Engineering ribosomes for designer bioproduction and antibiotic discovery

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THE BADRAN LAB

Biological engineers routinely harness the predictability of the central dogma to modify living organisms. This rule cannot be generally extended to manipulations of the central dogma itself, as even minor perturbations can have significant and often deleterious consequences on cellular viability. One such case is the ribosome, a colossal multi-component protein factory that functions as the nexus for cellular information and signaling events, integrating nutrient availability with growth dynamics and resource allocation.

Our lab is developing and applying methodologies to study the translation machinery of the cell using engineered orthogonal transcription-translation networks, overcoming challenges associated with ribosomal manipulation in vivo and providing a framework for high-throughput ribosomal interrogation. Our current work is focused on the (1) dissection of putative processivity-fidelity relationships during translation, (2) experimental validation of ribosomal divergence across prokaryotes, (3) prediction of ribosome-small molecule interactions and putative antibiotic resistance mechanisms, and (4) evaluating potential routes for evolution of the modern ribosome.

Our work is supported by the Broad Institute of MIT & Harvard, the NIH Director’s Early Independence Award, and the National Aeronautics and Space Administration.

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LAB NEWS

September 25th, 2018 – Fan receives L’Oreal Fellowship

Dr. Fan Liu has been awarded the L’Oreal USA For Women In Science Fellowship to support her study of antibiotic resistance mechanisms in bacteria. Congrats Fan!

January 14, 2018 – Alina joins the Badran Lab

Dr. Alina Chan joins us from Pamela Silver’s Lab at Harvard Medical School. She will be investigating heterologous ribosome production and antibiotics development. Welcome, Alina!

December 18, 2017 – Erika joins the Badran Lab

Erika DeBenedictis has joined the Badran Lab under the joint supervision of Drs. Bruce Tidor and Kevin Esvelt. Erika will lead efforts to engineer fully orthogonal translation in living cells. Welcome, Erika!

MEET OUR TEAM

Ahmed H. Badran, Ph.D.  

Principal Investigator

Ahmed H. Badran is a Principal Investigator and Fellow of the Broad Institute of MIT & Harvard. 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. 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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Sinisa Bratulic
Postdoctoral Associate I

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Alina Chan
HFSP Postdoctoral Fellow

erika

Erika DeBenedictis
Graduate Student

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Meredith Fedorov
Administrative Assistant

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Natalie Kolber
Research Associate I

Fan

Fan Liu
Postdoctoral Associate I

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Rajiv Movva
Undergraduate Researcher

OUR RESEARCH
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Orthogonal Translation

The ribosome plays a central role in orchestrating responses to nutrients and extracellular stimuli. As even minor perturbations to the ribosome can have a profound impact on cellular viability, we have devised synthetic translational machinery that operates orthogonally to the host apparatus and allows us to study cellular translation with comparative ease. Through this orthogonal translation system, we are motivated to probe the factors that contribute to balancing translational fidelity and processivity in vivo.

Heterologous Ribosomes

The modern interpretation of the tree of life relies on conservation of ribosomal RNA sequences. To generalize the analysis of ribosomal component divergence, we have developed a pipeline for the production of heterologous ribosomes in E. coli. Our efforts have provided insight into the evolution of the prokaryotic ribosome and constraints that lead to the modern mitochondrial translation. This platform has further facilitated the study of extant ribosomes from disparate species while obviating safety considerations and difficulties in microbe culturing.

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Evolution of Antibiotic Resistance

With a dwindling arsenal of antibiotics to combat human microbial pathogens, mechanisms to rapidly and robustly predict antibiotic resistance can inform best practices for antibiotic dissemination and stewardship. By combining state-of-the-art techniques from synthetic biology and directed evolution, we are actively working on a high-throughput technique for the prediction of antibiotics resistance mechanisms in bacteria. In addition to identifying putative resistance mechanisms in patients, this analysis can be leveraged to inform the impact of antibiotic combinations and treatment regimens on the rate and frequency of antibiotic resistance.

PUBLICATIONS
Directed Evolution

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

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 

CONTACT US

Badran Lab
The Broad Institute of MIT & Harvard University
Room 2018 (Office), Room 2175 (Lab)
415 Main Street
Cambridge, MA 02142
United States

Tel.: (617) 714-7144 (Office)
Email: ahbadran@broadinstitute.org

Administrative Assistant

Meredith Fedorov
Email: mfedorov@broadinstitute.org

JOIN US
The Broad Institute of MIT & Harvard is a world-renowned collaborative and multidisciplinary research institution committed to addressing medical challenges across the world. 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@broadinstitute.org with your CV (including a list of references) and summary of your prior research.
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