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Techniques that have armed scientists in the battle against COVID-19 have scooped two out of five US$3-million Breakthrough prizes — the most lucrative awards in science and mathematics. One award went to the biochemists who discovered how to smuggle genetic material called messenger RNA into cells, leading to the development of a new class of vaccine. Another was scooped by the chemists who developed the next-generation sequencing technique that has been used to rapidly track variants of the SARS-CoV-2 coronavirus. The prize were announced on 9 September.

“These two awards are for research that has had such an impact on the world that they elevate the stature of the Breakthrough Prize,” says Yamuna Krishnan, a chemical biologist at the University of Chicago in Illinois. “They have been saving lives by the millions.”

Vaccines developed by the Pfizer–BioNTech collaboration and Moderna, which have this year been administered worldwide, deliver mRNA that instructs cells to create SARS-CoV-2’s spike protein, which, in turn, stimulates the body to make antibodies. But for decades, mRNA vaccines were considered unfeasible because injecting mRNA triggered an unwanted immune response that immediately broke down the mRNA. The award’s winners — Katalin Karikó at the University of Pennsylvania (UPenn) in Philadelphia and at BioNTech in Mainz, Germany, and Drew Weissman, also at UPenn — demonstrated in the mid-2000s that swapping one type of molecule in mRNA, called uridine, with a similar one called pseudouridine by-passes this immune reaction1.

“This is a fantastic and incredibly timely award for work that began it all,” says Nobel laureate chemical biologist Jack Szostak at Harvard University in Cambridge, Massachusetts, who is a scientific adviser to Moderna. “It’s particularly inspiring because, early on, nobody believed it would be useful.”

Numerous rejections

Karikó recalls the scepticism surrounding her work in the 1990s that led to numerous grant-proposal and paper rejections (including the 2005 paper for which she is now being recognized), and forced her to take a demotion and a pay cut. “It was certainly not ‘warp speed’,” she says. Karikó hopes to funnel some of the prize money back into research into future mRNA vaccines and therapies, for instance, for tackling cancer. “I am happy to be one of the people who has contributed to this [vaccine], but it is mind-boggling how many advances needed to be made over the decades, in many fields,” says Karikó. “My respect goes to the hundreds of people involved.”

Shankar Balasubramanian and David Klenerman at the University of Cambridge, UK, and Pascal Mayer at the research firm Alphanosos in Riom, France, share a prize for inventing a technique in the mid-2000s that allows billions of DNA fragments to be imaged and read in parallel, speeding up sequencing by 10 million times. “I was shocked, and deeply honoured that we won,” says Balasubramanian.

He recalls his excitement in the 1990s about the human genome project, which relied on Sanger sequencing — the original gene-sequencing method — to sequence one DNA fragment at a time. But he soon realized that gene sequencing needed a “mammoth transformation to scale it up and make it faster and cheaper for health-care benefits”.

Krishnan likens the leap from Sanger sequencing to next-generation sequencing to the jump from the Wright brothers’ aeroplane to a Boeing aircraft. She notes that fast and efficient sequencing is also essential to genetic medicine and to foundational advances in illuminating protein structure and dynamics, in CRISPR gene-editing technologies and in RNA biology.

A third life-sciences prize was awarded to the chemical biologist Jeffery Kelly at Scripps Research in La Jolla, California, for working out the part that protein misfolding plays amyloidosis, a disease that can affect organs including the heart and can cause neurodegeneration — and for developing an effective treatment for them.

Perfect timing

The Breakthrough Prize in Fundamental Physics is shared by the optical physicists Hidetoshi Katori at the University of Tokyo, and Jun Ye at the US National Institute of Standards and Technology in Boulder, Colorado, for inventing the optical lattice clock — a device that would lose less than one second over 15 billion years2,3, improving the precision of time measurements by 10,000 times.

The award is “richly deserved”, says Helen Margolis, an optical physicist at the National Physical Laboratory in Teddington, UK.

Previous state-of-the-art caesium clocks are based on measuring microwaves emitted as the atoms transition between two energy states — a process triggered by dropping clouds of atoms and bombarding them with microwaves. Optical lattice clocks instead strike strontium atoms with optical light and measure emitted optical light, which has a frequency that is 100,000 times higher than that of microwaves. “This means you can measure faster ticks,” says Ye.

The clocks also use lasers to hold thousands of atoms still, in a lattice structure, for even greater accuracy — but this raises a new challenge. “The very act of trapping the atom can perturb it,” Ye says. Each energy state is usually distorted by a different amount. A key trick involved finding two energy states that happen to be disturbed by the same amount, so that when the difference between them is measured, this distortion cancels out.

Thanks to their increased accuracy and stability, “optical lattice clocks can be used to probe effects never seen before”, Margolis says. In 2020, Katori and colleagues reported work using two clocks, one placed at the foot of Tokyo’s Skytree tower and one 450 metres above it, at the top of the tower, to conduct the most precise ground-based test yet of the general theory of relativity4. Meanwhile Ye’s team is searching for the effect of the presence of one particular candidate for dark matter — the mysterious substance thought to make up the bulk of the Universe’s matter — on the ticks of an optical clock5. Such clocks could also help to improve the early detection of seismic and volcanic activity, and precision measurements of sea-level rise.

The Breakthrough Prize in Mathematics went to Takuro Mochizuki at Kyoto University in Japan, for extending the understanding of algebraic structures called ‘holonomic D-modules’ — which are related to certain types of differential equation — to deal with points at which the equations under study are not well defined.

Yuri Milner, a Russian Israeli billionaire, founded the Breakthrough prizes in 2012. They are now sponsored by Milner and other Internet entrepreneurs, including Facebook chief executive Mark Zuckerberg.