Ruth Nussinov, Ph.D. says her election as a 2020 American Physical Society fellow is an especially gratifying recognition and for a very basic reason: “I am not a physicist.”
But her contribution to the field of biophysics and “extraordinary advancements in scientific understanding” led the APS’s Division of Biological Physics to nominate Nussinov as a society fellow. Nussinov credits her husband, physicist Shmuel Nussinov, “whose great help with our three children after my eight-year break allowed me to embark on such an engaging scientific career.”
Curiosity and passion propel Nussinov to continually apply her expertise to new scientific problems. “I do what I do simply because I love it,” said Nussinov, a senior investigator at the Frederick National Laboratory for Cancer Research and now a part of the National Cancer Institute’s RAS Initiative headquartered at the Frederick National Laboratory (FNL).
A computational structural biologist, Nussinov has always been captivated by seemingly puzzling biological questions that could be elucidated by biophysics. She proposed the concept of “conformational selection and population shift” as an alternative to the classical “induced fit” model. This paradigm underlies binding processes and is now broadly accepted by the community.
She’s also been called a pioneer of DNA sequence analysis and was among the first to model amyloid conformations in Alzheimer’s disease. She is also a trusted expert on the study of repurposing drugs to treat emerging and challenging diseases and on the landscape of drugging active versus inactive molecules.
Professional passion lightens personal pain
The deep sense of satisfaction she finds in her work helped her cope with the death of her 49-year-old daughter, Dr. Orna Nitzan. An infectious disease specialist at an Israeli hospital, Dr. Nitzan died of cancer in September.
“When times are difficult, work helps hugely,” Nussinov said. “I am thrilled by my work and find it enormously challenging. If I did not have the work, it would have been much more difficult for me.”
Her latest effort seeks to solve the 30-year challenge of blocking RAS, the protein responsible for about a third of all human cancers including a high percentage of pancreatic, lung and colorectal cancers. Nussinov ’s previous work on protein-protein interactions and her biophysics outlook bring a pertinent perspective to the study of RAS and distinguishes her in the field.
“Dr. Nussinov has been a leader in theoretical approaches to the study of binding interactions of proteins,” said Jane Dyson, Ph.D., a professor integrative structural computational biology at the Scripps Research Institute in California. “Her insightful contributions have been very influential in the understanding of the thermodynamic underpinnings of allostery.”
Nussinov and her FNL colleagues are focused on the RAS protein and its interactions with effectors that communicate the signals of RAS and which drive and sustain malignant transformation and tumor growth. Among their works, they described how calmodulin interacts with KRAS and how this interaction can promote KRAS-driven cancers. These mechanistic insights are critical to developing better cancer drugs, and this work was recognized in the “Best of the AACR Journals Collection 2015.”
Building a foundation, right from the start
Beginning with her 1978 Ph.D. thesis, Nussinov has published seminal concepts that remain foundational to the field today. The “Nussinov algorithm” predicts the secondary structure of RNA and is taught in bioinformatics classes in universities across the United States and Europe.
Her question, “Is allostery an intrinsic property of all dynamic proteins?” and assertion that this is the case (1999, 2004) also made it into textbooks. Allostery is a change in the functional site that can result from a structural perturbation, or agitation, away from it.
The “Ma-Nussinov model” of Alzheimer’s ß amyloid, published in 2002, uses computational tools to provide insight into amyloid structures and aggregation mechanisms. The conformation and mechanism that they proposed were subsequently verified by solid state nuclear magnetic resonance studies.
“Election as a fellow of the American Physical Society is a milestone professional achievement,” said Ethan Dmitrovsky, M.D., FNL director. “Given Dr. Nussinov’s seminal contributions to the structure and function of biomacromolecules like RNA, this is a fitting and well-deserved recognition.”