Ruth Nussinov

Ruth Nussinov (Hebrew: פרופסורית רותי נוסינוב) is an Israeli-American biologist born in Rehovot who works as a Professor in the Department of Human Genetics, School of Medicine at Tel Aviv University and is the Senior Principal Scientist and Principal Investigator at the National Cancer Institute, National Institutes of Health. Nussinov is also the Editor in Chief of the Current Opinion in Structural Biology and formerly of the journal PLOS Computational Biology.

In 1978, Nussinov proposed the first dynamic programming approach for nucleic acid secondary structure prediction, this method is now known as the Nussinov algorithm.

In the 1990s, she pioneered the concept of dynamic conformational ensembles with distinct conformational states indicators of protein and cell function, and of allosteric drugs actions. She offered that the ability to perform biological function is determined by how stable, or populated, a protein is in its active (ON) conformation. She proposed that free energy landscapes are dynamic, offered that all conformations pre-exist and suggested “conformational selection and population shift” (as an alternative to the “induced fit” text-book model) to explain molecular mechanism of recognition and posited that population shift underlies allosteric regulation. The concept of dynamic energy landscape that she introduced tacitly explains that strong activating mutations in cancer work by shifting the ensemble to spend more time in the active state. In 2000, she extended this pre-existing ensemble model to catalysis, and more recently to oncogenic transformation, contributing to extraordinary advancements in understanding structure and function.

Nussinov has authored about 750 scientific papers with more than 51,000 citations as of 2023 and has given hundreds of invited talks. Most recently, she has pioneered the connection, on the structural and cellular levels, of cancer and neurodevelopmental disorders asking How can same-gene mutations promote both cancer and developmental disorders?.

A personal scientific overview of her biography has been published in 2018 as “Autobiography of Ruth Nussinov”.

Education
Ruth Nussinov received her B.Sc in Microbiology from University of Washington in 1966, her M.Sc in biochemistry from Rutgers University in 1967. After an 8-year break to have 3 children, she went back to school in 1975, and received her Ph.D. in biochemistry from Rutgers University in 1977. Her thesis was titled Secondary structure analysis of nucleic acids.

Career
She was a postdoctoral fellow at the Weizmann Institute (1977-1980) and subsequently a visiting scientist at Berkeley and at Harvard. Nussinov was in the Computer Science Department of Tel Aviv University as a senior lecturer. She took a position in Tel Aviv University Medical School in 1984 as Associate Professor and was promoted to Professor in 1990, where she is now Professor Emeritus.

Her association with the NIH started in 1983, first with the National Institute of Child Health and Human Development and, since 1985, with the National Cancer Institute. Nussinov is a senior principal investigator in the Cancer Innovation Laboratory since 1985. She is also an Adjunct Professor in the Department of Chemistry and Biochemistry at University of Maryland since 2016.

She is the Editor in Chief of the journal Current Opinion in Structural Biology and formerly of PLOS Computational Biology. She also served on the editorial boards of the journals Biophysical Journal, Physical Biology, Proteins, BMC Bioinformatics and the Journal of Biological Chemistry.

Awards & Fellowships

 * Elected Fellow of the Biophysical Society for "extraordinary contributions to advances in computational biology on both nucleic acids and proteins" (2011)
 * Distinguished Ulam Scholar, The Center for Nonlinear Studies (CNLS), Los Alamos National Labs (2012)
 * Elected Fellow of the International Society for Computational Biology (ISCB) (2013)
 * Theodore von Kármán Fellow Award (2015)
 * Special Lifetime Award, The Israeli Society for Bioinformatics and Computational Biology (ISBCB) (2015)
 * Computational Molecular Medicine: A minisymposium dedicated to Ruth Nussinov (2015)
 * KeyLab Award for "outstanding achievements in biomolecular simulations in translational medicine" (2018)
 * ISCB Accomplishments by a Senior Scientist Award (2018)
 * Annual Achievement Award, Frederick National Laboratory for Cancer Research (2020)
 * ACS Fall 2020 meeting “Dynamic ensembles, cell signaling and drug discovery: A symposium in honor of Ruth Nussinov (2020)
 * Elected Fellow of American Physical Society (APS) (2021)
 * Ruth Nussinov Festschrift, American Chemical Society (ACS) (2021)
 * The American Institute for Medical and Biological Engineering (AIMBE) College of Fellows Class of 2021 (Medical and biological engineering elite) (2021)

Scientific accomplishments
In 1978, Nussinov published a dynamic programming algorithm for RNA secondary structure prediction, which has since been the leading method. It has since been taught in bioinformatics and computational biology classes in Europe and the US, it is included in books, and exploited in multiple software packages.

Besides her work on nucleic acid secondary structure prediction, Nussinov is also regarded as a pioneer in DNA sequence analysis for her work in the early 1980s.

In the 1990s Nussinov pioneered the role of dynamic conformational ensembles in function, with distinct conformational states and their propensities indicators of protein and cell phenotype, and of allosteric drugs actions. She proposed that all conformations pre-exist, and the model of “conformational selection and population shift” as an alternative to “induced fit” to explain molecular recognition. The concept that she introduced emphasized that all conformational states preexist, available for a range of ligands to bind, followed by re-equilibration (shift) of the ensemble. It also clarified how allosteric posttranslational modifications can work, and underscored that lipids, ions and water molecules can also act via allostery. She also offered that all dynamic proteins are allosteric, the role of allostery in disease, and how allosteric drugs work at the fundamental level. This paradigm has impacted the scientific community's views and strategies in allosteric drug design, biomolecular engineering, molecular evolution, and cell signaling. In line with Nussinov’s proposition, dynamic population shifts are now broadly recognized as the origin of allostery. It also explains the effects of allosteric, disease-related activating mutations.

The new concepts that her group pioneered have changed the way biophysicists and structural biologists think about protein-ligand interactions and are now included in chemistry/biochemistry courses. The profound significance, and advance was also heralded in Science as innovating on the decades-old concepts, noting that "although textbooks have championed the induced fit mechanism for more than 50 years, data (especially NMR) unequivocally support the powerful paradigm for diverse biological processes". The conformational selection/population shift mechanism is now widely established. As Nussinov and others have shown, the new paradigm helps unravel processes as diverse as signaling, catalysis, gene regulation, and aggregation in amyloid diseases, and recently, the mechanisms of activating mutations in cancer, and addressing the puzzling question of how same-gene mutations can promote both cancer and neurodevelopmental disorders.