Engineering the central dogma using chemical and synthetic biology

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WELCOME

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.

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LAB NEWS

The Badran Lab has moved to Scripps Research in La Jolla, California! 

Interested in antibiotics development, genetic code expansion and/or improving carbon fixation? We’re actively recruiting on all fronts!

January 2021 – Article published at Nature Communications

Orthogonal Translation Enables Heterologous Ribosome Engineering in E. coli has been published in Nature Communications. A feature article published by the Broad Institute can be found here. Congrats to the whole team!

December 2020 – Alan’s artwork is featured on the cover of Trends in Biotechnology

Alan designed the cover of Trends in Biotechnology to complement his review Synthetic Biological Circuits within an Orthogonal Central Dogma. 

January 13, 2020 – Alan joins the Badran Lab

Dr. Alan Costello has joined the Badran Lab after working at the National Institute for Cellular Biotechnology in Dublin, Ireland. He will be working on ribosome minimization. Welcome Alan!

MEET OUR TEAM

Ahmed H. Badran, Ph.D.  

Principal Investigator

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. Following that, he was a Principal Investigator and Fellow of the Broad Institute of MIT and Harvard where his lab 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.

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Gavriela Carver
Research Associate I

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Alan Costello
Postdoctoral Associate

Ranan

Ranan Fattal
Research Associate I

Lab Alumni

Name

Role in lab

Current position

Sinisa Bratulic

Postdoctoral Associate I

Biostatistician, Chalmers University of Technology

Erika DeBenedictis

Graduate Student, MIT

Postdoctoral Associate, University of Washington (David Baker)

Natalie Kolber 

Research Associate I

Graduate Student, Stanford University (Xiaojing Gao)

Fan Liu

Postdoctoral Associate I

Consultant, Boston Consulting Group

Rajiv Movva

Undergraduate Researcher

Undergraduate Student, MIT

Stefan Wan

Undergraduate Researcher

Undergraduate Student, MIT

 

OUR RESEARCH
Website targeted antimicrobials1 2

Targeted Antimicrobials

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.

Biologics Production

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.

Website biologics production1
Website information maintenance1

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.

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PUBLICATIONS

Multiplex Suppression of Quadruplet Codons via tRNA Directed Evolution
DeBenedictis E*
, Carver GD*, Chung C, Söll D, Badran AH.
Submitted 2021

Continuous Directed Evolution of Ribosomal RNAs for Enhanced Activity In Vivo
Liu F*
, Bratulic S*, Costello A*, Badran AH.
Submitted 2021

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.
Accepted; Proceedings of the National Academy of Sciences USA 2021

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

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 PDFSI

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 SBadran 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 / SISI2 

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

CONTACT US

Badran Lab
Department of Chemistry
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037

Email: ahbadran@scripps.edu

Administrative Assistant

Mishelle McClanahan-Shinn
mshinn@scripps.edu

JOIN US
We are actively looking for passionate, highly motivated scientists to join our team. Scientists interested in directed evolution, ribosomal biology, antibiotics development and/or the origins of cellular translation are encouraged to apply! Prior training in any fields spanning biology, chemistry, or computational sciences is preferred, but not required.
 
If interested, please email Ahmed at ahbadran@scripps.edu with your CV (including a list of references) and summary of your prior research.
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