The Noyes Lab recently moved to the University of Pittsburgh School of Medicine after years at both Princeton University and the NYU School of Medicine. We are interested in how proteins interact with their targets from structural, computational and cell biology perspectives. We use this information to model proteins so that we can better predict natural protein function AND to design proteins with novel functions. These new proteins allow us to create therapies to treat human disease with a primary focus on neurobiology. Together, our goals involve developing new tools to sample interactions as comprehensively as possible so that we can model and design therapies with the greatest accuracy and potency. Our research could be classified as Systems an Synthetic Biology but we hope not to lose sight of the Cell Biology that this is all predicated upon.
Here are some potential lab projects:
Zinc fingers (ZFs) are the most common DNA-binding domain in metazoans and we loosely understand how they interact with DNA, but how do they interact with each other? Our first attempt to investigate how adjacent ZF domains influence one another led to the first AI-model of ZF design. However, this model was based on screens of just 5% of possible target compatibilities. In addition, the great majority of what we know about ZF is based on the Egr1 scaffold. Would other scaffolds have better affinity of specificity profiles?
Artificial transcription factors (ATFs) can be used as safe therapeutics if the can be delivered efficiently and avoid harmful immunogenicity risks. Zinc finger-based ATFs can be made with protein components that come exclusively from human proteins and small enough where several ZF-ATFs could fit in one AAV. As many neurodegenerative diseases are influenced by the expression of several genes, a multiplexed therapeutic that could influence sets of genes with multiple ATFs could provide a robust platform for ALS, Parkinsons, and Alzheimers diseases. This project will develop and apply combinations of ATFs designed to regulate up to 20 of the most common neurodegeneration contributors.
Most transcription factors bind short (6-10bp) and degenerate target sequences. This makes sense as an activated transcription factor needs to take a signal (its own stimulation) and amplify it by then regulating many targets. Therefore, it is advantageous for a transcription factor to bind many positions in the genome not few. This could also be applied when engineering networks with synthetic transcription factors. By using short zinger designs comprehensively, we can build synthetic networks to control cellular function. The first two proofs of concept: we will create synthetic versions of the yamanaka factors. We will create a synthetic program from neuron differentiation.
We have many disease-specific projects that focus the development of ATFs on a critical gene target. These include Huntington’s disease, Lupus, Amyotrophic Lateral Sclerosis (ALS), X-linked dystonia-parkinsonism (XDP, Dravet Syndrome and Angelman Syndrome.
Bio, Marcus Noyes PhD
Dr Evil in his old office...waiting for his new office at Pitt!
Dr. Marcus Noyes joined the Department of Computational and Systems Biology at the Pitt School of Medicine in the fall of 2025 after previously running labs at Princeton University and the NYU School of Medicine. His research rests on the edge of Systems and Synthetic Biology, focusing on the development of tools that allow us to understand the binding potential of common protein domains important for biological functions. Using comprehensive, large, synthetic screens of these protein domains, the goal of his research is to understand the complete functional capacity of a protein and not be limited by the sometimes small set of functions that have evolved. This approach has the added benefit of producing new proteins with novel functions that can be applied to therapeutic applications.