CA2375034A1 - Method and device for analysis of biological specimens - Google Patents

Method and device for analysis of biological specimens Download PDF

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Publication number
CA2375034A1
CA2375034A1 CA002375034A CA2375034A CA2375034A1 CA 2375034 A1 CA2375034 A1 CA 2375034A1 CA 002375034 A CA002375034 A CA 002375034A CA 2375034 A CA2375034 A CA 2375034A CA 2375034 A1 CA2375034 A1 CA 2375034A1
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Prior art keywords
specimen
substrate
cellular
components
layers
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CA002375034A
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French (fr)
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CA2375034C (en
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Michael R. Emmert-Buck
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National Institutes of Health NIH
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6841—In situ hybridisation
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B30/00—Methods of screening libraries
    • C40B30/04—Methods of screening libraries by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54386—Analytical elements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57434—Specifically defined cancers of prostate
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6845—Methods of identifying protein-protein interactions in protein mixtures
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4712—Muscle proteins, e.g. myosin, actin, protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4742—Keratin; Cytokeratin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
    • G01N2333/7051—T-cell receptor (TcR)-CD3 complex
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96433—Serine endopeptidases (3.4.21)
    • G01N2333/96441—Serine endopeptidases (3.4.21) with definite EC number
    • G01N2333/96455—Kallikrein (3.4.21.34; 3.4.21.35)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96486—Metalloendopeptidases (3.4.24)

Abstract

Disclosed herein are substrates having different capture regions, such as contiguous layers, wherein the different capture regions of the substrate contain different identification molecules. Components of the specimen are transfered through the capture regions under conditions which allow the components to interact with different identification molecules in the different regions of the substrate. Transfer is effected by capillary action of a solution moving through the cellular specimen or by electrophoresis. The transfer may occur in such a way as to maintain a geometric correspondence to the specimen, e.g. a correspondence to the cytoarchitecture of a cellular specimen. Example of cellular specimens include tissue sections such as tumor tissue sections. Cytostat sections cut slightly thicker than usual, i.e. 25 to 50 µm, allow the detection of molecules of moderate and low level abundance.

Claims (66)

