Heart attacks struck Sek Kathiresan's family. He's devoted his life to stopping them.
Sekar Kathiresan was driving home when his cell phone rang. The voice on the other end belonged to his father. It was the evening of Sept. 12, 2012, his father's 65th birthday. But that wasn't why he was calling.
"Senthil collapsed at home," Kathiresan's father said. "He's in the hospital."
Senthil, Kathiresan's older brother, was a seemingly healthy 42-year-old, training for a race. But that night he returned from a run dizzy and sweating profusely. He called 911, then had a seizure as paramedics arrived.
Senthil had had a heart attack; his brain starved of oxygen for minutes. He died a little over a week later.
His death devastated Kathiresan, an immigrant from India who spent his early childhood overseas with his brother, waiting for the day they'd join their parents in the U.S. "We relied on each other," Kathiresan said. Both had thrived in the U.S. They were married the same year and each had young children.
This story might be familiar to the millions of people and families affected by heart disease, the world's leading cause of death. But it's more than that for Kathiresan, who, when Senthil died, was a cardiologist and emerging as one of the field's leading geneticists.
"It really shook Sek. It shook all of us," said David Altshuler, the former Broad Institute of MIT and Harvard geneticist, a Vertex Pharmaceuticals executive and mentor to Kathiresan. "It was a tragic irony."
Kathiresan channeled his despair into motivation. He rose to the top of his profession, making discoveries that changed the way people think about heart disease. He launched a startup with an exceptionally ambitious aim to prevent heart attacks, for life, with a single treatment. Nearly a decade after his brother's death, the startup, called Verve Therapeutics, could soon test that treatment in people.
"I tried to turn that negative energy into Verve," Kathiresan said, "to make sure what happened to Senthil doesn't happen to others."
The road ahead is daunting still. Kathiresan is an academic-turned-CEO on a personal mission, not a seasoned biotech executive. His company is attempting a scientific moonshot, relying on cutting-edge, but unproven, gene editing technology to develop a one-time medicine for one of the most prevalent diseases. In doing so, he will have to prove the world needs what is essentially a longer-lasting version of cholesterol-lowering drugs that are already available.
"It's a pretty high bar to say gene editing has an important role to play here," said Richard Lifton, the president of Rockefeller University and a geneticist known for research into heart disease.
"But the flip side of that," he added, is a drug "that could last, potentially, a lifetime."
Kathiresan was only four years old when his world upended.
Kathiresan's father, an aspiring engineer, had received a full scholarship at the University of Pittsburgh, thousands of miles away from the tiny southern India village of Viramathi he, his wife and three children called home. He dreamed of coming to the U.S. and pursuing a higher education, but couldn't afford to bring the whole family, Kathiresan said. So, in 1975, he left for the U.S. with his wife, baby daughter Davi and about $40. Sek and Senthil stayed in India.
Kathiresan remembers a sense of loss, a "yearning." He didn't see his parents or hear their voices for five years. There were no phones in the house the brothers shared with their grandparents, nor at the boarding school they attended. They communicated through letters sent across the ocean. "I'm not sure I would have had the courage to leave my kids behind," he said, reflecting on his father's decision.
But the plan worked. Kathiresan's father earned a Ph.D. and saved enough money to bring his sons to the U.S.
Kathiresan vividly remembers the flight from Mumbai to New York. The brothers, who had never seen a plane before, were awestruck. They flew by themselves, with an attendant as their guardian. Picked up at the airport by their father, their first meal in the U.S. was at McDonald's, where Kathiresan had french fries for the first time. He devoured them and asked for more.
"We can't afford another one," his father told him.
The Kathiresan family soon moved into a house outside of Pittsburgh. The brothers, who spent half their childhood in a town with no running water, would live the other half in a middle-class and predominantly White U.S. suburb, an upbringing each wrestled with.
Growing up, Kathiresan was one of the few people of color in his school. Though he made fast friends, he wasn't comfortable, caught between his two worlds: weekly prayers at a nearby Hindu temple and weekend football games at school. His mother pushed him and Senthil to remember their heritage, anxious they would become "too American."
While Kathiresan dated and met his wife in college, Senthil had an arranged marriage. "We respected each other's approach," he said. "Some immigrants want to jump right in and be all in," and others "want to keep as much of their home culture as possible."
