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The next big challenge in Human Biology

After having deciphered the human genome deciphering the molecular networks of the cell, encompassing the myriads of cellular functionalities, is the next big challenge in human biotechnology. The precise knowledge of this entire functional plan, called the toponome, is the prerequisite to understand the cellular functions of proteins and other elements of spatially determined molecular networks. The first elementary Imaging Cycler® robot technology (a system for the imaging of the toponome) capable to decipher toponomes directly in a cell or tissue has been established. It is the result of 20-years of continuous technology development. It runs cycles of fluorescence tagging and imaging in situ. This technology combines several advances:


  • a fluorescence technique capable of mapping hundreds of different proteins in one tissue section or cell sample;
  • a method selecting the most prominent combinatorial molecular patterns by representing the data as vectors;
  • a system for mapping the distribution of these protein groupings in a “toponome map”,
  • a system of real time protein profiling and slicing across thousands of interlocked protein clusters in one single tissue section or cell sample, and
  • a system for simultaneous imaging of subcellular structures at < 40nm resolution along with the corresponding protein network code.
  • Toponome - The Universe of Molecular Networks in one Cell. For more details see “HUTO project, applications”

The Imaging Cycler (IC) robotics method (TIS: Toponome Imaging System) is today more precisely referred to as MUSIC robotis (Molecular Unlimited Systems Imaging Cycler Robotics). It is based on the solar light theory (W. Schubert, Island of KOS, Greece, 1987), which states that one can transmit a quasi unlimited number of distinct biological information without steric hindrance through one and the same fluorescence channel with only one sun-scattering-like stimulus, to measure the high-dimensional combinatorial molecular system directly in the tissue: the principle of the n-dimensional quasi-channels. Overview: click here. The first proof of this method was published in 1990 in a short two-page paper (Schubert W. Multiple Antigen Mapping Microscopy of Human Tissue. In: Advances in Analytical Cellular Pathology. Burger G. Oberholzer M. Vooijs G.P. (Eds.) Elsevier Science Inc. New York, 1990). Please find here a brief technology overview.

Publications

Schubert, W.

Schubert, W. Therapeutic Depletion of Axotomy Competent Cells in Amyotrophic Lateral Sclerosis (ALS), Adv Neur Neur Sci, 2 (1), 2019
Advances in Neurology and Neurosciences 2019


Hillert R, Gieseler A, Krusche A, Humme D, Röwert-Huber HJ, Sterry W, Walden P, Schubert W. Large molecular systems landscape uncovers T cell trapping in human skin cancer. Sci Rep. 2016 Jan 13;6:19012. doi: 10.1038/srep19012. PubMed
PMID: 26757895; PubMed Central PMCID: PMC4725819.

Schubert W. Advances in toponomics drug discovery: Imaging cycler microscopy correctly predicts a therapy method of amyotrophic lateral sclerosis.Cytometry 2015 Aug;87(8):696-703. doi: 10.1002/cyto.a.22671. Epub 2015 Apr 13. Review.
PubMed PMID: 25869332; PubMed Central PMCID: PMC4676937.

Schubert W., Dress A, Ruonala M, Krusche A, Hillert R, Gieseler A, Walden P.
Imaging cycler microscopy. Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):E215. doi: 10.1073/pnas.1319017111. Epub 2014 Jan 7. PubMed PMID: 24398531; PubMed Central PMCID: PMC3896151.

Schubert W., Dress  A., Ruonala M., Krusche A., Hillert R., Gieseler A., Walden P. Imaging cycler microscopy.
Proc Natl. Acad. Sci USA  14; 11(2) (2014).

Schubert W., Systematic, spatial imaging of large multimolecular assemblies and the emerging principles of supramolecular order in biological systems.
J. Mol. Recognit. 27: 3–18 (2014)

Schubert W., de Wit N.C.J., Walden, P. Systems Biology of Cancer. In: Pelengaris S., Khan M. (Eds) Molecular Biology of Cancer. 2nd edn. John Wijley&Sons  552-582 (2013)

Schubert W., Gieseler A., Hillert R., Krusche A.  Direct, spatial imaging of randomly large supermolecules by using parameter unlimited TIS imaging cycler microscopyIn: Konferenzband Mikroskopie-Kongress 2013, 25-30 Aug 2013, Regensburg; Proceedings Part II Life Sciences (LS) Multimodal and Interdisciplinary Microscopies (MIM); 436-437 (2013)

Schubert W., Toponomics. In: Encyclopedia of Systems Biology, Dubitzky W., Wolkenhauer O, Cho KH, Yokota H (eds). Springer Science: Berlin, Heidelberg; 2191-2212  (2013)

Oeltze St., Klemm P., Hillert R., Preim B., Schubert W. Visualization and Exploration of 3D Toponome Data. VCBM 2012 - Eurographics Workshop on Visual Computing for Biology and Medicine (115-122), Norrköping, (2012)

Gieseler A, Hillert R, Krusche A, Schubert W., Visualization of synaptic protein networks by functional super-resolution microscopy TIS. 8th Forum of Neuroscience (FENS) Barcelona/Spain, July 14-18, (2012)

Schubert W., Toponomanalyse. In: Lottspeich F., Engels J.W., (Eds.) Bioanalytik, 3nd edn. Springer Spektrum, Berlin, Heidelberg: 1140-1151 (2012)

