Dr. Jennifer Doudna is a member of the departments of Molecular and Cell Biology and Chemistry at UC Berkeley, the Howard Hughes Medical Institute, and Lawrence Berkeley National Lab, along with the National Academy of Sciences, and the American Academy of Arts and Sciences.
- Fellow, American Academy of Arts and Sciences (2003)
- Professor of Biochemistry and Molecular Biology, Department of Molecular and Cell Biology, the University of California, Berkeley (2003)
- Professor of Biochemistry and Molecular Biology, Department of Chemistry, the University of California, Berkeley (2003)
- Faculty, Biophysics Graduate Group, the University of California, Berkeley (2003)
- Faculty Scientist, Physical Biosciences Division, Lawerence Berkeley National Laboratory (2003)
- Member, National Academy of Sciences (2002)
- Member, Board of Trustees, Pomona College (2001)
- American Chemical Society Eli Lilly Award in Biological Chemistry (2001)
- R. B. Woodward Visiting Professor, Harvard University (2000-2001)
- Alan T. Waterman Award (2000)
- Investigator, Howard Hughes Medical Institute (1997)
- Searle Scholar, Kinship Foundation’s Searle Scholars Program (1996)
- Henry Ford II Professor of Molecular Biophysics and Biochemistry, Center for Structural Biology, Department of Molecular Biophysics and Biochemistry, Yale University (1994-2002)
- Lucille P. Markey Scholar in Biomedical Science, University of Colorado (1991-1994, Dr. Thomas R. Cech)
- Postdoctoral Research Fellow, Molecular Biology, Massachusetts General Hospital and Harvard Medical School (1989-1991, Dr. Jack W. Szostak)
- Ph.D. Harvard University (1989, Dr. Jack W. Szostak)
- B.A. Pomona College (1985, Dr. Sharon M. Panasenko)
Glioblastoma multiform (GBM) is one of the most common and aggressive forms of brain cancer, but current therapeutic treatments are limited. My research focuses on using the gene-editing CRISPR/Cas9 system in order to first further understanding of genes underlying tumor cell immortality in GBM, and second develop in vivo delivery methods to achieve CRISPR/Cas9 editing of GBM tumor cells, with the ultimate goal of inhibiting tumor growth.
Diverse CRISPR-Cas systems are now known to function as integral components of the immune repertoire of many microorganisms, with the currently known catalog of systems spanning two of the three domains of life and contributing to the capacity of these bacteria and archaea to thwart viral infection. Eukaryotes conspicuously lack endogenous CRISPR-Cas systems, but it is not yet known if these molecular surveillance complexes can be co-opted to achieve therapeutically relevant inhibition of viral infection in humans through direct interference with the genomes of human viruses. While investigating strategies to improve the therapeutic potential of CRISPR-Cas components, I will also examine our ability to temporally control the editing activity of diverse CRISPR effectors.
Camille and Henry Dreyfus Environmental Chemistry Fellow
The vast majority of microbial diversity remains unexplored due to the inability to cultivate most microbes in a lab. My research focuses on a group of uncultivated bacteria called the candidate phyla radiation (CPR), which comprises over 15% of Domain Bacteria. Currently, almost no experimental characterization of CPR bacteria has been performed and many identified genes have unknown biological function. My work focuses on cultivation, biochemical characterization, and ultimately genetic engineering of CPR bacteria.
Hepatitis C virus (HCV), which infects 170 million people globally and leads to liver cancer, employs an unusual strategy to hijack host ribosomal subunits and translation initiation factors to synthesize viral proteins using internal ribosome entry site (IRES) RNA. Although this mechanism play an important role in viral life cycle, a detailed understanding of the interplay between host immunity and virus infection will be needed to identify and characterize unrevealed RNA-mediated translational regulation. To this end, my research goal is to apply cutting edge genomic, molecular, biochemical, and animal modeling approaches to: 1) determine IRES RNA mediated mechanisms for controlling HCV translation, and 2) study the host cellular responses to HCV translation. Successful completion of the proposed work will provide a deep understanding of virus-host translational interactions during tumorigenesis and lead to developing more effective cancer prevention and therapies.
Prokaryotes (Archaea and Bacteria) have evolved a nucleic acid-stimulated immune system that shares similar functions with RNA interference in eukaryotes. CRISPR/Cas system is a microbial nuclease system involved in defense against invading phages and plasmids by integrating spacers from invading genetic elements and subsequently directing the specific cleavage of invasive homologous DNA sequences. My research is focused on the elucidation of the molecular mechanism of the RNA-guided DNA endonuclease Cas9 from the type II CRISPR system. My current research involves in understanding the detailed mechanism by which viral anti-CRISPR proteins inhibit bacterial CRISPR immunity.
The CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) systems arose in bacteria and archaea as an adaptive innate immune response to combat viral infection. In Class 2 type II CRISPR systems, the single protein effector Cas9 is guided by a CRISPR-RNA to cleave complementary target sequences within foreign DNA. With biochemical and structural data to define their molecular mechanisms, Cas9 and the Class 2 type V effector, Cpf1, have been readily employed as tools for genome engineering. However, the CRISPR-Cas systems show remarkable diversity across microbial species, with the recent identification of highly divergent class 2 single effectors that share little to no resemblance to Cas9. My research focuses on understanding the molecular mechanisms of the expanding ‘CRISPR universe’ using biochemistry and X-ray crystallography.
