Trainee Paper Spotlight: Iris Nira Smith

(Photo courtesy: Iris Nira Smith)

Author: Iris Nira Smith, PhD

Postdoctoral Fellow
Genomic Medicine Institute
Lerner Research Institute
Cleveland Clinic

Smith IN, et al. Conformational dynamics and allosteric regulation landscapes of germline PTEN mutations associated with autism compared to those associated with cancer. 2019 American Journal of Human Genetics. May 2;104(5):861-878\

Why do mutations in the same gene sometimes lead to completely different diseases? In this month’s Trainee Paper Spotlight, Iris Nira Smith and colleagues use computational approaches to ask this question for PTEN, a dual-specificity phosphatase in which missense variants can lead to different outcomes such as cancer, autism spectrum disorder (ASD), or sometimes both. They find that variants that tend to lead to one outcome over the other had distinctly different predicted effects on the structure of the PTEN protein, which in turn altered the way PTEN interacted with other proteins in the ASD or cancer “interactomes,” or the network of interacting proteins associated with each disease. These results have implications for the design of drug therapies targeting PTEN for each outcome, as the variants leading to one disease versus the other have distinct effects on the structural communication of the mutant PTEN.

ASHG: Could you describe your research for us?

Dr. Smith: As a computational biophysicist, my research interests have been largely directed towards utilizing computational models to understand the structure-function relationship of biomolecules at the atomistic level, and the predicted molecular mechanism of the dysfunction (i.e. genetic variation) of these biomolecules that lead to disease. The current focus of my research is to investigate the structure-function mechanism of germline PTEN mutations leading to cancer predisposition or to the seemingly disparate autism spectrum disorder (ASD). The integrative approaches I use provide a greater understanding of the mutational effects of PTEN variants that lead to distinct disease states, and offer rich and diverse opportunities to further guide clinical management, including targeted therapy, for individuals with ASD and cancer.

ASHG: What are your career goals?

Dr. Smith: My long-term career goal is to interrogate the molecular structure-function of biomolecules for therapeutic intervention in human disease. Much effort is underway to develop the infrastructure made by computational biophysicists to support genomics-informed personalized medicine. I aim to be at the interface of this burgeoning intersection to establish a mechanistic linkage between pathogenic variations and their consequences to provide a rational basis for targeted therapeutics and precision care.

ASHG: Why did you choose genetics as your field of study?

Dr. Smith: From a very young age, I was fascinated by the human body and how it worked. In fact, one of my favorite Christmas gifts at the age of 8 was the book, Grey’s Anatomy. Yet it wasn’t until I was personally affected by the enigmatic disease — endometriosis — that my interest in understanding disease piqued and I began my research career in computational biophysics. A serendipitous encounter with my current mentor Dr. Charis Eng brought me to the Cleveland Clinic, where I have had the opportunity to answer genetics-based questions I had early in my career as a computational biophysicist. 

ASHG: If you could pick three words that describe yourself, what would they be?

Dr. Smith: Inquisitive, Compassionate, Driven

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