Streptomyces hygroscopicus started to show astonishing results.
A laboratory is no place to go wild. “Controls” are crucial in biology and microbiology. Sehgal and his team would likely have created the perfect conditions for fungi to grow on one petri dish: right temperature, right food and so on. In another petri dish, the same: only, this batch of fungi would have had contact with rapamycin. What might they have seen under the microscope? The fungi rapidly multiplying in the first dish and the same organism simply freezing in the one touched by rapamycin.
That was sufficient to kick off a series of studies on rapamycin’s antifungal properties. Two years after Sehgal’s initial discovery, a different team at Ayerst came up with the chemical structure of the molecule. It was named rapamycin after the island on which it was found.
“Uma, it’s a fantastic compound, it’s a miracle,” Sehgal would tell his wife during these early encounters. “Anything it touches gives good results.” On 28 October 1975, a whole decade after Nógrády scooped soil on Easter Island, Sehgal published his first paper on rapamycin in the Journal of Antibiotics. A new antifungal antibiotic had been discovered, he declared.
hen Sehgal had first set foot in North America in 1957, it was with less than $10 in his pocket. His wife Uma recalled a story her husband loved to tell. At Delhi airport, customs had seized the money his father had given him. That prompted a kind German family he met on the plane to take him to a fair in Frankfurt, where he had a layover, and feed him lunch. The following day, he boarded a flight for Montreal, where an Indian friend met him, bought him lunch and put him on the train to Ottawa, where he became a postdoctoral researcher.
Sehgal joined Ayerst in Montreal in 1959. (He stayed with the company till retirement, through mergers, acquisitions and name changes. [3] ) His workplace had enormous fermenters to grow microorganisms in large batches, something that was terribly exciting for an antibiotics enthusiast.
When he was 30, he went back to India for a winter holiday and returned to Canada as a married man. When Uma Kapur first came to Montreal, it was January 1962, the dead of winter. The newlyweds started their life together in a small one-bedroom flat. There were only half a dozen Indian families in Montreal at the time. One of these included Uma’s sister and brother-in-law, who happened to be the Indian High Commissioner.
Uma’s mother had warned her future son-in-law that her daughter was wanting in household matters. But the besotted man paid no heed. Uma’s sister urged her to stay with her for a few days, so she could teach her to cook. “Everyone was worried about how I would manage, but Suren said to my sister, ‘Don’t worry, I will teach her,’” Uma told me. “There was no rolling pin, so he made chapatis with a wine bottle, rolling the dough on the table-top.” She warmly remembered the metal table with the vinyl surface.
Life was picking up in Canada. Sehgal, Uma discovered, was a gregarious Punjabi, not one to be a wallflower at a party. Her husband was also organised to a fault. “He behaved like the house was his lab and wanted everything in order,” Uma said. “I told him once, ‘You run your lab, I will run the house.’”
Family Life
hat first memorable year, when the snow had finally melted, Uma stepped out of home in a saree. Her picture appeared in the newspaper the following day. The president of the Canadian Pacific Railway invited her to his house to talk about sarees and bindis. The photo of that meeting, too, appeared in the paper. “Those were the days,” Uma laughed at the recollection. “Suren said nobody had ever written about him, but then came his wife, and took over the Montreal newspapers.” His time would come soon.
He was not a “typical Indian man,” Uma said, which means he did everything for their children, two boys named Ajai and Neel. The boys grew up as most second-generation Indian immigrant children: steeped in Indian culture at home, while being shaped by the country of their birth. Their parents insisted on excellence in academics and extracurricular activities. Ajai, the older son, remembered watching all the televised Apollo missions. He had a particular memory of watching the moon landing of 1969 as a six-year-old. His father had roused him from sleep and plopped him in front of the television. “You have to watch this,” he told Ajai. “It is history in the making.”
Sehgal tried to steer his sons towards the world of science and discovery. Their days buzzed with electrical experiments involving soldering and wires. “We also had a chemistry set and worked with dad in measuring various compounds, mixing them together and watching them foam up,” said Neel. (Eventually, Neel went into accounting, Ajai did engineering.)
