Joe W. Gray, Ph.D.

Joe Gray, PhD

Contribution to Science

Dr. Gray's first major scientific contributions involved development of flow cytometric techniques for cell and genome analysis.  These included techniques for high-speed chromosome sorting1-3, and BrdUrd/DNA analysis of cell proliferation4.  Sorter-purified chromosomes were cloned to produce chromosome-specific DNA libraries that were distributed world-wide and were used to assemble early chromosome maps in the human genome project. Aspects of high speed sorting that they developed are now incorporated in all modern sorters.  BrdUrd/DNA analysis has become a standard technique for assessment of cell proliferation.

1.    Gray, J.W., Carrano, A.V., Steinmetz, L.L., Van Dilla, M.A., Moore, D.H. II, Mayall, B.H. and Mendelsohn, M.L. (1975) Chromosome measurement and sorting by flow systems. Proc. Natl. Acad. Sci. USA, 72(4):231-1234.

2.    Gray, J.W., Langlois, R.G., Carrano, A.V. and Van Dilla, M.A. (1979) High resolution chromosome analysis: One and two parameter flow cytometry. Chromosoma, 73(1):9-27.

3.    Gray, J.W., Dean, P.N., Fuscoe, J.C., Peters, D.C., Trask, B., van den Engh, G., and Van Dilla, M.A. (1987) High speed chromosome sorting. Science, 238(4825):323-9.

4.    Dolbeare, F., Gratzner, H., Pallavicini, M.G., Gray, J.W. (1983) Flow cytometric measurement of total DNA content and incorporated bromodeoxyuridine. Proc. Natl. Acad. Sci. USA, 80(18):5573-7; US Patent #4,780,406

The availability of chromosome specific libraries inspired the Gray and Pinkel Laboratories to develop fluorescence in situ hybridization (FISH) to stain specific chromosome regions5. FISH dramatically simplified metaphase chromosome classification and enabled detection of numerical and structural aberrations in interphase cells.  Their papers describe the first uses of FISH for gene amplification (specifically ERBB26), gene deletion (specifically RB18) and translocation (specifically BCR-ABL7) in clinical samples.  FISH has been licensed to Abbott Diagnostics and is now used world-wide for disease diagnosis, molecular assessment of chromosome abnormalities and analysis of the organization of interphase nuclei.

5.    Pinkel, D., Landegent, J., Collins, C., Fuscoe, J., Seagraves, R., Lucas, J., and Gray, J.W. (1988) Fluorescence in situ hybridization with human chromosome specific libraries: Detection of trisomy 21 and translocations of chromosome 4. Proc. Natl. Acad. Sci. USA, 85(23):9138-42; US patent # 5,447,841, #6,500,612

6.    Kallioniemi, O.-P., Kallioniemi, A., Kurisu, W., Thor, A., Chen, L.-C., Smith, H. S., Waldman, F., Pinkel, D., Gray, J. W. (1992). ERBB2 amplification in breast cancer analyzed by fluorescence in situ hybridization. Proc. Natl. Acad. Sci. USA, 89(12):5321-25.US Patent #5,856,097

7.    Tkachuk, D.C., Westbrook, C.A., Andreeff, M., Donlon, T.A., Cleary, M.L., Suryanarayan, K., Homge, M., Redner, A., Gray, J.W., Pinkel, D. (1990) Detection of bcr-abl fusion in chronic myleogeneous leukemia by in situ hybridization. Science, 250(4980):559-62.US Patent #6,280,929

8.    Kallioniemi, A., Kallioniemi, O.-P., Waldman, F.M., Chen, L.-C., Yu, L.-C., Fung, Y.K., Smith, H.S., Pinkel, D., Gray, J.W. (1992) Detection of retinoblastoma gene copy number in metaphase chromosomes and interphase nuclei by fluorescence in situ hybridization. Cytogenet. Cell Genet., 60(3-4):190-3.

Experience with FISH led the Gray, Pinkel and collaborating laboratories to the invention of comparative genomic hybridization (CGH) for genome-wide assessment of copy number abnormalities9-11. CGH enabled interpretation of previously intractable complex cancer genomes by mapping the aberrations onto representations of normal genomes. These studies inspired Gray and Collins Laboratories to develop a genome sequencing based approach to assessment of copy number and genome structure abnormalities called End Sequence Profiling (ESP).  ESP was based on mapping sequences from the ends of clones from tumor libraries onto a normal representation of the normal genome12. This approach is now the basis for paired end sequencing applications implemented using massively parallel sequencing.

9.      Kallioniemi, A., Kallioniemi, O.-P., Sudar, D., Rutovitz, D., Gray, J., Waldman, F., Pinkel, D. (1992). Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science, 258(5083):818-21; US Patent #5,665,549.

10.    Pinkel, D., Segraves, R., Sudar, D., Clark, S., Poole, I., Kowbel, D., Collins, C., Kuo, W.-L., Chen, C., Zhai, Y., Dairkee, S., Lejung, B., Gray, J., and Albertson, D. (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays.  Nat. Genet., 20(2):207-11; US Patent #6,210,878,

11.    Hodgson, G., Hager, J.H., Volik, S., Hariono, S., Wernick, M., Moore, D., Nowak, N., Albertson, D.G., Pinkel, D., Collins, C., Hanahan, D., Gray, J.W. (2001) Genome scanning with array CGH delineates regional alterations in murine islet carcinomas.  Nat. Genet., 29(4):459-64.

