“DNA makes RNA makes protein makes life.”
Our bodies rely on millions of tiny proteins to stay healthy and alive. Messenger RNA tells cells which proteins to make. What if you could design mRNA to create any protein you might desire – antibodies to fight infection, enzymes to reverse disease or growth agents to mend damaged heart tissue? This was the quest of two very different scientists from opposite ends of the world. The two were an unlikely tag team and their combined efforts are a big part of why we have approved vaccines for COVID-19 in record time. Their complimentary strengths were critical, even though they never worked together.
One was a Hungarian biochemist who spent 40 years chasing an answer when others gave up, and the other was a Harvard scientist and serial entrepreneur who got the green light, literally, that led to today’s modern medical miracle. We can thank Katalin Karikó and Derrick Rossi for the shot at a return to normal in 2021. The two couldn’t be more different, and it was hardly a straight path to success.
Growing up in Kisújszállás, Hungary, Katalin Karikó was introduced to science by watching her father, the butcher, at work. In the 1970s, while studying biochemistry in Hungary, a mentor of Karikó suggested that if they could make a synthetic version of RNA, they might be able to treat cancer or viral disease. From that moment, she was on a quest to make synthetic RNA that could cure illness.
But she couldn’t secure funding in Hungary. In 1985, she received an offer from Temple University in Philadelphia. If she could get to the United States, a job was waiting for her. But in the US, things did not go as planned. Karikó’s bosses changed, she couldn’t get funding and she lost her job. Her supervisor cited her for deportation. Desperate to stay in the United States, Karikó accepted a researcher post.
For all its promise, synthetic RNA was proving to be a headache. Around the world, scientists were encountering the same problem: cells dying off in the culture dish. The synthetic version was identified as an invader, trigging the immune system to attack it. Karikó was convinced there was a workaround. But she couldn’t convince others. Funding was denied again, and she was demoted.
But she remained convinced. “I always had a Cassandra feeling,” she says, referring to the priestess in Greek mythology who possessed the gift of prophecy but was cursed to never be believed. Karikó was not a good salesperson for her idea, she admits. “I couldn’t get money. I couldn’t convince people.”
By 1997, Karikó met Dr. Drew Weissman, a physician and immunologist. Over the next decade, Karikó and Weissman discovered that cells in the lab were dying because synthetic mRNA provoked an inflammatory reaction. But if they modified one of the four building blocks of RNA, known as nucleosides, the cell no longer flagged synthetic RNA as a foreign invader. It could be delivered into a cell without causing inflammation. It was a game-changer.
Their findings were published in the journal Immunity in 2005. To their frustration, the report went largely unnoticed in the scientific community.
Derrick Rossi was born in Canada in 1966 and raised in a blue-collar family to Maltese immigrant parents. The youngest of five, his father worked in an auto body shop, and his mother co-owned a Maltese bakery. Derrick credits a high school science teacher with his inspiration. “As soon as I learned about molecular biology that was it, I knew what I wanted to be,” Rossi says.
A couple of undergraduate degrees, a stint in Helsinki where he met his wife, a doctorate and stops in Texas and Stanford followed before Rossi landed at Harvard in 2007. Rossi was fascinated by stem-cell research and wondered if he could use mRNA to deliver mature cells that had been converted into stem cells using a newly developed transcription process. But he encountered the same problem Karikó did – cells dying in dishes.
Searching for a solution, Rossi came across Karikó and Weissman’s discovery, then almost three years old. In his first experiment using this approach, Rossi made a modified mRNA for the enzyme in fireflies that makes them emit light. They injected the modified mRNA into the thigh muscles of anaesthetized mice and placed the animals in a machine devoid of light. As the researchers watched, the legs of the mice glowed green – a clear ‘green light’ to pursue things further.
“It worked on the very first shot. That tells you something about the robustness of the technology,” says Rossi. The implications were clear: modified mRNA could be used to express a protein, possibly any protein—whether it was needed to treat disease, cure it or maybe prevent it.
Rossi co-founded Moderna in 2010, using a combination of the words modified and RNA. Unlike Karikó, Rossi is a charismatic storyteller with a talent for explaining complex scientific concepts in easy-to-understand terms, and he persuaded giants in America’s biotech industry to invest. Moderna spent a decade developing potential treatments and raising $2 billion before their record-setting IPO in 2018.
Moderna’s COVID-19 vaccine is the company’s first approved treatment.
The advantages of mRNA vaccines are remarkable: there is no risk of infection from the virus or permanent changes to the genome, and the mRNA rapidly degrades so nothing remains. The vaccine can be designed on a computer and rapidly scaled up for manufacturing. There is work under way on mRNA vaccines for cancer, influenza, Ebola and Zika.
Katalin Karikó joined BioNTech in 2014, and she and Weissman have been suggested as deserving candidates for the Nobel Prize, given their groundbreaking contributions to vaccines. Karikó says she’s not motivated by rewards. “I care about one thing: that this vaccine stops the infection.”
Derrek Rossi has gone on to found four other company, focused on cures for multiple sclerosis and cancer, continuing to leverage his ability to identify promising science and attract investors. “If someone I loved were sick, I’d be up day and night thinking, how could I possibly help them?” Rossi says.
Different people on different paths, Katalin Karikó and Derrick Rossi share two key traits – optimism and tenacity. The only two approved vaccines in the US wouldn’t exist without Karikó’s relentless pursuit of a solution and Rossi’s entrepreneurial spirit.