Medical Student Research Fellowship for Summer 2008

Mentor: Harold Garner
Department: McDermott Center
Room number: NC8.308
Mail Code: 9185
Phone number: 214-648-1661
E-mail: Harold.garner@utsouthwestern.edu

Project 1

Project title: Computer driven drug discovery

Human subjects IRB approved project number (where applicable): Adi F. Gazdar, M.D. IRB File No. 191 36400 "Research Depository of Normal and Neoplastic Human Tissues" Approved Date: 2/15/2002

Animal subjects IRB approved project number (where applicable): N/A

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) basic research

Brief Description of Project:
Our laboratory has developed a platform technology and refined a discovery process that enables us to identify new uses for existing pharmaceuticals for a wide variety of medical indications.

Using our software package, IRIDESCENT, new uses for existing FDA approved compounds are hypothesized for various classes of disease for which there are no available therapeutics. These candidate drug-disease relationships are studied to select the best-suited FDA approved compounds for more extensive studies. And subsequently, straightforward laboratory tests are performed for a given class of disease, for example cardiac hypertrophy, to confirm the predicted therapeutic potential of the candidate compounds. This new paradigm for drug development, which enables fast and cost efficient introduction of new therapeutics for the treatment of almost any target disease, and we have demonstrated this on the initial focus area of cardiac disease, now having shown that 6 different drugs and drug combinations that we predicted were indeed efficacious in mouse studies. We are now working with a private company to conduct clinical trials on one of these drugs.

Medical students with different skill sets could contribute to various components of this research project. We need students willing to use the software to develop a test set of drugs for a given disease of interest, provided there is a readily available mouse model, and then test those drug predictions in the model. We also need students to work on the software to improve its performance and extend its functionality.

Project 2

Project title: Text Similarity as a method to detect duplicate papers and grants

Human subjects IRB approved project number (where applicable): N/A

Animal subjects IRB approved project number (where applicable): N/A

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) basic research

Brief Description of Project:
With little chance for discovery and decreasing budgets, yet sustained pressure to publish, the unethical practices of duplicate publication and plagiarism can be enticing to some. These practices are difficult to detect and have therefore largely gone unchecked because there is a lack of robust methods to identify partial or full duplications of article text. Here we show that approximately 0.04% of Medline abstracts are plagiarized and 0.67% are duplicated, which would correspond to 3,500 and 58,300 documents, respectively. Using the text similarity engine eTBLAST, we sampled 5,000 citations in each of the last 11 years to identify potential duplicate publications based upon the author list and text within their titles and abstracts, with all highly similar abstracts validated manually. The rate of duplicate publication has been relatively constant over the last 11 years. eTBLAST is freely available to all, with special functionality for editors and reviewers, as a screening tool to identify putative duplicate articles and thus may act as a deterrent.

We wish to extend this work to improve the algorithms and computer programs to more accurately and efficiently detect these duplicates. We wish to apply this to additional databases of non-biomedicine abstracts (NASA, physics, business, law), and also apply this to the NIH CRISP database to determine if there is significant overlap in the abstracts of funded NIH grants. A student would be expected to contribute to either programming or data analysis, depending on their interests and skills. In particular, we are interested in including Harrison's Internal Medicine in our search capability, and investigate the ability to find confirming information for a differential diagnosis.

Project 3

Project title: Fabrication and Evaluation of a Combined Near Infrared Fluorescence and Hyperspectral Imaging System for Carbon Nanotube Vectors

