University of Colorado Cancer Center member Karolin Luger, PhD, a distinguished professor of biochemistry at CU Boulder, has been awarded the 2023 World Laureates Association (WLA) Prize in Life Science or Medicine.
Luger is joined in the WLA prize by Daniela Rhodes, emeritus group leader at the MRC Laboratory of Molecular Biology at Cambridge University, and Timothy J. Richmond, professor emeritus of crystallography of biological macromolecules at ETH Zurich.
Defining the nucleosome structure
Luger, Richmond, and Rhodes partnered on groundbreaking research published in 1997 that “revealed details of the nucleosome structure that have guided subsequent studies on chromatin-binding proteins, histone-modifying enzymes and nucleosome positioning and remodeling and their control of transcription regulation and DNA replication,” the WLA notes. The three laureates “have left an indelible mark on the history of our understanding of chromosome structure” through their more than two decades of research.
“DNA is mind-boggling in its physical size,” says Luger. “It’s the equivalent of six feet of a very thin thread stuffed into a very tiny compartment. Our discovery was how the genome is organized in three dimensions, at its most fundamental level. It’s been known for a long time that it contains very abundant proteins that form little spools, and the DNA is wrapped around that.”
The work done by the three researchers led to the new field of epigenetics, the study of how cells control gene activity without changing the DNA sequence. Cells need certain genes turned off and on at certain times in order to perform their specific function, but when those genes are mutated, cancers can occur, Luger says.
“We have one project that’s funded by the National Cancer Institute where we look at proteins that specifically interact with these structures,” Luger says. “Because of their role in DNA damage repair, they’re actually drug targets. We’re using our understanding of epigenetics to develop better cancer drugs.”
How PARP inhibitors work
Part of that research involves the role of drugs called PARP inhibitors in treating hereditary breast and ovarian cancers. PARP, or poly-ADP-ribose, works to repair broken DNA in cancers that also have mutations in the BRCA gene. By inhibiting that process, the medications cause the cancer cells to die.
“It acts on certain cancer cells really well, and it doesn’t have a lot of side effects on healthy cells,” Luger says. “This protein also binds to the nucleosomes, it shapes their architecture, and it regulates access to the DNA replication and transcription machinery."
The road to better cancer drugs
Luger and fellow CU Cancer Center member Dan LaBarbera, PhD, have received an AB Nexus award — co-sponsored by the CU Cancer Center — to look more closely at how PARP inhibitors work, and how they might interact with other proteins to more effectively prevent cancer from growing and spreading.
“It’s not really known why some PARP inhibitors are better than others,” Luger says. “We’re trying to understand that, and we have some novel ideas as to why that’s the case. The biggest problem in all cancer therapies is that people develop resistance to the drugs. This research could result in drugs where resistance is slower to develop and where the dosage can be minimized because the medicine is more targeted.”
The World Laureates Association (WLA) Prize is an international science prize established in 2021 that recognizes researchers and technologists worldwide for their contributions to science. It aims to “support global science and technology advancement, address the challenges to humanity, and promote society’s long-term progress,” according to the WLA. Winners in two categories — computer science or mathematics, and life science or medicine — share approximately $1.38 million as part of the award.