Protein and Cellular Engineering

In a nutshell

Making molecular vehicles to track, alter traffic

Think of the thousands of protein molecules active in a cell as varied types of cars and trucks driving along our complex biological highways. Enzymes are like sports cars, accelerating chemical reactions. Membrane transporters are like trucks, moving molecules and energy across borders.

Protein engineers alter these molecules so they carry out new tasks; for example, they might remodel a “police car” enzyme that would normally ticket other proteins for destruction by instead instructing it to affix harmless bumper stickers. These labels let researchers track cellular traffic patterns, detecting problems sooner and determining what works best to fix traffic jams. Or scientists might make an antibody “tow truck” that latches onto a specific enzyme and sets off a siren indicating when that protein is active, then therapeutically “impounding” it if it is part of a disease process.

Like their automotive counterparts, protein engineers also design vehicles from scratch—molecular vehicles—by inserting new blueprints into genetic factories to create models with unique features to treat disease.

Cellular engineers move up the biological design ladder, building communities of related, interacting human cells, also known as tissues, to study how changes in composition and structure at the level of individual cells affect function and health.

Protein engineers alter, design, and synthesize protein molecules for new and specialized uses, both to explore biology and to exploit new therapeutic opportunities.

Their work includes monitoring vital biological processes via enzymes altered to affix affinity labels and proximity tags, or via recombinant antibodies that selectively bind other proteins, disclosing their locations, co-factors and activities. Such engineering could eventually lead to the molecular-level diagnosis of disease, as well as more precise treatment targeting and rapid analysis of therapeutic efficacy.

More fundamentally, the design and systematic modification of model proteins allows scientists to experimentally analyze the factors that drive the folding of these polypeptides into their complex native conformations, as well as how the structures generate functions that underlie health and go awry in disease.

Cellular engineering, as practiced here, programs self-assembling tissues with specific cell-type compositions and three-dimensional structure to study how inter-cellular and tissue-to-cell signaling promote health and how perturbations in those processes give rise to disease.

Department scientists develop and apply an array of protein engineering approaches that include:

  • Rational design: Precisely modifying protein structures to alter their functions as both enzymes and substrates
  • Phage display: Using bacteriophages to generate billions of antibodies with different combinations of amino acids at antigen contact points, then testing for those that selectively bind a target protein
  • De novo design: Using computational algorithms to select amino acid sequences that will fold into protein structures to achieve specific chemical and biological properties such as catalysis, binding, and transmembrane transport

Challenges include

  • Monitoring enzyme activity and disease biomarkers
  • Generating human proteome antibodies via phage display and directed evolution
  • Globally analyzing and dissecting apoptosis
  • Proximity tagging of protein-protein interactions
  • Investigating cellular interactions in tissues
  • Creating fluorescent probes targeting the genome and key bio-pathways
  • De novo design of catalytic and membrane proteins
  • Probing and modulating membrane proteins