Human subjects IRB approved project number (where applicable): N/A

Animal subjects IRB approved project number (where applicable): N/A

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) basic research

Brief Description of Project:
The structural and electronic properties of single-walled carbon nanotubes (SWCNTs) lend themselves to a variety of biomedical applications involving the detection and treatment of diseases, most notably cancer. For example, the structural change in DNA upon shifting from the B to Z conformation sufficiently perturbs the electronic structure of SWCNTs such that the change can be detected optically from living cells that have taken up DNA-SWCNT complexes. This and other works demonstrate how CNTs can be used as sensors within living cells. In another example, exposing cells containing SWCNTs to near infrared (NIR) radiation kills the cells due to the efficient optical-to-thermal energy conversion of SWCNTs, demonstrating that they can potentially be used in targeted cancer therapies to eliminate cancer cells. However, despite these and other intracellular applications, there remains technical challenges towards realizing the potential benefits of CNTs in medicine. Namely, there is a need for methodologies that can provide real-time, direct, label-free imaging of CNTs and CNT-based nanovectors in living cells and tissue. The fabrication of the first combined NIR fluorescence hyperspectral imaging (HSI) system would not only meet these bioanalytical requirements, its use with CNT-based nanovectors should enable a variety of novel diagnostic strategies. Furthermore, the use of HSI toward investigating the intracellular fate of CNTs should yield data sets capable of answering fundamental biological questions of major relevance to the field of bionanotechnology.

A student would be expected to help fabricate, calibrate and test this system, and to initially perform some proof-of-principle experiments.

Project 4

Project title: Identification of microsatellite polymorphisms in the genome and their role in disease, quantitative traits and disease

Human subjects IRB approved project number (where applicable): N/A

Animal subjects IRB approved project number (where applicable): N/A

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) basic research

Brief Description of Project:
There are ~2,000,000 microsatellites in the human genome that are likely to be polymorphic. Whereas microsatellite mutations are responsible for numerous human diseases, their role in speciation and the development of quantitative traits and complex diseases are largely understudied. We designed an oligonucleotide microarray with ~60,000 unique probes for every possible repetitive nucleotide motif from 1-mers to 6-mers to assay for hybridization differences in the genomes from multiple species. There were 24 microsatellite motifs that were statistically and reproducibly differential between humans and chimpanzees, including motifs that were specifically enriched in chimpanzees (TAGCC)-, humans (CAGC)-, or upper primates (AATGG). Computational measurements of the occurrences of each probe in the completed human and chimpanzee genomes recapitulated the array results. An exhaustive manual examination of every differential motif location in the human and chimpanzee genomes revealed that certain motifs, such as (CAGC)n and (TAAG)n, were found almost exclusively within the introns or 5'UTR regions of genes involved in neurological processes, craniofacial development, and muscular functions, an ontological pattern that was statistically significant. In critical human and chimpanzee genes associated with embryological development, mcirosatellites with sequence differences, deletions, or genetic insertions may contribute significantly to species differentiation.

The student will develop new PCR reagents for the genotyping and sequencing of a panel of humans and some other species for 100s of specific loci within genes implicated in a variety of human diseases, especially cancer, neurological and developmental, which also contain repetitive elements, especially in their promoter regions. This data will be correlated with phenotype and disease state, and other variables such as expression. Those loci found to be polymorphic will be pursued with extended panels of publicly available DNA samples and cell lines.

Previous Research Activities or Publications with Medical Students:

Jyoti K. Shah, Harold R. Garner , Michael A. White, David S. Shames and John D. Minna, sIR: siRNA Information Resource, a web-based tool for siRNA sequence design and analysis and an open source siRNA database, BMC Bioinformatics. 2007 May 31;8:178.

Paras Khandheria and Harold R. Garner, Developing a Modern Web Interface for Database-Driven Bioinformatics Tools, in press, IEEE Engineering in Biology and Medicine, November, 2006

Elizabeth M. Flood, Robert S. Kumar, Rashmi Shah, Quinlan Amos, Jonathan D. Wren, Ralph V. Shohet, and Harold R. Garner, Melatonin administration does not affect isoproterenol-induced left ventricular hypertrophy, Vol. 25, No. 3, IEEE Engineering in Biology and Medicine, May/June, 2006.

Hyperspectral Imaging: A Novel Approach for Microscopic Analysis, R.A. Schultz, T. Nielsen, J. Zavaleta, R. Ruch, R. Wyatt, H.R. Garner., Cytometry 43: 239-247 (2001)

K. M. O'Brien, J. Wren, V. K. Dave, D. Bai, R. D. Anderson, S. Rayner, G. A. Evans, A. E. Dabiri, and H. R. Garner, "ASTRAL, a Hyperspectral Imaging DNA Sequencer," Review of Scientific Instruments, Vol. 69, No. 5, May, 1998.