1. A method of analyzing a biological specimen, comprising:
placing the biological specimen on a substrate with one or more different capture regions, wherein the one or more different capture regions of the substrate contain different identification molecules that interact with different biological molecules from the biological specimen; and transferring components of the biological specimen through the one or more different capture regions under conditions that allow the components to interact with the different identification molecules in the different capture regions of the substrate to produce a pattern that is informative about the identification of the biological molecule.
2. The method of claim 1, wherein the different capture regions of the substrate are layers.
3. The method of claim 1, wherein the biological specimen is a cellular specimen.
4. The method of claim 1, wherein the different capture regions of the substrate are layers, and the biological specimen is a cellular specimen.
5. The method of claim 4, wherein the layers are contiguous, and components of the cellular specimen are transferred through the different layers of the substrate by capillary action of the substrate.
6. The method of claim 4, wherein the layered substrate comprises contiguous porous layers that exert capillary pressure on the cellular specimen.
7. The method of claim 4, wherein the components of the cellular specimen are transferred through the different layers of the substrate by electrophoresis.
8. The method of claim 4, wherein the components maintain a cellular architecture of the specimen as the components are transferred through the layers of the substrate.
9. The method of claim 8, further comprising correlating interaction between different identification molecules and the components of the cellular specimens, with a cellular architecture of the specimen.
10. The method of claim 4, further comprising placing multiple different discrete cellular specimens on a surface of the substrate, wherein a correspondence is maintained between the multiple discrete cellular specimens and particular transferred components.
11. The method of claim 10 wherein at least 20 different cellular specimens are placed on the surface of the substrate.
12. The method of claim 4, wherein the cellular specimen is a section of a tissue specimen.
13. The method of claim 12, wherein the cellular specimen is a section of a tumor.
14. The method of claim 4, further comprising correlating a pattern of interactions of different identification molecules in the different layers of the substrate with a component having a known identity.
15. The method of claim 4, wherein there are at least 10 layers of the substrate.
16. The method of claim 15, wherein there are at least 100 layers of the substrate.
17. The method of claim 4, wherein the layers of the substrate have a thickness of at least about 25 µm.
18. The method of claim 4, wherein the identification molecules are antibodies that interact with the components of the cellular specimen.
19. The method of claim 4, wherein the identification molecules interact with different cellular regions of the cellular specimen, and interaction of the identification molecules is correlated with a region of the cellular specimen.
20. The method of claim 4, wherein the cellular specimen is placed on a surface of the layered substrate prior to transferring components of the cellular specimen through the substrate.
21. The method of claim 4, wherein the specimen is treated, prior to transferring components of the cellular specimen through the layers, to selectively transfer components through the layers.
22. The method of claim 21, wherein the specimen is placed on a surface of the layered substrate in a gel, and a concentration of the gel is varied to selectively transfer components of different molecular size.
23. The method of claim 22, wherein a high concentration gel is used to selectively transfer proteins of a relatively smaller molecular size.
24. The method of claim 4, comprising identifying the component of the specimen by determining which identification molecule the component interacts with.
25. The method of claim 24, further comprising reacting an identified component with a second identification molecule, to determine whether the identified component is associated with an other component.
26. The method of claim 25, wherein the cellular specimen is a tumor specimen, and the identified component is an intact protein, and identification of the other component is used to determine whether a second protein is associated with the protein in the tumor.
27. The method of claim 26, wherein multiple tumor specimens are placed on the substrate, and components of the multiple tumor specimens are simultaneously separately transferred through the substrate.
28. The method of claim 27, wherein the multiple tumor specimens are specimens of a particular type of tumor at different stages of tumor progression.
29. The method of claim 28, wherein the multiple tumor specimens are specimens of a tumor from a particular subject at different stages of tumor progression in that subject.
30. The method of claim 4, wherein the cellular specimen is obtained by dissecting a cell population of interest from a larger cell population.
31. The method of claim 30, wherein dissecting a cell population of interest comprises laser capture microdissection of the cell population.
32. The method of claim 4, wherein the cellular specimen comprises a cell lysate from a cell population of interest.
33. The method of claim 4, wherein one or more of the layers is an electrically conductive layer.
34. The method of claim 33, wherein the layers are separable, and are separated after transferring the components of the cellular specimen, for individualized identification of the components of the cellular specimen retained in each separated layer.
35. The method of claim 33 wherein the each layer is selected from the group consisting of a high concentration agarose gel, a low concentration agarose gel, a high concentration polyacrylamide gel, a low concentration polyacrylamide gel, and a membrane.
36. The method of claim 4 wherein the identification molecules are molecules selected from the group consisting of antibodies, nucleic acids, peptides, receptors, and ligands.
37. The method of claim 4 wherein the identification molecule comprises a capture molecule which retains a component of the cellular specimen in the layer, the method further comprising exposing the identification molecule to a detection molecule that associates with a combination of the capture molecule and the component of the sample, or associates with a region of the component different than a region that is recognized by the identification molecule.
38. The method of claim 37, wherein the component is a protein, the identification molecule recognizes a first domain of the protein, and the detection molecule recognizes the different region of the protein.
39. The method of claim 38, wherein the detection molecule is selected from the group consisting of antibodies, nucleic acids, peptides, receptors, ligands and stains.
40. The method of claim 4, wherein the identification molecules capture components of the transferred components in relative abundance to a quantity of the components in the cellular specimen, and provide a quantitative indication of the relative abundance of the components in the cellular specimen.
41. The method of claim 4, wherein the cellular specimen is selected from the group consisting of a tissue section, cultured cells, and a cytology sample.
42. The method of claim 1 or 2, wherein the transferred components that interact with the different identification molecules comprise intact proteins or intact nucleic acid molecules that have not been subjected to proteolytic or nucleolytic reactions prior to transfer through the different layers of the substrate.
43. The method of claim 1 or 2, further comprising capturing a component of the components of the cellular specimens, and performing mass spectroscopy sequencing to identify the captured component.
44. The method of claim 1 or 2, wherein transferring components of the cellular specimen through the layered substrate produces a three dimensional matrix, wherein a surface of the substrate on which the cellular specimen is placed provides a two dimensional cytocoherent matrix, and a third dimension is provided by transfer of components of the cellular specimens through the different layers, wherein there is an identifiable correspondence between a position of the component of the cellular specimen in the two dimensional cytocoherent matrix and a position of the transferred components in the three dimensional matrix.
45. The substrate with the three dimensional matrix of claim 44.
46. A method of analyzing a cellular specimen, comprising:
providing a substrate comprising a plurality of different layers having contiguous faces, each layer including a corresponding capture molecule capable of interacting with and capturing a component of the cellular specimen;
applying the cellular specimen to a face of the substrate, and transferring intact components of the specimen through the contiguous faces of the different layers of the matrix;
reacting the intact components of the specimen with the capture molecule; and correlating a pattern of capture in the different layers with information about the cellular specimen.
47. The method of claim 46, wherein the capture molecule captures the component in an amount that corresponds to a quantity of the component in the cellular specimen.
48. The method of claim 46, wherein the intact components comprise one or more of proteins or nucleic acids that have not been subjected to a proteolytic or nucleolytic processing step.
49. The method of claim 46, wherein applying the cellular substrate to a face of the substrate comprises applying multiple different cellular specimens to the face of the substrate.
50. The method of claim 46, wherein the pattern of capture comprises a three dimensional matrix, in which a pattern of the cellular specimen applied to the face of the substrate forms a cytocoherent two dimensional matrix, and a pattern of capture in the different layers forms a third dimension, wherein there is a correspondence between the cytocoherent two dimensional matrix and the third dimension, such that the pattern of capture can be correlated to specific cellular architecture in the cellular specimen.
51. The method of claim 46, wherein transferring intact components of the specimen comprises introducing an electrical current through the contiguous faces of the substrate, so that the current flows transverse to the plurality of different layers.
52. The method of claim 51, wherein the plurality of different layers comprises a plurality of contiguous electrically conductive gels through which the electrical current is conducted.
53. The method of claim 46, wherein transferring intact components of the specimen comprises transferring by capillary action.
54. The method of claim 53, wherein the plurality of different layers comprise contiguous nitrocellulose layers that exert capillary pressure on the cellular specimen.
55. A device for analyzing a cellular specimen, comprising:
a layered substrate having a surface to which the cellular specimen may be applied and maintained in cytocoherence, wherein successive layers of the substrate contain different identification molecules, each of which is capable of interacting with a corresponding intact component of the cellular specimen, and retaining the corresponding intact component;
wherein the layers are contiguous and conductive, and capable of transferring intact components of the cellular specimen through the layers, while maintaining a correspondence between a position on a surface of the substrate and a position in the substrate to which the component is transferred.
56. The device of claim 55, wherein the layered substrate is capable of exerting capillary pressure on the cellular specimen to transfer the component through the substrate.
57. The device of claim 56, wherein the layered substrates are porous nitrocellulose layers.
58. The device of claim 55, wherein the layered substrate is electrically conductive.
59. The device of claim 58, further comprising electrodes positioned in relationship to the substrate to introduce an electrical current through the surface of the substrate to the different layers of the substrate.
60. The device of claim 59, further comprising a cellular specimen on the surface of the substrate.
61. The device of claim 60, wherein the intact components of the cellular specimen have been transferred through the layers to establish a three dimensional matrix in which cellular architecture on the surface corresponds to unique components in the plurality of layers.
62. The device of claim 55 wherein the successive layers are substantially parallel.
63. The device of claim 59 wherein the electrical current moves substantially transverse to the layers.
64. A system for molecular analysis of a biological sample, the system comprising:

a sample support capable of holding the sample during the movement of a component of the sample from the sample through a plurality of separation matrices stacked face to face;
multiple contiguous separation matrices stacked face to face, wherein each matrix comprises a capture molecule which is capable of hybridizing to one or more components of the sample;
a transport means for moving of at least one component of the sample from the sample support, through the faces, into the separation matrices;
a housing for holding the multiple separation matrices in face to face alignment during the movement of the sample components, but allowing for separation of the multiple separation matrices from each other so further analysis can be performed; and a second housing in which the hybridization between the capture molecule and the component of the sample can be further analyzed.
65. The system of claim 64 wherein the transport means comprises a pair of electrodes positioned to introduce an electrical current through the faces of the matrices.
66. The system of claim 64, wherein the transport means comprises a porous structure of the support which creates capillary pressured which moves the component through the separation matrices.
CA2375034A 1999-07-26 2000-07-26 Method and device for analysis of biological specimens Expired - Lifetime CA2375034C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14561399P 1999-07-26 1999-07-26
US60/145,613 1999-07-26
PCT/US2000/020354 WO2001007915A2 (en) 1999-07-26 2000-07-26 Layered device with capture regions for cellular analysis

Publications (2)

Publication Number Publication Date
CA2375034A1 true CA2375034A1 (en) 2001-02-01
CA2375034C CA2375034C (en) 2012-01-03

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US (2) US6602661B1 (en)
EP (1) EP1218743B1 (en)
JP (1) JP4137444B2 (en)
AT (1) ATE328277T1 (en)
AU (1) AU771499B2 (en)
CA (1) CA2375034C (en)
DE (1) DE60028393T2 (en)
ES (1) ES2269171T3 (en)
WO (1) WO2001007915A2 (en)

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