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The complex inner workings of cells, from their architecture to their signaling, underlie much of multicellular organic life. How are they built? How do their proteins interact? And most crucially, how can understanding these functions improve our knowledge of biological outcomes such as disease?

CU Boulder Distinguished Professors Karolin Luger and Natalie Ahn have studied questions such as these for decades. Last year, both were elected to the听, one of the most prestigious honors a scientist can receive. The duo will be formally inducted on Saturday, April 27, at the organization鈥檚 annual meeting.

鈥淚t鈥檚 a high honor because it comes from peers,鈥澨齭aid Luger, the endowed chair of CU Boulder鈥檚听Department of Biochemistry听and a听听Investigator. 鈥淚t鈥檚 primarily a听wonderful acknowledgement of the collective work of all the former and present students, post-docs and technicians who have contributed to this research.鈥�

Like an archeologist piecing together the origins of ancient structures, Luger and her students examine the fundamental building blocks of genomic processes and untangle their cellular machinery.

Luger began her career with an interest in x-ray crystallography, a technique used to discern 3D molecular structures. Eventually, her focus shifted to chromatin, the material that holds DNA, RNA and proteins together in a compact package within eukaryotic cells. As recently as the late 1980s, before the advent of the Human Genome Project, chromatin was thought to be unimportant, similar to packaging material that only serves to hold more valuable items inside.

鈥淚t was a binary mentality back then, but it turned out to be much messier, with lots of variation between individual cells,鈥� Luger said. 鈥淭he packaging, so to speak, has very important implications for how cell types differentiate.鈥�

Imagine a space filled with labeled cardboard boxes full of books, she says. By reading the labels on the boxes, humans can discern which boxes they鈥檒l need soon and which ones they can safely stash away. Chromatin operates similarly: A fertilized egg cell needs everything鈥攁ll the genomic information it can get鈥攚hereas a more mature cell, such as a liver cell, can read the packaging and know what it can safely ignore.

Early advances in electron microscopy revealed chromatin鈥檚 elegant structure, which appears as 鈥渂eads on a string,鈥� dotted with nucleosomes. Luger went on to determine the structure of nucleosomes at near-atomic resolution, revealing the structure of DNA in all multicellular organisms

More recently, Luger has been examining how and why many multicellular organisms鈥攈umans, yeast, trees鈥攁ll fold their DNA using the same molecular mechanisms. In 2017, her lab and collaborators听identified the microbes Archaea听(which predate multicellular organisms by 3 billion years)听as the likely 鈥榠nventors鈥� of genome folding and nucleosome structure that we still observe today.

鈥淚鈥檓 always interested in how these structures came about,鈥� she said of the evolutionary discovery. 鈥淚t鈥檚 a lot of work to bend DNA, and Archaea had developed a nifty system to do this, which was then appropriated and further refined by the first eukaryotic organisms.鈥�

Luger credits her students and post-doctoral researchers for their painstaking work on these research topics, adding that she deliberately recruits from different backgrounds such as physics, cell biology and chemistry in order to cultivate interdisciplinary problem-solving.

鈥淪tudents come in with new ideas for everything and help me view a scientific problem from all angles,鈥� she said. 鈥淵ou have to let yourself be challenged.鈥澨�

Ahn arrived at CU Boulder over 25 years ago, bringing expertise in the field known as signal transduction, which involves enzymatic processes that allow cells to respond to external signals.听听Ahn was the first to describe the enzyme known as mitogen-activated protein kinase kinase (MAP2K), now known to be a crucial activation point in some types of cancer, particularly melanoma. Upon arriving at CU Boulder, she and her new lab proved that aberrant activation of MAP2K causes cancer, making this enzyme a viable target for therapeutic intervention.听听

The ubiquity of MAP2K in all cells鈥攈ealthy and diseased alike鈥攍ed to initial skepticism that it could be a useful drug target, Ahn said, but several cancer-inhibiting treatments focusing on MAP2K have subsequently been approved by the FDA for clinical use.

鈥淢any thought these would never become drug targets because there might be too many side effects,鈥� Ahn said. 鈥淏ut it turned out that, remarkably, the drugs are actually very well tolerated, even more so than chemotherapy.鈥�

Ahn was also a pioneer in the field of proteomics, which determines the chemistry of proteins by 鈥渨eighing鈥� molecules using a technology called mass spectrometry.听听She was an early investigator to adopt proteomics technologies, and use them to study signal transduction.听听Proteomics is now widely applied in all aspects of biosciences.

For Ahn, her election to the NAS came as a pleasant surprise, the culmination of a long career in basic research that has yielded promising avenues for clinical discoveries.

鈥淚 can鈥檛 quite believe it, but I鈥檓 grateful and lucky enough to have really great scientists as colleagues,鈥� Ahn said. 鈥淭he university gave me the space to be creative in my research.鈥�

The dual NAS recognition also speaks to the cumulative strength of CU Boulder鈥檚 biochemistry discipline, which recently became a stand-alone academic department in the College of Arts and Sciences.

鈥淎braham Lincoln founded the National Academy of Sciences to give trustworthy scientific advice to the President,鈥� said Distinguished Professor Thomas Cech, CU Boulder鈥檚 first Nobel laureate and the director of the听BioFrontiers Institute. 鈥淏eing elected to the NAS is a rare honor, and in a typical year zero or one scientist might be elected from the entire state of Colorado. So for a single department to have two of its faculty elected in the same year is therefore rare and it鈥檚 worthy of celebration!鈥�

鈥淭his is an amazing department with a strong teaching mission,鈥� Luger said. 鈥淲e always have undergraduates participating in the labs who bring a lot of excitement and energy. There is tremendous opportunity here.鈥