Engineering the central dogma using chemical and synthetic biology
Biological engineers routinely harness the predictability of the central dogma to modify living organisms. However, this rule cannot be easily extended to manipulations of integrated signaling networks such as central dogma, as even minor perturbations can have significant and often deleterious consequences on cellular viability. Our lab is developing and applying methodologies to study the most central biomolecular machines in living systems. We aim to understand their molecular capabilities, and to extend these capabilities to new-to-nature bioactivities.
We combine principles of chemical biology, bioengineering, directed evolution, genome editing and synthetic biology to (re)engineer highly integrated cellular signaling networks towards researcher-defined function. Our research interests are broad and are focused on addressing issues of immediate global impact, namely antimicrobial development, biologics production, information maintenance and transmission, and climate change.
Our work is currently supported by the Scripps Research Institute, NIH Director’s Early Independence Award, NASA, DTRA, and NIBIB.
Ahmed H. Badran, Ph.D.
Ahmed H. Badran is an Assistant Professor in the Department of Chemistry at The Scripps Research Institute. His works aims to probe and engineer the most fundamental biomolecules and genetic circuits in living cells, and to develop next generation solutions to long-standing global issues in healthcare and climate change.
Dr. Badran earned his B.Sc. in Biochemistry & Molecular Biophysics, as well as Molecular & Cellular Biology, from the University of Arizona. Subsequently, he earned his Ph.D. in Chemical Biology from Harvard University under the guidance of Prof. David R. Liu, leading the development and application of rapid methods for continuous directed evolution. He later became Fellow of the Broad Institute of MIT and Harvard, he developed new technologies to reprogram protein translation. Badran has earned several distinctions for his undergraduate and graduate research, including the Arnold and Mabel Beckman Scholarship, the National Science Foundation Graduate Research Fellowship, the Harvard Graduate School of Arts and Sciences Merit Fellowship, and the National Institutes of Health Director’s Early Independence Award.
Broad-spectrum antibiotics enable physicians to treat diverse infections without identifying the causative bacterium. Yet broad-spectrum inhibition, alongside poor antibiotics stewardship, incentivize the development of resistance to our dwindling arsenal and can have significant consequences on patient microbiomes. We’re actively developing ‘targeted’ ribosomal antibiotics that co-opt species-specific liabilities to act against a single microbe, which may be used to affect invading pathogens or to edit the composition of patient microbiomes.
Recombinant protein production can be limited by polypeptide length, amino acid composition, mRNA secondary structure and ribosome fidelity. Using principles of chemical and synthetic biology, we are exploring the factors that may contribute to balancing translational fidelity and processivity in vivo. These efforts have yielded ribosomes with radically altered translation capabilities, most notably in improving protein biologics production.
Information Maintenance & Transmission
Cellular nucleic acids encode information that can be translated into proteins, which in turn catalyze numerous catalytic processes inside living cells. However, the complexity of this information remains limited by the chemical diversity of the nucleic acid and protein building blocks. We are exploring new technologies that can encode, decode and transmit information using chemically diversified building blocks or completely bioorthogonal counterparts. These technologies may enable access to new-to-nature functions and activities.
Greenhouse Gas Fixation
The Earth’s climate has significantly been altered by the continued atmospheric release of carbon dioxide and other greenhouse gases.In addition to emissions regulation and development of carbon-neutral technologies, rapidly deployable methods are critically needed to reduce the existing atmospheric deposits of these greenhouse gases. We are designing new molecular approaches to efficiently fix atmospheric gases into cellular metabolism, spearheaded by the archetypal enzyme Ribulose-1,5-bisphosphate carboxylase-oxygenase, commonly known as RuBisCO.
Natural and Engineered Precision Antibiotics in the Context of Resistance
Johnston, CW, Badran AH.
Current Opinion in Chemical Biology 2022 PDF
Multiplex Suppression of Quadruplet Codons via tRNA Directed Evolution
DeBenedictis E*, Carver GD*, Chung C, Söll D, Badran AH.
Nature Communications 2021 PDF / SI
Highlighted at The Scripps Research Institute and Phys.Org.
Continuous Directed Evolution of Ribosomal RNAs for Enhanced Activity In Vivo
Liu F*, Bratulic S*, Costello A*, Miettinen TP, Badran AH.
Nature Communications 2021 PDF / SI
Highlighted at The Scripps Research Institute.
Bacterial translation machinery for deliberate mistranslation of the genetic code
Vargas-Rodrigueza O, Badran AH, Hoffman KS, Chen M, Crnkovića A, Ding Y, Krieger JR, Westhof E, Söll D, Melnikova S.
Proceedings of the National Academy of Sciences USA 2021 PDF / SI
Clinically relevant mutations in core metabolic genes confer antibiotic resistance
Lopatkin AJ, Bening SC, Manson AL, Stokes JM, Kohanski MA, Badran AH, Earl AM, Cheney NJ, Yang JH, Collins JJ.
Science 2021 PDF / SI
Orthogonal Translation Enables Heterologous Ribosome Engineering in E. coli
Kolber N, Fattal R, Bratulic S, Carver GD, Badran AH.