Sehgal’s passion for rapamycin was infectious. “Every day, he spoke of rapamycin with great excitement,” Uma told me. When the clinical trials for the drug took off later, she accompanied her husband to meetings, where she sat in the back and listened. Often, he practised his presentations and speeches in front of her. Once, at a conference on transplants in Paris, a famous scientist asked Uma: “Do you know you are sleeping with a genius?”
Sehgal on a weekend getaway at Gatineau, north of Ottawa, circa 1959. Credit: Courtesy Sehgal Family
Back in the lab, as Sehgal and his team were studying rapamycin’s antifungal properties, they realised it also had immunosuppressant qualities. This would make it very useful in countering the advance of autoimmune diseases such as rheumatoid arthritis and lupus. Crucially, it could help in post organ transplant recovery.
Rapamycin’s suppressant qualities also presaged great news for cancer treatment. Chemotherapy, the only treatment option at the time, was an aggressive approach that not only killed cancerous cells but also other fast-dividing healthy cells. Rapamycin, on the other hand, could potentially inhibit cell multiplication.
Buoyed by its overall potential, Sehgal sent samples of the compound to the US National Cancer Institute for screening, where it showed encouraging results on tumours. Shortly afterwards, NCI and Ayerst collaborated on testing rapamycin along with chemotherapeutic drugs on mice. These results turned out to be spectacular. NCI designated rapamycin a priority drug. “It was a totally new class of anti-cancer agents we were looking at—cytostatic. To that point, they were all cytotoxic agents,” Sehgal said in an interview to the Journal of the National Cancer Institute in October 2001.
But scientific research is long, gruelling and hinges on generous funding. In 1983, rapamycin research received a big blow from the exigencies of business and regulation. Ayerst shut down the facilities in Montreal, laid off 95 percent of their employees and moved a small cohort of 30-odd researchers and staff to Princeton, New Jersey. [4]
Not for Eating
ehgal was one of the 30, but he was still furious. That was because rapamycin was no longer a “company priority.” In fact, Ayerst had even ordered the destruction of “non-viable compounds.” This is what prompted him to do something that could be out of a sci-fi film. Before the Montreal lab was dismantled, he made one last batch of rapamycin in the fermenter. He brought that batch home in glass jars. The substance was white and pasty, a little like ice cream but waxier. He put the jars in the freezer with a sticker that said “NOT FOR EATING.”
“I wondered if they could take it across the border because it was essentially a living organism. But my father asked me to do as told.”
Uma and Sehgal moved to the US on a cold December day. Ajai, who had moved out by now, came up to help. Sehgal instructed his son to buy dry ice to transport his beloved compound. “I wondered if they could take it across the border because it was essentially a living organism,” Ajai said. “But my father asked me to do as told.”
After piling the dry ice at the bottom of the freezer, they transferred the jars into an ice cream container on which Sehgal wrote ‘DO NOT EAT.’ They surrounded the treasure with frozen meat and layered it with more ice. The contraption was sealed with duct tape. Dry ice produces carbon dioxide, and a pressure build-up could lead to a catastrophe. “So we poked holes all around to make sure it was vented,” Ajai told me. “When the movers came, I told them to take the freezer and said it had food in it.”
The rapamycin made its way to its new home without incident. It would be five years before it was taken out from the refrigerator in the house on Sayre Drive, Princeton.
Matters of the Heart
n 1987, Wyeth took over Ayerst to become Wyeth Pharmaceuticals. A new management meant Sehgal could pitch rapamycin once again. His presentations often ended up in heated arguments. Uma told me that he was given the pink slip thrice, but was asked to return each time.
In 1989, his tireless proselytising finally came good. It was time to bring out the culture that had been languishing in the freezer at home. He dashed it to the lab and put it to the test. To his utter delight, the culture was alive and thriving.
It is challenging to reconstruct what exactly Sehgal and his team did in the lab, so I asked biologists and microbiologists if they could tell me how the work might have played out.
“It really depends on what is being investigated, but you usually get the results for microorganisms in two or three days,” Juan-Carlos Acosta, research professor at the Spanish Research Council and an expert in cellular senescence, told me. “It can be obvious to figure out whether a culture is alive when you’re dealing with a liquid that is transparent. You put a small number of whatever you’re investigating in the culture. You set it to the optimal temperature, and the organisms happily swim around in this perfect soup.”
In a day or two, Acosta explained, if the liquid becomes turbid and dense with a lot of precipitates floating around, it means the microorganisms have grown. If the liquid remains transparent, there has been no growth.