Kathiresan majored in history and even flirted with a career in finance before finding medicine, which he said "offered a sense of purpose and a mission."
His choice of profession was also personal, even before Senthil's death. Kathiresan's uncle, a physician, had died of a heart attack. So had his grandmother. His father had a heart attack at 54. Each time Kathiresan was more certain he'd become a cardiologist.
He embraced the grueling hours and sleepless nights that came with residency training at Massachusetts General Hospital, undeterred even when accidentally stuck by a needle that had been in the neck of an HIV patient. "I saw my whole life flash in front of me," he recalled, yet, after initially panicking, he took antiviral drugs and went back to the hospital.
"It comes with the territory," he said. "You're teaching, you're trying to help, but there's risk, you know?"
Kathiresan wasn't satisfied being a doctor, though. He wanted to understand why the people closest to him were getting sick and learn how to do something about it.
David Altshuler recalls sitting in his office at MGH one morning in 2000 when he heard a knock on the door.
Altshuler was already well on his way to being recognized as one of the world's top geneticists. His academic lab would soon co-lead three large genetic research studies — the 1,000 Genome Project, the SNP Consortium and the International HapMap Project — and he would become one of the founding members of the Broad Institute.
Kathiresan, then a young cardiology fellow, sought him out and burst into his office.
"I want to figure out what causes people to have premature heart attacks," Kathiresan exclaimed, according to Altshuler.
Dressed in scrubs, Kathiresan looked exhausted, having gone to Altshuler's office straight from an overnight shift at the hospital. Altshuler can still recall the big, dark circles under Kathiresan's eyes.
Many people can talk a good game. But Sek is the real deal. He reminds us of why we do what we do.
"How are you going to do that?" he asked.
Kathiresan laid out a plan to discover what puts people at risk for heart attacks. Then he'd figure out which risk factors were actually important, before finding a way to intervene before health problems began.
"I need to learn genetics," Kathiresan told Altshuler. "That's why I'm here."
Altshuler was impressed. "He was personally compelling," he said, "and obviously incredibly motivated." When Kathiresan finished his doctoral training three years later, he went to work for Altshuler at the newly founded Broad Institute.
The experience was a crash course in genetics. Altshuler pushed Kathiresan to answer scientific questions that mattered, not just the ones he could solve. He taught Kathiresan how to manage and develop talent, skills he'd call on in the future. "He had an immeasurable influence on me," Kathiresan said.
Over the next decade, the two wrote grants together and teamed up on studies aimed at identifying genetic markers for heart attacks. They became good friends and confidants. Along the way, Kathiresan emerged as "the leading person in the world studying the genetics of coronary artery disease, certainly of his generation," Altshuler said.
"Many people can talk a good game," Altshuler said. "But Sek is the real deal. He reminds us of why we do what we do."
A research lab is like a small company. There's money to raise, a budget to manage. A team to put together, mold and motivate. Careers to foster and a vision to rally a team around. Kathiresan got that chance in 2008, when he started a lab at MGH and the Broad to search for genetic clues into the underpinnings of heart disease.
As a first-time lab leader, Kathiresan had to convince people to believe in him. One of the first was Kiran Musunuru, a young heart doctor doing a fellowship at Johns Hopkins University.
At the time, Musunuru was disillusioned with cardiology. There were plenty of ways to treat heart disease, he said, but not enough tools to prevent it. Musunuru thought genetic research was the key and desperately wanted to be a part of the building "wave" of studies. That led him to Kathiresan's lab at MGH.
Kathiresan didn't have experience. His lab was brand new and his future there wasn't secure. But Musunuru felt a kinship with him. "In the same way that I was, he was all in," he said. "You've got to take some risks, right?"
What followed was a prolific partnership. Musunuru became Kathiresan's mentee, one of his first post-doctorate students, and eventually, the head of his own lab at the University of Pennsylvania and a Verve co-founder. They were willing to put in "insane amounts of time" to finish work and publish papers as quickly as possible, according to Musunuru. Conditioned by working long hospital shifts, they'd each wake up before dawn, texting and calling one another.
The two partnered on a number of important research papers, looking into, among other things, the genetic basis of cholesterol and a protective gene known as ANGPTL3 that would become a top therapeutic target of drugmakers — including, years later, Verve.