Schubert W., Gieseler A., Krusche A., Serocka P., Hillert R. Next-generation biomarkers based on 100-parameter functional super-resolution microscopy TIS.
N Biotechnol. 29 (5): 599-610. (2012)

Oeltze S, Freiler W., Hillert R, Doleisch H, Preim B, Schubert W., Interactive, graph-based visual analysis of highdimensional, multi-parameter fluorescence microscopy data in toponomics.
IEEE Trans Vis Comput Graph. 17(12): 1882-91 (2011)

Gieseler A., Hillert R., Krusche A., Schubert W. (2010): Detection of protein clusters in neuronal cells: Analyzing the proteome topology of synapses by using the multi-epitope-ligand cartography (MELC/TIS). 7th Forum of Neuroscience (FENS) Amsterdam/Netherlands, July 2-8, (2010)

Barysenka A., Dress A.W., Schubert W. An information theoretic thresholding method for detecting protein colocalizations in stacks of fluorescence images.
J. Biotechnol. 149(3): 127-131 (2010)

Herold J., Schubert W., Nattkemper TW. Automated detection and quantification of fluorescently labeled synapses in murine brain tissue sections for high throughput applications.
J. Biotechnol. 149(4): 299-309 (2010)


Bhattacharya S., Mathew G., Ruban E., Epstein D.B., Krusche A., Hillert R., Schubert W., Khan M. Toponome imaging system: in situ protein network mapping in normal and cancerous colon from the same patient reveals more than five-thousand cancer specific protein clusters and their subcellular annotation by using a three symbol colde.

Schubert W., On the origin of cell function encoded in the toponome.
J Biotechnol 149(4): 252-9 (2010)

Gieseler A., Hillert R., Krusche A., Schubert W., Detection of protein clusters in neuronal cells: Analyzing the proteome topology of synapses by using the multi-epitope-ligand cartography (MELC/TIS). Neuroscience Meeting Chicago/USA, October 17-21 (2009)

Schubert W., Gieseler A., Krusche A., Hillert R. Toponome mapping in prostate cancer: detection of 2000 cell surface protein clusters in a single tissue section and cell type specific annotation by using a three symbol code.
J Proteome Res. 8(6): 2696-707 (2009).

Franke J., Hesse T., Tournier C., Schubert W., Mawrin C., LeHuec J.C., Grasshoff H. Morphological changes of the multifidus muscle in patients with symptomatic lumbar disc herniation.
J. Neurosurg. 11(6): 710-714 (2009)

Herold J., Friedenberger M., Bode M., Rajpoot N., Schubert W., Nattkemper TW. Flexible Synapse Detection in Fluorescence Micrographs by Modeling Human Expert Grading. In: Proc. of 2008
IEEE International Symposium on Biomedical Imaging 2008: 1347-1350 (2008)

Schubert W., Bode M., Hillert R., Krusche A., Friedenberger M. Toponomics and neurotoponomics. A new way to medical systems biology.
Expert Rev Proteomics 5 (2): 361-9 (2008).

Schubert W., Friedenberger M., Bode M., Krusche A., Hillert R. Functional achitecture of the cell nucleus: towards comprehensive toponome reference maps of apoptosis.
Biochim Biophys Acta. 1783: 2080-2088 (2008).

Dress A., Lokot T., Schubert W., Serocka P. Two theorems about similarity maps.
Annals of Combinatorics  12 (3): 279-290 (2008)

Bode M., Irmler M., Friedenberger M., May C., Jung K., Stephan C., Meyer H.E., Lach C., Hillert R., Krusche A., Beckers J., Marcus K., Schubert W., Interlocking transcriptomics, proteomics and toponomics technologies for brain tissue analysis in murine hippocampus.
Proteomics 8, 1170 – 1178 (2008)

Friedenberger M., Bode M., Krusche A., Schubert W. (2007) Fluorescence detection of protein clusters in individual cells and tissue sections by using toponome imaging system: sample preparation and measuring procedures.
Nat Protoc.  2(9):2285-94 (2007)

Schubert W., Breaking the biological code.
Cytometry A 71, 771 – 772 (2007)

Schubert W., A three symbol code for organized proteomes based on cyclical imaging of protein locations.
Cytometry A 71: 352-360 (2007)

Friedenberger, M., Bode, M., Krusche A., Schubert W.: Fluorescence detection of protein clusters in individual cells and tissue sections by using toponome imaging system: sample preparation and measuring procedures.
Nat Protoc  2: 2285-2294 (2007)

Schubert W., Bonnekoh B., Pommer A.J., Philipsen L., Boeckelmann R., Maliykh J., Gollnick H., Friedenberger M., Bode M., Dress A.W. Analyzing proteome topology and function by automated multidimensional fluorescence microscopy.
Nat Biotechnol 24: 1270-1278 (2006)

Schubert W., Antikörperbasierte Toponomanalyse mit Multi-Epitop-Ligand-Kartierung (MELK) In: Bioanalytik . München : Spektrum Akad. Verl., ISBN 3-8274-1520-9, S. 1036-1048, 2006

Schubert W., Cytomics in characterizing toponomes - towards the biological code of the cell.
Cytometry A 69(4): 209-211 (2006)

Schubert W., Exploring molecular networks directly in the cell.
Cytometry A. 69(3):  109-112 (2006)

Dress A.W.M., Lokot T., Pustyl’nikov L.D., Schubert W., Poisson Numbers and Poisson Distributions in Subset Surprisology.
Annals of Combinatorics 8(4): 473-485 (2005)


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