Computational protein design and protein structure prediction have earned three scientists the 2024 Nobel Prize in Chemistry.
David Baker, a Howard Hughes Medical Institute (HHMI) Investigator at the University of Washington School of Medicine, and Demis Hassabis and John M. Jumper of Google DeepMind were announced as this year’s recipients by the Royal Swedish Academy of Sciences today.
Building new proteins has been a dream of scientists, said Heiner Linke, Chair of the Nobel Committee in Chemistry, at a press conference earlier today. “This is the problem that David Baker solved. He developed computational tools that now enable scientists to design spectacular new proteins with entirely novel shapes and functions, opening endless possibilities for the greatest benefit to humankind.”
"David Baker’s revolutionary work in protein design has already opened the door to a vast number of new discoveries and medical therapies,” said HHMI President Erin O’Shea. “He is an exemplary scientist, leader, and mentor who is demonstrating the power of basic scientific discoveries to make our world better.”
Designing from scratch
A protein’s folded, 3D shape is dictated by how its atoms either attract or repel each other and the water molecules that surround them. Even in a small protein, trillions of potential interactions create an unlimited number of possible shapes. But evolution has only tapped into a very small percentage of these protein-folding patterns. To design a wide range of new proteins from scratch, David Baker and his group are investigating the rules that govern protein folding.
Baker’s interest in protein folding began when he was a senior at Harvard University. “We had to write a term paper on something to do with biochemistry, and I asked the professors if I could look at protein folding. They discouraged me, saying ‘no one really knows how it works.’” Baker left the question alone, but it continued to nag at him. He finally revisited the topic after starting his own research lab at the University of Washington.
To tackle the protein structure prediction problem, Baker and coworkers created a program called Rosetta in 1998. The program, now used by researchers globally, can predict the structures of small proteins from their amino acid sequences. But because the calculations needed to predict proteins are extremely time intensive, Baker developed a version of Rosetta in 2004 that anyone could load on their home computer to help perform some of the algorithm’s calculations. By early 2008, nearly 200,000 volunteers had downloaded and installed Rosetta@home. And, after some of the volunteers expressed their desire to help guide the folding of proteins on their computer screens, Baker developed and released Foldit, a multiplayer online protein-folding game.
“The dream is that people working together all around the world can make a significant contribution to science and global health,” said Baker. Rosetta@home volunteers and Foldit players continue to make a number of invaluable contributions to Baker’s research projects.
Over time, Baker’s focus has shifted from computing the structures of naturally occurring proteins to designing and building proteins from scratch. “It’s not such a leap to start thinking about making new amino acid sequences that encode new structures,” he explains.
The process, called de novo protein design, allows Baker and his team to create new proteins with sequences that are unlike anything seen in nature. So far, they have designed proteins that protect animals against the flu, catalyze chemical reactions, sense small molecules, and assemble into new materials. Further, Baker and his lab contributed to the development of the world’s first computationally designed protein medicine, a vaccine for COVID-19 pioneered by colleagues at UW Medicine, according to a press release from the institution.
"David Baker is a force of nature. His work on computational protein design has transformed our understanding of our world in ways that promise to improve the lives of countless people,” said HHMI Chief Scientific Officer Leslie Vosshall. “David’s curiosity, passion, and persistence have made him a vital part of our HHMI Investigator community, and we congratulate him and the many students and postdocs who contributed to this work on this honor.”
Baker reasons that while naturally occurring proteins elegantly solve the problems that arose during evolution, modern-day challenges require new proteins with new functions. His goal: to develop a whole new world of synthetic proteins to address such issues in medicine, energy, and technology.
“My philosophy is, if you’re going to tackle a problem, you should really go all out,” he says. “Most interesting problems aren’t going to be solved if you go at them halfheartedly.”
Baker has been an HHMI Investigator since 2000. He is an elected member of the National Academy of Sciences and a recipient of numerous awards, including the 2021 Breakthrough Prize in Life Sciences, the 2022 Wiley Prize in Biomedical Sciences, and the BBVA Foundation’s 2023 Frontiers of Knowledge Award in Biomedicine, which he received alongside Hassabis and Jumper. Earlier this year, Baker was also named among TIME’s 100 Most Influential People in Health.
Baker is now one of 35 current or former HHMI scientists who have won the Nobel Prize. Prior to Baker, the most recent HHMI Investigator to receive the Nobel Prize in Chemistry was Carolyn Bertozzi in 2022. Bertozzi was recognized alongside Morten Meldal of the University of Copenhagen and K. Barry Sharpless of Scripps Research Institute for their work on the development of click chemistry and bioorthogonal chemistry.
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