In the meantime, Kathiresan's lab turned into a training ground for dozens of other young scientists. By the time he stepped away, Kathiresan taught more than 60, many of whom are now faculty members. And he had discredited a long-held belief about heart disease.
For many years, Ethan Weiss, a cardiologist at the University of California, San Francisco, told his patients to exercise so their levels of "good cholesterol" would increase. He wasn't alone. Doctors were taught in medical school that high levels of high-density lipoprotein, or HDL, were associated with fewer heart attacks. Conventional wisdom was "you wanted to do everything you could to get your HDL up," Weiss said.
But researchers didn't know much about HDL and its relationship to fats in the blood called triglycerides, which were also linked to heart disease. High HDL, for example, was associated with low triglycerides and vice versa. "The question has been, which of these is the dominant one? Which one carries risks?" said Lifton, of Rockefeller. "It's been very hard to disentangle."
Researchers and drugmakers were nonetheless convinced HDL was the key, and that medicines that raised it would prevent heart attacks. Years of research led to drugs, known as CETP inhibitors, that could boost HDL. Several were thrust into large clinical trials early last decade, poised to become the next big thing in heart medicine.
"But correlation," Kathiresan said, "does not mean causation."
He basically changed a paradigm that we had clung to forever.
In 2012, Kathiresan's lab at MGH made a startling discovery: Good cholesterol isn't so good after all. By studying the genes of more than 100,000 people, they separated the effects of triglyceride levels from HDL. They found people with more HDL weren't safer from heart attacks.
HDL appeared to be a mirage, its link to heart disease perhaps conflated with other factors. Drugs that raise it likely wouldn't protect people from heart attacks, the team wrote in a paper published in The Lancet in May 2012.
The news stunned cardiologists. "He basically changed a paradigm that we had clung to forever," said Weiss, who now tells patients to ignore HDL levels because "it doesn't seem to matter."
The findings rippled across the pharmaceutical industry. One by one, CETP inhibitors from Roche, Amgen, Merck & Co. and Eli Lilly failed in clinical trials or were dropped by their developers. The class was largely shelved, along with a long-running hypothesis.
"It was a beautiful demonstration of using large-scale genomics to address a clinically vexing and important problem," Lifton said.
Just a few months after the paper's publication, Kathiresan's brother died of a premature heart attack.
Kathiresan took time off work and reexamined his own health. He went for heart tests, committed to being more active and dropped weight he’d put on in college but hadn't lost.
"You mourn," Kathiresan said, and then "focus on the things you have control over."
So Kathiresan kept going. He and his labmates found more genes associated with either risk of early heart attacks or protection against them, confirming research by others in the process. They used a trove of genetic data from the U.K. to develop a diagnostic test that can identify higher risks of coronary artery disease, diabetes and other conditions in seemingly healthy people. "He decided, 'I will redouble myself to this effort,'" Altshuler said. "That took courage."
By 2018, they'd amassed a body of work so impactful that Kathiresan received the same Curt Stern award — an honor given to pioneering human geneticists by the American Society of Human Genetics — that Altshuler previously won.
In his acceptance speech, Kathiresan recalled the journey that took him from a small town in India to an awards stage in San Diego.
He then showed an ambulance report from the 911 call a 42-year-old made before he suffered a heart attack. He shared the man's electrocardiogram, his cholesterol and triglyceride levels and troubling family history. He explained how he died. He went through all the work he and his team had done to understand why the same thing happens to millions of other people.
The patient was his brother, he explained. New drugs were needed to avert the same tragedy in others, he said, and that was something he was working on. A high-profile competition he had recently lost gave him an opportunity.
In January 2016, the American Heart Association, the British drugmaker AstraZeneca and Google's life sciences arm Verily came up with an idea for a competition. Called "One Brave Idea," they promised a $75 million award and partnership opportunities to a researcher with the best idea to cure heart disease.
"What we're seeing is this growing epidemic of cardiovascular disease worldwide," said AHA CEO Nancy Brown, in a video describing the competition, "and we know that we need a new answer."
The AHA received 349 applications from research teams in 22 different countries. Kathiresan submitted one of them. Musunuru, then at UPenn, wrote another.
Unknown to one another, both pitched the same idea: a single shot of a gene editing drug that could drive down "bad cholesterol," or LDL, as low as possible for as long as possible.