Even if a culture is alive in a laboratory, it guarantees nothing in the outside world. The next step is animal testing. Sehgal contacted five external investigators to carry out this work. [5] The timing was perfect. Organ transplantation had taken off in a big way, and there was a need for drugs that would prevent transplant rejection, or the body’s inability to cope with a new organ. Cyclosporine and FK-506, the existing drugs, were not very effective.
One of the five external investigators was Stanford University’s Randall Morris. (Another was the surgeon-painter Sir Calne.) He worked on transplantation using mice and rats. Last autumn, speaking from his home in Carmel, California, Morris spoke to me about how he carried on his trials in those days. He’d pick a young brown mouse to be a donor and a white one as a recipient. He’d remove the heart from the brown mouse, make a little pocket under the ear of the white mouse and place the whole heart under it.
If everything went well, within two or three days, the white mouse’s new blood vessels would grow into heart tissue. And then, and this was truly the money moment, the little heart would begin to beat.
Morris recalled the day when he received that call from Sehgal. “I looked at the structure of rapamycin and thought, well, this is going to be a rather boring project. Half of it resembled the compound of another immunosuppressant molecule of the time: FK-506,” Morris said. “But at that stage, I had very little experience to know that very small changes in a drug structure can dramatically affect the way the drug works.” He agreed to the collaboration anyway. [6]
His scepticism eroded as the experiments began. Over weekly calls, Sehgal’s team would advise on dosage. Sehgal recommended that the drug be injected into the mouse’s abdomen for better absorption. “And what we saw was amazing,” Morris told me. “We were surprised by how potent the drug was. We kept lowering the dose and the drug kept working.” Two months and dozens of mouse sacrifices later, Morris published his data in a 1989 issue of Progress in Immunology. It was the first ever publication on rapamycin as a potential drug for organ transplantation. [7] Morris has preserved the first vial he used for this experiment. He showed it to me on our video call.
Trick and Treat
ver the next few years, rapamycin continued to deliver promising results in various studies. People had started asking the question: how exactly does it work? The answer came in the PhD thesis of biologist David Sabatini of Johns Hopkins University. [8] “Sehgal had very kindly sent us a large amount” of rapamycin, Sabatini wrote in 2017. But “just as importantly, he had also sent a book titled ‘Rapamycin Bibliography’ with a little note wishing us luck. That book became my inspiration.”
Sabatini, as well as other scientists elsewhere, simultaneously concluded that rapamycin latched itself onto a hitherto unknown protein which they called mTOR—the mammalian target of rapamycin. [9] This protein, they found, exists in every cell of every multicellular organism, including humans.
Cells need nutrients to stay alive. This is where the protein mTOR springs into action, like a traffic policeman coordinating the metabolic decisions in a cell. When it receives messages from other proteins about there being enough nutrients—sugars, fatty acids, amino acids, for instance—in the cell, it gives the cell the green signal to divide and proliferate. When nutrients are lacking, it flashes the red light, ordering the cell to stop making merry.
Sehgal in his lab at the National Research Council of Canada, Ottawa, circa 1959. Credit: Courtesy Sehgal Family
This process is great for healthy cells but can have a disastrous effect on cancer cells that grow rapidly. Here is where rapamycin comes to the rescue. It latches on to mTOR and tricks the cell into believing that there aren’t enough nutrients to grow.
Our immune system is a major catalyser for cell activity. Immune cells are wired to launch an attack as soon as they sense danger. But at times, the system is not as discerning. A transplanted organ—technically a foreign body—is seen as the enemy. The drugs that control these unnecessary, overzealous attacks are known as immunosuppressants. Rapamycin’s deceptive quality made it a good immunosuppressant.
In 1996, human clinical trials to test rapamycin as an immunosuppressant were in full swing. Phase 1 studies on patients with kidney transplants were showing positive results. Sehgal was in the audience at a conference in Switzerland where Dr. Rakesh Sindhi, a transplant surgeon at the Medical University of South Carolina in Charleston, was presenting a paper on immunosuppression. After Sehgal told him about his new drug, Sindhi became one of 30-50 investigators in the phase 3 trial of the drug, which led to FDA approval. [10]
“We noticed right away that it had fewer side effects than the usual drugs, and yet seemed to have a good effect in terms of preventing rejection.” Sehgal went on to become a mentor figure for him. He was the rare scientist who gave freely of his time and knowledge to the medical community, Sindhi told me.