Nature Communications 2021 PDF / SI
Highlighted at the Broad Institute, Phys.org, and Chemical and Engineering News.
Continuous Bioactivity-dependent Evolution of an Antibiotic Biosynthetic Pathway
Johnston C, Badran AH, Collins JJ.
Nature Communications 2020 PDF/ SI
Synthetic Biological Circuits within an Orthogonal Central Dogma
Costello A, Badran AH.
Trends in Biotechnology 2020 PDF
A Deep Learning Approach to Antibiotic Discovery
Stokes J, Yang K, Swanson K, Jin W, Cubillos-Ruiz A, Donghia N, MacNair C, French S, Carfrae L, Bloom-Ackermann Z, Tran V, Chiappino-Pepe A, Badran AH, Andrews I, Chory E, Church G, Brown E, Jaakkola T, Barzilay R, Collins J.
Cell 2020 PDF
Continuous Directed Evolution of Proteins with Improved Soluble Expression
Wang T, Badran AH, Huang TP, Liu DR.
Nature Chemical Biology 2018 PDF / SI
Modern Methods for Laboratory Diversification of Biomolecules
Bratulic S, Badran AH.
Current Opinion in Chemical Biology 2017 PDF
Programmable Base Editing of A•T to G•C in Genomic DNA Without DNA Cleavage
Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR.
Nature 2017 PDF / SI
Editing the Genome Without Double-Stranded DNA Breaks
Komor AC‡, Badran AH‡, Liu DR‡. ‡Corresponding Author
ACS Chemical Biology 2017 PDF
Improved Base Excision Repair Inhibition and Bacteriophage Mu Gam Protein Yields C:G-to-T:A Base Editors with Higher Efficiency and Product Purity
Komor AC, Zhao KT, Packer MS, Gaudelli NM, Waterbury AL, Koblan LW, Kim YB, Badran AH, Liu DR.
Science Advances 2017 PDF / SI
CRISPR-Based Technologies for the Manipulation of Eukaryotic Genomes
Komor AC, Badran AH, Liu DR.
Cell 2017 PDF
Continuous Evolution of Bacillus thuringiensis Toxins Overcomes Insect Resistance
Badran AH, Guzov VM, Huai Q, Kemp MM, Vishwanath P, Kain W, Nance AM, Evdokimov A, Moshiri F, Turner KH, Wang P, Malvar T, Liu DR.
Nature 2016 PDF / SI / SI2
Development of Potent In Vivo Mutagenesis Plasmids with Broad Mutational Spectra
Badran AH, Liu DR.
Nature Communications 2016 PDF / SI
Continuous Directed Evolution of DNA-Binding Domains Generates TALENs with Improved DNA Cleavage Specificity
Hubbard BP, Badran AH, Zuris JA, Guillinger JP, Davis KM, Chen L, Tsai SQ, Joung JK, Liu DR.
Nature Methods 2015 PDF / SI
In Vivo Continuous Directed Evolution
Badran AH, Liu DR.
Current Opinion in Chemical Biology 2015 PDF
A System For the Continuous Directed Evolution of Proteases Rapidly Reveals Drug-Resistance Mutations
Dickinson BC*, Packer MS*, Badran AH, Liu DR.
Nature Communications 2014 PDF / SI
Negative Selection and Stringency Modulation in Phage-Assisted Continuous Evolution
Carlson JC, Badran AH, Guggiana-Nilo DA, Liu DR.
Nature Chemical Biology 2014 PDF / SI
When Tight is Too Tight: Dasatinib and Its Lower Affinity Analogue for Profiling Kinase inhibitors in a Three-Hybrid Split-Luciferase System
Ogunleye LO, Jester BW, Badran AH, Wang P, Ghosh I.
Medicinal Chemistry Communications 2014 PDF / SI
Evaluating the Global CpG Methylation Status of Native DNA Utilizing a Bipartite Split-Luciferase Sensor
Badran AH, Furman JL, Ma AS, Comi TJ, Porter JR, Ghosh I.
Analytical Chemistry 2011 PDF / SI
Turn-On DNA damage Sensors for the Direct Detection of 8-Oxoguanine and Photoproducts in Native DNA
Furman JL, Mok PW, Badran AH, Ghosh I.
Journal of the American Chemical Society 2011 PDF / SI
Toward A General Approach for RNA-Templated Hierarchical Assembly of Split Proteins
Furman JL, Badran AH, Ajulo O, Porter JR, Stain CI, Segal DJ, Ghosh I.
Journal of the American Chemical Society 2010 PDF / SI
Direct DNA Methylation Profiling Using Methyl Binding Domain Proteins
Yu Y, Blair S, Gillespie D, Jensen R, Myszka D, Badran AH, Ghosh I, Chagovetz A.
Analytical Chemistry 2010 PDF
Systematic Evaluation of Split-Fluorescent Proteins for the Direct Detection of Native and Methylated DNA
Furman JL, Badran AH, Shen SY, Stains CI, Hannallah J, Segal DJ, Ghosh I.
Bioorganic & Medicinal Chemistry Letters 2009 PDF / SI
Department of Chemistry
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037