Kathiresan cowrote an application with Anthony Philippakis, another Altshuler trainee who worked with the venture firm GV; and Feng Zhang, also of the Broad and one of the leaders of CRISPR gene editing research. Musunuru's team included UPenn gene therapy pioneer James Wilson.
The proposals were "eerily similar," Musunuru said. "Almost interchangeable."
Neither even made it to the competition's final round. The award went to a group of researchers led by Calum MacRae, chief of cardiovascular medicine at Brigham and Women's Hospital, who won for a genomics project meant to detail the biological changes that occur when heart disease begins.
The loss still bothers both of them. "I was bitterly disappointed," Kathiresan said. Musunuru calls it a "big, lost opportunity for the AHA."
Musunuru turned his attention back to research. Kathiresan decided to change careers.
Academia and the drug industry are closely linked. Academic researchers, after all, often make the discoveries that companies turn into medicines.
But that doesn't make it easy to leave the research bench for an industry job. The switch involves learning an entirely new language. Kathiresan, for example, had never heard the term "CMC," which is industry parlance for the process and regulation of drug manufacturing.
Jumping from academia to biotech can also mean giving up a secure position for a role in a company that, history would suggest, is likely to fail. Scientific glory isn't the only goal for a biotech, either: it has to eventually make money.
Kathiresan said he didn't have the "antipathy to the for-profit model that some people have." Previously, he had been focused on research, turning down industry job offers along the way. But his perspective changed after Altshuler left the Broad Institute in 2015 for a job as Vertex's top scientist. That "opened my eyes to the fact that there's a much larger world out there, and ways to have impact," he said.
So after losing the One Brave Idea competition, Kathiresan turned to Philippakis. It was a role reversal, of sorts: Kathiresan had advised Philippakis throughout medical school and after. "I really consider him a mentor in my life," Philippakis said.
Now it was Kathiresan who needed help. Philippakis cowrote the AHA application, he said, to help figure out how to build a company around the one-shot project. And Philippakis, who was well-versed in the biotech business because of his role with GV, could teach Kathiresan how to make that happen.
For almost two years, they gathered a small group every Friday to go through all the steps and potential roadblocks ahead. They tried to convince themselves "that this was actually doable," Philippakis said. They discussed how and where they'd get the intellectual property. The type of gene editing medicines they'd make. The business plan. How to raise the money and which firms to contact. Who the founders would be.
They came up with the name Endcadia Therapeutics — a nod to ending coronary artery disease — and prepared a pitch for GV.
Krishna Yeshwant is a venture capitalist who has worked with GV since its inception more than a decade ago. Over that time he's invested in dozens of healthcare startups. He's been asked to back plenty more.
Yeshwant has heard plenty of stories like the one Kathiresan told. Different versions of how "this family member of mine, this boyfriend or girlfriend, came down with this condition and I've devoted my life to it," he said. An emotional pitch only goes so far, though. And venture capitalists don't often invest in heart drugs because of how expensive they are to develop and test. In recent years, they've taken a back seat to promising new cancer and rare disease medicines.
But Yeshwant, who had joined Kathiresan and Philippakis for many of those Friday morning meetings, thought they were on to something. The treatment they envisioned, if successful, could change "how society works," he said, and Kathiresan was devoted to seeing it through. The plan they'd laid out was realistic as well: First they would prove the drug could work in a rare, inherited heart disease, a faster and less expensive clinical development path. Then they would go bigger and broader.
"It's aspirational," Yeshwant said, "but there was a nice on-road to it."
The others agreed. The startup became the first drugmaker GV — better known for forming digital health companies — ever incubated. The firm led a $59 million financing that closed in August 2018 and was announced the following year.
In the meantime, Kathiresan weighed his future. Academic founders tend to play passive roles in the biotechs they form, rather than change jobs to lead them. Kathiresan was still in charge of labs at MGH and the Broad. He wasn't sure if he was ready to run a company, or if the board of directors of the startup, now named Verve, wanted him to.
People close to Kathiresan say he won't pretend he's adept in a field he doesn't know well. He'll ask questions and defer to those who are, and surround himself with people who are strong in areas he lacks experience.
"That's a very positive attribute, both in a scientist and a leader," Musunuru said. "But it's not necessarily common."
Kathiresan, for instance, wasn't an expert in messenger RNA or lipid nanoparticles, each key parts of the treatments Verve is now developing. He'd never put an investor syndicate together, taken a company public or developed a drug. Some of those skills are prerequisites for running a new biotech. Venture investors tend to prefer proven executives, or people they at least know and trust.