The discovery of intron-derived RNAs and cytoplasmic intron-retaining transcripts (CIRTs) hints that intronic RNAs, previously regarded as “junk”, play an important role in cellular processes. I aim to unravel the dynamics of intron-derived RNA synthesis, transport and function in vivo by taking on a multi-disciplinary approach: a combination of gene editing technologies with the most advanced tools in biochemistry, structural biology and live cell imaging.
Research interest1: LncRNAs play key regulatory roles in various cellular pathways. For example, Host lncRNAs NRON and NEAT1 strongly affect latent infection by exerting a rigorous regulation-cycle on HIV-1 transcripts and proteins. However, detailed 3D structural information is lacking. Leveraging the technical advantages of cryo-EM technology, I’m seeking to establish general methods to help researchers determine the 3D structures of lncRNAs more efficiently.
Research interest2: Various alternative Class2 Cas proteins from different organisms have been characterized that show a number of advantages with respect to SpyCas9. Understanding the structural basis for these special properties of different Cas proteins will greatly benefit the design of an optimized gene-editing tool. Furthermore, anti-CRISPR proteins have been identified as specific and genetically encodable ‘‘off-switches’’ for Cas9 which may help clinical difficulties and safety concerns, but the structural mechanism is yet unknown. I’m interested to explore the guide RNA-binding and DNA-targeting mechanisms for Class2 Cas proteins, and to determine, in atomic detail, how different typeII anti-CRISPR proteins control the activity of Cas9 proteins.
Joint with Staskawicz Lab
My research focuses on understanding how gene editing outcomes in plant cells are influenced by different Cas9-gRNA complex designs and the host DNA repair machinery. In particular, I am working on developing robust CRISPR/Cas9-mediated homology-directed repair (HDR) tools in plant crop species in order to exploit genome engineering beyond producing NHEJ-mediated indel knockouts. Additionally, we are establishing novel delivery methods of CRISPR-Cas9 reagents to overcome the physical barrier imposed by the plant cell wall and thus improve gene editing efficiency and scalability in a transgene-free manner. Finally, we are using comparative and functional genomics to identify, test and deploy genetic engineering of biotic (disease resistance) and abiotic (drought tolerance) stress pathways and traits in plant crop species with emphasis on tomato, rice, and wheat.
Bastian is a postdoctoral scholar in the Innovative Genomics Institute’s agricultural genomics branch. He started working on genome-editing in the food staple rice during his time as a Beachell-Borlaug International Scholar at Penn State. He now continues his efforts to improve disease resistance and yield of crops at UC Berkeley under supervision of Drs. Jennifer Doudna and Brian Staskawicz. Bastian’s first goal during his time at the Innovative Genomics Institute is to develop tools for precise genome-editing and accelerated plant breeding using advanced plant tissue culture and CRISPR methods. Another interest of him is to develop bioinformatic tools to avoid off-target editing in plants and to increase on-target activity. As ultimate goal, Bastian tries to develop an efficient gene repair system to easily change genetic information in crops to make them healthier and sturdier.
It is truly fascinating how all the information required for functioning of any complex living organism can be stored and maintained in DNA molecules. Molecular mechanisms that allow for maintenance of genome integrity, faithful transmission of genetic information to next generations, as well as mechanisms altering the DNA are of particular interest. My PhD thesis was focused on structural aspects of DNA replication initiation mechanism in bacteria. Currently the focus of my work is structural studies of various CRISPR-Cas systems that provide bacteria with acquired immunity against phage infections, and have a potential of being employed as gene-editing tools.
Dominant genetic disorders, in which a mutant allele (version) of a gene causes disease in the presence of a second, normal allele have been challenging to treat. There are no cures and treatments are to alleviate symptoms. Current therapeutics involving pharmacological and biological drugs are not suitable to target mutant gene alleles selectively due to structural indifferences of the normal variant of their target from the mutant variant. Therefore there is a need for therapeutics to target these previously inaccessible targets. Nucleotide-based approaches including RNA interference (RNAi) and CRISPR/Cas9 (a RNA-guided DNA endonuclease) systems hold promise as methods that can discriminate and repress a mutant allele from normal alleles.
Whereas RNAi can repress a mutant allele at the mRNA level, gene-editing systems including zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALENs) or CRISPR/Cas9 can permanently edit a mutant allele to disrupt it or correct it. These technologies disrupt target genes by creating double-strand breaks that are repaired by the non-homologous end joining DNA repair pathway (NHEJ). Alternatively if a DNA repair template is co-delivered with the gene-editing system, mutant allele correction is accomplished via the homology-directed repair (HDR) pathway.
CRISPR/Cas9 has been used for gene-specific editing/regulation in human cells (Cong, Ran et al. 2013; Jinek, East et al. 2013; Mali, Yang et al. 2013; Qi, Larson et al. 2013). However its utility as an allele-specific editor/regulator has not been tested. My research goals are to develop the CRISPR/Cas9 system for allele-specific gene regulation/editing of the genetically dominant gene Huntingtin (HTT) that causes Huntington’s disease (HD). A second goal is to develop robust cellular delivery methods for CRISPR/Cas9 into target cells of HD. There are currently no curative therapies and development of therapies to delay the onset, slow its progression or cure HD remains a major clinical need.
In the constant battle between bacteria and phages both have evolved machinery to try to evade the other’s defenses. I study this back-and-forth with the goal of using these defense-evading systems to engineer new tools for gene control.
Former Postdoctoral Associates
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