A few years later, Sindhi started working with the Children’s Hospital in Pittsburgh, where he is currently co-director of the Liver and Intestine Transplant Program. The team began to administer rapamycin to children suffering from the side effects of other drugs. “The results were dramatic when we switched them to rapamycin,” Sindhi said. “Mothers would say, ‘Oh my child is a little bit better at focusing.’ Even if there were side effects, they were minor and well-tolerated.”
In 1999, the Food and Drug Administration granted Wyeth a licence to market rapamycin as a drug to prevent renal transplant rejection. [11] Rapamycin, with the brand name Rapamune, would finally be on the market.
year earlier, in 1998, Sehgal had felt something was off in his own body. A blood test he did on himself showed slight anaemia. A general physician advised eating red meat but Sehgal got a colonoscopy. A tumour showed up in the upper core component. The following day, they cut him open to find four affected lymph nodes. It was stage 4 metastatic colon cancer. Sehgal was given six months to live.
“Whenever he met people after that he would say, you watch, I am going to live another five years,” Uma said. Along with chemotherapy and radiation, Sehgal started to take his own drug, rapamycin. He felt good. The year after his diagnosis, he retired from Wyeth and moved to Seattle to be close to his son and grandchildren. He worked as a consultant for the next few years, travelling the world for conferences, meetings and leisure.
“Whenever he met people after that he would say, you watch, I am going to live another five years.”
Once, he underwent radiofrequency ablation in Pittsburgh to burn inoperable tumours in his liver. While recovering from the procedure, he was surrounded by liver transplant patients. Word soon spread that the discoverer of the drug that had given them a new lease of life was on their floor. People came in, one by one, some on wheelchairs, to shake his hand and thank him. “It was an amazing thing to witness, you know,” Neel told me. “How often does it happen that you’re having surgery on the floor where all these recipients of your drug are?”
Sometime during the last six months of his life, he developed a doubt: how was he to know if rapamycin was the reason for his good health? After all, he had undergone chemo and radiation too. The scientist became the experiment. He stopped taking the drug and the cancer returned with a vengeance. Within two months, it had spread to his lungs. “He said in his last days that it was his biggest mistake,” said Neel.
His last days remained busy. Family and friends kept visiting. True to form, he was working on a paper until five days before his death, with an oxygen mask on his face. [12] The day before he passed, he was in pain. The nurse looking after him at home suggested he take morphine. He refused, saying he didn’t want his brain to be foggy. He spent the day watching Star Wars. Surendra Nath Sehgal died at home, surrounded by loved ones, on 21 January 2003.
cience is not a discipline for lone wolves. Hagiographies often play up the image of the scientist as a reclusive genius, ploughing a lonely furrow in the lab at odd hours. To get a drug like rapamycin to market and actually transform people’s lives, many people have to work late and lonely nights. They also have to talk to each other, as Skoryna did with Nógrády, as Sehgal did with Morris and Sindhi and so many others, as Sabatini must have with his thesis advisor. But the eureka moment remains special, and Sehgal was there for it, captaining a team that saw a simple culture experiment produce a remarkable result.
While he was alive, Sehgal already knew that his work had moved the needle on something critical.
Uma was recently at a local art gallery in Seattle with her daughter-in-law. A professor from the University of Washington was making sculptures there. He asked if she would be willing to model for him. While she sat, a woman from the art gallery asked the sculptor how he was feeling.
“I asked what happened and he said he was just back from his third kidney transplant,” Uma told me. “He said if it hadn’t worked this time, he’d have died. I asked him which drug he was on, and he said Rapamune.” When she told him her husband had discovered it, he asked if he could meet him. “When I told him he was no more, he came and shook my hand.”
Uma knows what her husband would have said had he been alive. Many years ago, when rapamycin had not yet been formally approved, a doctor had sought it on compassionate grounds for a six-year-old’s kidney transplant. The surgery had been a success. “I don’t care if the company makes even a cent out of it,” Sehgal had said to Uma. “My work is done. A child has survived.”
Sukhada Tatke is a journalist from Mumbai, currently in Edinburgh.