Integrative Molecular Biotechnology Centers Mission

George Church, updated 2004

 

  • Genome Technology Center (DOE HGP, since 1987)
  • Harvard-Lipper Center for Computational Genetics (CCG since 1997)
  • Harvard/MIT Genomes-to-Life Center (DOE GtL since 2002)
        Synthetic Biology Project (SBP, based on  DARPA  2001)
  • Center of Excellence in Integration of Genomics & Informatics (PhRMA, 2002-5)
  • National Program of Excellence in Biomedical Computing Center (NPEBC 2002-4)
  • Center of Excellence in Complex Biomedical Systems Research (NIGMS CECBSR, 2003 Murray) Modular Biology.
  • Molecular and Genomic Imaging Center (MGIC NIH CEGS since 2004)
        Personal Genome Project (PGP, since 2004)
  • National Center for Biomedical Computing (NIH NCBC  I2B2 2004, Kohane)

    The mission of our group is to develop broadly distributed, integrated models for biomedical & ecological systems. To make these systems-biology models useful & accurate, we develop biotechnologies suitable for comprehensive yet cost-effective systems measures & synthesis of designed biosystems. In particular, we focus on replication of four systems -- mammalian stem cells, cell-cycle metabolism, microbial ecosystems (e.g. ocean circadian cycles & biofilms), & "in vitro" mini-genomes. Each of these has advantages for developing "systems analysis" tools & each represent existing clinical or commercial practice ripe for improvements (e.g. respectively, stem cell transplants, metabolic engineering, environmental bioremediation, & molecular biology "kits").

    Although in some ways broad & interdisciplinary, the integration of systems-analyses & "-omics" technologies does represent a specialized discipline. It requires a focused & dynamic tool-set & outlook. Examples of technologies include proteomic mass spectrometry, microarrays (for whole -genome RNA, mutant growth rates, & DNA-protein interactions), polymerase colony ("polony") amplification (for RNA splicing, haplotyping, sequencing), & chemical synthesis of genes & genomes. These are integrated with each other & with relevant systems models. These models include metabolic optimization, clusters of transcription factor motifs, & 3D (& with time 4D) models of genome folding & replication.

    1) Proteomics:  Beginning with our 1989-1997 work (Andy Link's PhD thesis), we have pursued comprehensive proteomics, including mass-spectrometry open-source software for quantitation and protein complexes.  We have pipeline on the first set of "complete" microbial proteomes [Jaffe 04] and on human and mouse stem cells (see below).

     

    2) Stem Cells: This began with embryonic stem cell work (with Gail Martin) in 1984. More recently, we have been collaborating with James Sherley, David Gottlieb, and George Daley's groups.  Our goal is to automate homologous recombination and methylation readout and reprogramming and assessing the resulting cell clones for unwanted genetic and epigenetic side-reactions.

     

    3) Human genomics:   Using polymerase clone sequencing-by-synthesis ("plone-SBS", which is now 10 to 360kbp per minute per microscope) we are contributing to the NIH $100K & $1K human genome technology goals. This will help analyses of common diseases caused bycombinations of rare alleles in many genes with occasional common alleles which confer heterozygote advantage [Vitkup 03].  We have initiated of a "Personal Genome Project" including comprehensive non-anonymous (i.e. "open" and linked) physiological phenotypes and complete genome sequences of cancers and normal controls from the same patient [Shendure 04]. 

     

    4) RNA: We were among the first labs using microfabricated and spotted arrays and are now pioneering features which go beyond arrays, i.e. RNA splicing [Zhu 03] and microRNAs [Kim 04].  We are interested in the comparative functional genomics of aging.

     

    5) Synthetic genes & genomes: The array work in item #4 has also led to a breakthrough in our ability to make synthetic genes. We are testing a new oligonucleotide method in the 4000 base/$ range (rather than the current 1 to 10 base/$) and we have improved error rates by 10-fold in way that should easily allow another two logs of improvement [Tian et al. 2004].  We are working to integrate this with our E.coli homologous recombination work [Reppas & Church] and with the ES cell work (item #2),

     

    6) Therapeutics:  We have developed a new class of drug which catalyzes degradation of any selected protein target.  We are applying this to targets in cancer.  This method is also valuable for establishing physiological systems time-series data.  We also hope that the synthetic capabilities (item #5) will lead to new drugs, antibodies, delivery polymers, and cell therapies. [Forster04].

     

     

    Forster AC & Church, GM (2004) A Synthetic Biology Project (Nature in review).

     

    Jaffe JD, Berg, HC, Church GM (2004) Proteogenomic mapping reveals genomic structure and novel proteins undetected by computational algorithms. Proteomics. 4(1): 59-77.

     

    Kim, J, Kirchevsky, A, Grad, Y, Hayes, GD, Kosik, KS, Church, GM & Ruvkun, G. (2004) Identification of many microRNAs that copurify with polyribosomes in mammalian neurons. Proc Natl Acad Sci U S A 101(1): 360-5.

     

     

    Segre, D, Vitkup, D, and Church, GM (2002) Analysis of optimality in natural and perturbed metabolic networks . Proc. Nat. Acad. Sci USA 99: 15112-7.

     

    Shendure, J,  Mitra, R, Varma, C, Church, GM. (2004) Advanced Sequencing Technologies: methods and goals.  Nature Reviews of Genetics (in press).

     

    Tian, J, Gong, H,  Sheng , N,  Zhou, X,   Gulari, E,  Gao, X,  & Church, GM (2004) Accurate Multiplex Gene Synthesis from Programmable DNA Chips.  (Nature in review).

     

    Vitkup,D, Sander,C, Church,GM (2003) The Amino-acid Mutational Spectrum of Human Genetic Disease. Genome Biol. 4: R72.

     

    Zhu,J, Shendure,J, Mitra, RD, Church, GM (2003) Single Molecule Profiling of Alternative Pre-mRNA Splicing. Science. 301(5634):836-8.