CRISPR 2.0: The Scientist With Your Genetic Life in His Hands
WHY YOU SHOULD CARE
Using new gene-editing technology, David Liu is on his way to treating, and possibly eradicating, thousands of diseases.
Adam Zwan is one of just 18 people in the United States battling a rare genetic disease called Wolfram syndrome, which causes childhood diabetes and hearing and vision loss. The average life expectancy for sufferers is 30 to 40 years, and Zwan is 30. Growing up, he took nine different prescription medications but has managed, through diet and exercise, to bring that number down to three. Still, there is no known cure for Wolfram syndrome.
Enter David Liu, a chemistry and chemical biology professor at Harvard and senior associate member of the Broad Institute of Harvard and MIT. Liu has developed a new class of DNA base editors that can switch a single letter of DNA with another, opening the door to treatments, and possibly cures, for thousands of genetic diseases caused by one small “typo” in DNA. Think of it as CRISPR 2.0, a new iteration of the powerful gene-editing tool that could alter the genomic structure of mutations associated with diseases like sickle cell anemia, hemophilia, genetic blindness and more. Years of research are needed before any kind of drug therapy could reach the market, but Harvard has granted a worldwide license to Beam Therapeutics Inc., co-founded by Liu, to develop and commercialize a suite of DNA base editing technologies for treating human disease.
I was very interested in harnessing evolution to solve interesting problems.
As a kid in Riverside, California, Liu, now 45, was already into science. He insists his physics professor mother and aerospace engineer dad would’ve been happy with any career he chose, “as long as it wasn’t illegal.” Liu picked chemistry because he was fascinated by how individual molecules behave. “I wanted to understand this natural phenomenon in detail,” he says.
Harvard has long been Liu’s academic home. As a freshman there in 1990, he joined E.J. Corey’s lab after meeting him in Stockholm, where the organic chemist was awarded the Nobel Prize for his work in retrosynthetic analysis. “David is an incredibly bright individual with a love of discovery and scientific adventure,” Corey says.
“Incredibly bright” is an understatement: Liu graduated first in his class at Harvard and, according to Corey, his final thesis was perfect. “There’s not a single thing I would’ve changed.”
Liu swapped coasts to begin a Ph.D. at the University of California, Berkeley, where he worked with chemist Peter Schultz, celebrated for his work synthesizing new molecules for desired functions and, in particular, efforts to expand the genetic code in living cells. When Liu was midway through his graduate degree, Corey invited him back to Harvard to deliver a seminar on his research. Corey’s colleagues were so impressed with Liu that he was offered a full-time faculty position — at age 26. “That’s almost unheard of,” Corey says. He finished his Ph.D. at Berkeley in June 1999 and started as an assistant professor at Harvard a few weeks later.
Liu’s graduate work on the expansion of the genetic code led him to pioneer DNA-templated synthesis, now called DNA-encoded libraries, which involves affixing DNA strands with small molecules to create numerous combinations of new molecules. “I was very interested in harnessing evolution to solve interesting problems,” he says. Liu eventually started his own lab at Harvard to integrate chemistry and evolution and to develop new forms of human therapeutics.
Alexis Komor, assistant professor of chemistry and biochemistry at the University of California, San Diego, helped develop the CRISPR base editing tool as a student in Liu’s lab in 2017. She says he showed a lot of faith in her. “I don’t think he knew how little of a biology background I had,“ Komor says. Liu worked with her to develop a project, rather than simply assigning one, and the experience shaped how Komor runs her own lab at UCSD, where they focus on studying DNA damage and repair. “I work with the students to develop projects so they have ownership,” she says.
So far, much of Liu’s research has remained in the lab where he’s made considerable advancements with his base editor in animal studies. “Our lab has corrected the mutation that causes rapid aging disease in mice,” he says. Humans, however, are a more fickle beast. To bring this technology to clinical trials is a complicated, multistep process and, adds Liu, the biology must be “bulletproof.” Once it’s been proven both safe and effective in humans, you still have to apply to the FDA, a hurdle that can take years to clear.
But Liu’s getting a lot closer with the help of four biotech startups he’s launched (he’s founded six in total but two are no longer active). Editas Medicine is focused on developing therapies for genetic diseases, and Pairwise Plants is using Liu’s base editor to genetically modify fruits and vegetables with financial backing from Monsanto. Somewhat surprisingly, Liu says he’s yet to receive pushback for taking money from the controversial agrochemicals corporation.
Just last month, Editas received FDA approval to test a new drug application designed to treat the leading cause of childhood blindness. If the clinical trials happen as planned, it will be one of the first times CRISPR has been administered as medicine inside the body of a human patient. Still, the trials require “broad expertise and hundreds of millions of dollars,” Liu says.
Beyond the staggering sums of money, time and resources needed to bring any CRISPR therapy to market, there’s the issue of access. “These procedures will likely remain extremely expensive for years to come,” says Ross Wilson, an investigator at the Innovative Genomics Institute in Berkeley, who worries insurers won’t cover the cost until the price comes down.
Liu agrees on the need for broader access and he’s confident that CRISPR therapies will drop in price over time. “I would be very disappointed if pricing were a major limitation to patient benefit from therapeutics that developed from our work, and I’m pretty sure most therapeutics companies would share my disappointment,” he says. For now, though, ensuring the safety and efficacy of the treatment is his top priority.
It’s a priority you’d think wouldn’t allow for much downtime, but Liu enjoys a number of hobbies, from woodturning and photography to playing video games and watching reality television — the talent competition variety, he clarifies, “not the ones where the whole point is personal drama.”
One hobby he’s had to let go of due to lack of time is gambling. In the early 2000s, Liu trained a group of Harvard undergrads to count cards with astonishing accuracy, earning them six-figure winnings at Las Vegas blackjack tables. “It was a great use of applied math,” Liu says with the hint of a smile.
For now, Liu will stick to using his math skills in the lab, where the payoff could be even bigger.
OZY’s 5 Questions With David Liu
- What’s the last book you read? Born a Crime, by Trevor Noah.
- What do you worry about? That humans seemed to have evolved to make hasty, black-and-white judgments, but making good decisions usually requires a more nuanced consideration of all the shades of gray.
- What’s the one thing you can’t live without? This rectangle of glass and metal I’m tapping now.
- Who’s your hero? Whoever invented beef jerky. Especially the spicy kind.
- What’s one item on your bucket list? Cure a genetic disease.
Read more: This scientist turned CEO wants to gene edit a way to cure cancer.