12.    Volik, S., Zhao, S., Chin, K., Brebner, J.H., Herndon, D.R., Tao, Q., Kowbel, D., Huang,  G., Lapuk, A.,  Kuo, W.-L., Magrane, G., de Jong, P., Gray, J.W. and Collins. C. (2003) End-sequence profiling: sequence-based analysis of aberrant genomes. Proc. Natl. Acad. Sci. USA, 100(13):7696-701; US Patent #6,785,614

Their applications of these approaches to human and model cancers revealed the remarkable genomic complexity that characterizes most solid tumors and demonstrated the presence of recurrent genome aberrations in a broad range of human cancers.  In particular, they showed that human breast cancers pass through telomere crisis and become immortal during progression from usual ductal hyperplasia to carcinoma in situ13.  This is important since it suggests strategies to prevent this critical transition. They also integrated diverse data types to identify breast and pancreatic cancer subtypes associated with disease progression and response to treatment14-16.

13.    Chin, K., de Solorzano, C.O., Knowles, D., Jones, A., Chou, W., Rodriguez, E.G., Kuo, W.L., Ljung, B.M., Chew, K., Myambo, K., Miranda, M., Krig, S., Garbe, J., Stampfer, M., Yaswen, P., Gray, J.W., Lockett, S.J. (2004) In situ analyses of genome instability in breast cancer. Nat. Genet., 36(9):984-8.

14.    Collisson, E.A., Sadanandam, A., Olson, P., Gibb, W.J., Truitt, M., Gu, S., Cooc, J., Weinkle, J., Kim, G.E., Jakkula, L., Feiler, H.S., Ko, A.H., Olshen, A.B., Danenberg, K.L., Tempero,  M.A., Spellman, P.T., Hanahan, D., Gray, J.W. (2011) Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nature Med., 17:500-503. PMC3755490

15.    Chin, K., DeVries, S., Fridlyand, J., Spellman, P.T., Roydasgupta, R., Kuo, W.-L., Lapuk, A., Neve, R.M., Qian, Z., Ryder, T., Chen, F., Feiler, H., Tokuyasu, T., Kingsley, C., Dairkee, S., Meng, Z., Chew, K., Pinkel, D., Jain, A., Ljung, B.M., Esserman, L., Albertson, D.G., Waldman, F.M., Gray, J.W. (2006) Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell, 10(6):529-41.

16.    Daemen, A., Griffith, O.L., Heiser, L.M., Wang, N.J., Enache, O.M., Sanborn, Z.,  Pepin, F., Durinck, S., Korkola, J.E., Griffith, M., Hur, J.S., Huh, N., Chung, J., Cope, L., Fackler, M.J., Umbricht, C., Sukumar, S., Seth, P. Sukhatme, V.P., Jakkula, L.R., Lu, Y., Mills, G.B., Cho, R.J., Collisson, E.A., van  ’t Veer, L.J., Spellman, P.T., Gray, J.W. (2013) Modeling precision treatment of breast cancer. Genome Biol., 14(10):R110. PMC3937590.

Most recently, we have elucidated mechanisms of cancer progressionand developed systems biology approaches for identification of molecular markers that predict and determine response to therapeutic treatment17,19.  We also developing aspects of the OHSU Center for Spatial Systems Biology to elucidate how genomic and epigenomic events influence the few Ǻngström to millimeter scale structures that enable function in cells and tissues18,20. These studies integrate results from measurements of the genome, proteome, and multiscale cellular and molecular structure and are directly relevant to the work proposed in this application.

17.    Heiser, L.M., Sadanandam, A., Kuo, W.L., Benz, S.C., Goldstein, T.C., Ng, S., Gibb, W.J., Wang, N.J., Ziyad, S., Tong, F., Bayani, N., Hu, Z., Billig, J.I., Dueregger, A., Lewis, S., Jakkula, L., Korkola, J.E., Durinck, S., Pepin, F., Guan, Y., Purdom, E., Neuvial, P., Bengtsson, H., Wood, K.W., Smith, P.G., Vassilev, L.T., Hennessy, B.T., Greshock, J., Bachman, K.E., Hardwicke, M.A., Park, J.W., Marton, L.J., Wolf, D.M., Collisson, E.A., Neve, R.M., Mills, G.B., Speed, T.P., Feiler, H.S., Wooster, R.F., Haussler, D., Stuart, J.M., Gray, J.W., Spellman, P.T. (2012) Subtype and pathway specific responses to anticancer compounds in breast cancer. Proc. Natl. Acad. Sci. USA., 109(8):2724-9. PMC3286973

18.    Nan X., Collisson, E.A., Lewis, S., Huang, J., Tamgüney, T.M., Liphardt, J.T., McCormick, F., Gray, J.W., Chu S. (2013) Proc. Natl. Acad. Sci. U S A. 110:18519-24. Single-molecule superresolution imaging allows quantitative analysis of RAF multimer formation and signaling. PMC3831949

19.    Chang, Y.H., Korkola J., Amin D.N., Moasser M.M., Carmena J.M., Gray J.W., Tomlin C.J. (2015) Disentangling multidimensional spatio-temporal data into their common and aberrant responses. PLoS One10: e0121607. PMC4406848

20.    Nan, X., Tamgüney, T.M., Collisson, E.A., Lin, L.J., Pitt, C., Galeas, J., Lewis, S., Gray, J.W., McCormick, F., Chu, S. (2015) Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway. Proc. Natl. Acad. Sci. USA, 112(26):7996-8001. PMC4491781

The following link is to publications by Joe Gray or publications linked to grants on which he was PI:

The Scopus h-index for Joe Gray is 101.