Messenger RNA: How a Long Idea Led to Covid-19 Vaccines

The Hungarian-American scientist Katalin Kariko’s obsession with researching a substance called mRNA to fight diseases once cost her a faculty position at a renowned university, which dismissed the idea as a dead end.

Now her pioneering work that paved the way for Pfizer and Moderna Covid-19 vaccines could save the world from a 100-year pandemic.

“This is just amazing,” she told AFP on a video call from her Philadelphia home, adding that she was unused to the attention after years of working in the dark.

It shows why “it is important that science is supported on many levels”.

Kariko, 65, spent much of the 1990s submitting grant applications to fund her research into “messenger ribonucleic acid” – genetic molecules that tell cells which proteins to make to keep our bodies alive and well keep healthy.

She believed mRNA was key to treating diseases where more of the right kind of protein can help – like repairing the brain after a stroke.

But the University of Pennsylvania, where Kariko was on his way to a professorship, decided to pull the plug after the number of refusals for grants increased.

“I was ready for a promotion and then they just demoted me and expected me to walk out the door,” she said.

At the time, Kariko was not a US citizen and needed a job to renew her visa. She also knew she couldn’t get her daughter off to college without the huge staff discount.

She decided to move on as a lower level researcher and get past a meager salary.

It was a low point in her life and career, but “I just thought … you know the (lab) bench is here, I just need to do better experiments,” she said.

The experience shaped her philosophy for dealing with adversity in all areas of life.

“Think about it and in the end you have to say what can I do?”

“Because then you won’t waste your life.”

Determination runs in the family – their daughter Susan Francia went to Penn for a Masters degree and won gold medals with the US rowing team in 2008 and 2012.

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In the body, mRNA delivers the instructions stored in DNA to cells, the molecules that carry all of our genetic code.

In the late 1980s, much of the scientific community focused on the use of DNA to provide gene therapy, but Kariko believed that mRNA holds great promise too, as most diseases are not hereditary and do not require solutions that permanently alter our genetics.

First, however, it had to overcome a major problem: In animal experiments, synthetic mRNA caused a massive inflammatory reaction when the immune system recognized an intruder and rushed to fight it.

Kariko, along with her main collaborator, Drew Weissman, discovered that one of the four building blocks of the synthetic mRNA was defective – and they were able to overcome the problem by replacing it with a modified version.

You published an article about the breakthrough in 2005. In 2015, they found a new way to transport mRNA into mice by using a fat coating called “lipid nanoparticles” that prevents the mRNA from breaking down and helps place it in the right part of cells.

Both innovations were key to the Covid-19 vaccines developed by Pfizer and its German partner BioNTech, where Kariko is now Senior Vice President, as well as to the recordings produced by Moderna.

Both work by instructing human cells to make a surface protein from the coronavirus that simulates infection and trains the immune system on when it encounters the real virus.

The mRNA breaks down quickly and the instructions it gives the body are not permanent, making the technology an ideal platform for a wide variety of uses, Kariko said.

These could range from new vaccines against influenza, which are faster to develop and more effective than the current generation, to new disease treatments.

For example, AstraZeneca is currently working on an mRNA treatment for patients with heart failure that provides signaling proteins that stimulate the production of new blood vessels.

Although as a foreign-born woman she doesn’t want to make too much of it in a male-dominated field, she occasionally felt underrated – she said people would approach after the lectures and ask, “Who is your manager?”

“They always thought, ‘That woman with the accent, there must be someone behind her who’s smarter or something,'” she said.

If all goes well with the Pfizer and Moderna vaccines, it is easy to imagine the Nobel Prize Committee rewarding Kariko and other mRNA researchers.

That would be bittersweet for Kariko, whose late mother called her every year after the announcements to ask why she hadn’t been selected.

“I told her, ‘I never get (federal) scholarships in my life, I’m nobody, not even faculty,'” she would laugh. To which her mother would reply: “But you work so hard!”