For the past five years, David Liu – a professor at the Broad Institute of MIT and Harvard, a biomedical research facility in Massachusetts – has marked Thanksgiving by handing over his entire annual salary, after taking care of taxes, to the staff and students in his laboratory.
It started as the pandemic broke and Liu heard that students who wanted to cycle instead of taking public transport could not afford bicycles. Given how hard they worked and how little they were paid, Liu stepped in. He couldn’t unilaterally raise their incomes, so emailed them Amazon eGift cards. This ran into problems too, however. “Everyone thought they were being scammed,” he recalls. And so he switched to writing cheques.
As the co-founder of several companies, Liu can make ends meet without his Harvard salary, and has set up a charitable foundation to further scientific research. Its coffers are due to swell considerably now that Liu has received the $3m Breakthrough prize for life sciences, which he was presented with on Saturday at the annual awards ceremony in Los Angeles.
The Breakthrough prizes, described by their Silicon Valley founders as the Oscars of science, are awarded annually to scientists and mathematicians chosen by committees of previous winners. This year, two further life sciences prizes were given for landmark research on multiple sclerosis and GLP-1 agonists, better known as “skinny jabs”.
Other winners on the night were Dennis Gaitsgory, a mathematician in Bonn, for his work on the Langlands program, an ambitious effort to unify disparate concepts in maths, and more than 13,000 researchers at Cern for testing the modern theory of particle physics.
Liu was chosen for inventing two exceptionally precise gene editing tools, namely base editing and prime editing. Base editing was first used in a patient at Great Ormond Street in London, where it saved the life of a British teenager with leukaemia.
Scientists have worked on gene editing for more than a decade. Progress, they hope, will lead to therapeutics that correct the mutations responsible for thousands of genetic diseases. But the first generation of gene editing tools had limited success: they were good at disabling faulty genes, but not at correcting them.
Base editing allows scientists to make changes to single letters of the genetic code, while prime editing has been compared to the search and replace function in a word processor, giving researchers the power to rewrite whole stretches of DNA. Together, they have enormous potential. “The vast majority of known pathogenic mutations can now be corrected using prime editing or base editing,” Liu says.
Liu grew up in Riverside, California, and traces his interest in science to playing with bugs in his back yard. He went to Harvard and worked with EJ Corey, a Nobel laureate considered one of the greatest chemists of our time. “That was the start of what turned into a lifelong love of experimental molecular science,” Liu says. “He encouraged me to follow my passions and curiosity.”
His curiosity was not confined to chemistry. Liu read that radio-controlled plane enthusiasts wanted a plane that flew slowly enough to pilot around a room. After working the equations, he built the Wisp, a six-gram carbon fibre plane that zoomed around at a leisurely one mile per hour. Another project merged Lego bricks with the heat sensor from a burglar alarm to produce the “mouseapult”, a device that detected cats and lobbed toy mice in their direction.
Video games also featured heavily. In the early 1990s, Liu hung out with Andy Gavin and Jason Rubin, the students behind the games developer Naughty Dog. He tested games and was an occasional voice actor. One performance made it into Way of the Warrior for the 3DO games machine. “I said something like…” he pauses to adopt a mocking tone “…‘my dead grandfather fights better than you’.”
A riskier hobby took root while Liu was in hospital recovering from an operation. He wanted to beat blackjack and wrote a simulator to understand the mathematics. Before long, he had worked out a series of card counting techniques and went to Las Vegas to test them. He did so well that he was banned from all MGM Grand casinos and, to use the gaming euphemism, “back-roomed” twice to be read the Nevada trespass laws.
Later, as a professor at Harvard, a group of students persuaded Liu to run a class on card counting. “The best decision I made about that team was that no members put in their own money and no members took out their own money. It all went back into the fund for us to fly to Las Vegas and pay for our hotel and meals,” he says. “It was all about the fun of learning something really difficult.”
In the lab, Liu was trying to crack a very different problem. Gene editing at the time could disable genes, but not rewrite the letters of the DNA code. But disabling genes would never be enough to treat genetic diseases. “They need to be treated by fixing the gene,” he says.
The first breakthrough came in 2016 when Liu’s team described base editing, a way to correct single-letter mutations that account for nearly a third of genetic diseases. The procedure used Crispr guide molecules to find the faulty code and an enzyme to change the aberrant letter. Waseem Qasim, a paediatric immunologist at Great Ormond Street hospital, remembers reading the paper over breakfast the day after it was published. “My kids were relatively small at the time. I spat on my cornflakes and said, look at this, guys, science fiction!”
A follow-up paper in 2019 described prime editing, a less efficient but more powerful technique that in principle can repair nearly all disease-causing mutations.
The benefits of base editing became clear in 2022 when Qasim’s team became the first in the world to use the procedure on a patient. Alyssa Tapley, a 13-year-old from Leicester, had run out of options after chemotherapy and a bone marrow transplant had failed to treat her leukaemia. The cancer affected her T-cells, a group of immune cells that normally fight infections.
The doctors collected T-cells from a healthy donor and modified the genetic code so that when infused into Alyssa they would seek out and attack her cancer cells. The treatment worked: more than two years later, Alyssa remains in complete remission.
More than a dozen clinical trials are now under way to test base editing and prime editing. Positive results have already been reported for leukaemia, sickle-cell disease, beta-thallasaemia and high cholesterol. But major hurdles remain. While Alyssa’s treatment involved editing cells outside the body and sending them in, most diseases require mutations to be fixed inside the patient. This is a trick scientists have yet to crack.
It’s not the only problem. Qasim’s team is treating more patients in a trial, but when the trial ends, there may be no one to fund future treatments. “We are going to end up with treatments that work, but that nobody wants to pay for.”
Liu is optimistic that researchers can find ways to deliver the therapies and reduce the costs, but he has grave concerns about the future of science, particularly in the US. He believes the recent wave of firings and funding cuts pose an existential threat to the next decade or two of progress that will have ramifications around the world.
“To me, slashing funding and people from science in the United States is like burning your seed corn. It’s not even eating your seed corn. It’s just destroying it,” he says. “What can be more human than wanting to use all of our knowledge, all of our effort, all of our resources, to try to make the lives of our kids safer and better than our own lives? A huge part of that aspiration requires, and is indeed driven by, science.”