Picking a CEO is "one of the hardest parts of the job for all of us" venture capitalists, Yeshwant said. "You're essentially getting married to that person," but on "relatively limited amounts of data. Sometimes we get it wrong."
Kathiresan was a risky bet. He was both inexperienced and emotionally invested, which can be a drawback when the time comes to make tough decisions. "The easiest person to trick is ourselves," Yeshwant said.
But Verve's board was convinced Kathiresan could do the job. He was willing to be coached and be self-critical. He thought through all the reasons why something might not work. "He brings a lot of skepticism and clear thinking to everything he does," Yeshwant said.
He would also be surrounded by more experienced executives, like Andrew Ashe and Andrew Bellinger, each of whom came from senior biotech positions and could "cover the gaps," Ashe said. "He has good judgment," added Bellinger, and "he learns from his mistakes very quickly."
So far, at least, their work has paid off. Verve has gone from a tiny startup to a publicly traded company with more than 100 employees and a market value of nearly $2 billion. Much of its progress was made during a once-in-a-century pandemic, when Kathiresan led an effort to create a COVID-19 testing protocol that was adopted by dozens of Boston biotech companies. The company hasn't missed a development milestone.
Among newly public biotechs, Verve's stock is also one of the best performing in a year in which young drugmakers have struggled to maintain their valuations.
Its biggest challenges still lie ahead, however.
Six years ago, the Food and Drug Administration approved two drugs that can dramatically lower cholesterol in people with heart disease. Known as PCSK9 inhibitors, the injectable treatments, administered every few weeks, were hailed as medical breakthroughs and future blockbuster medicines.
They never reached those heights. Insurers, wary of their high prices, made the drugs tough to get. They demanded proof PCSK9 blockers could prevent heart attacks and strokes, not just drop cholesterol. The drugs' developers, Amgen and Regeneron, struggled to sell them until they got that data and even then were forced to drastically cut prices. Today, the two medicines are still typically reserved for patients with severe disease or who are at "very, very high risk" of a future heart attack, according to Weiss, of UCSF.
What happened with PCSK9 inhibitors is a cautionary tale for Verve, which has advanced two experimental treatments that use a form of genetic surgery known as base editing to switch off genes involved in regulating cholesterol. One drug targets PCSK9. The other goes after ANGPTL3, one of the genes Kathiresan studied. Both are meant to be one-time treatments.
To me, it's as clear as day. If we can get this to work safely, this is the answer to heart attack.
Kathiresan argues this approach is the solution he's sought, one that could protect people like Senthil as well as those who don't continue taking their pills or injectable drugs. If the treatment proves its worth in people with genetically elevated cholesterol, Verve would move on to test it in those who have suffered heart attacks and are therefore likely to have another one.
The ultimate goal is a preventive treatment, akin to a vaccine for heart attacks. If truly long-lasting, each would save the healthcare system money, Kathiresan claimed, even at a price tag he estimates could be between $50,000 and $200,000.
"To me, it's as clear as day," Kathiresan said. "If we can get this to work safely, this is the answer to heart attack."
But others aren't so certain. Even if successful, Verve would eventually compete with drugs that effectively keep cholesterol levels in check for most people, many of which are generic and inexpensive. Another of the powerful new PCSK9-targeting drugs, Leqvio, could soon be approved in the U.S. and requires only two injections a year.
"Theoretically, the idea of one-and-done is very attractive," said Dae Gon Ha, an analyst with the firm Stifel. But patients will already have "a suite of options," he added, and may not feel urgency to try something new.
Additionally, currently available medicines are made with established technologies that have longer track records of safety. The long-term effects of gene editing, if any, aren't known.
"There is some attendant risk to the [gene-editing] approach that, I suspect, will give some people pause," said Lifton, of Rockefeller.
Kathiresan acknowledges the skepticism. "We'll have to prove it to people," he said. But he went through all these questions before he joined Verve, considering the very real chance he'll fail, or won't have the impact he hopes. He thought of his family and his three children, the oldest of whom is now in college. He remembered the decades of work that led him to this and all the people still dying from heart attacks.
"If it doesn't work, for whatever reason, then the failure would be a noble failure," he said. "Why would you spend your life doing anything else?"