The 6^th Dieter and Inge Hoehn Lectures
in Bioanalytical Chemistry

( December 7 - 8, 2004)

The 2004 Dieter and Inge Hoehn Lectures in Bioanalytical Chemistry took place on December 7 and 8, 2004. This was the sixth lectureship in the series endowed by the Hoehns, and its theme focused on Molecular Imaging. 

    Dr. Richard M. Caprioli (Director, Mass Spectrometry Research Center, Vanderbilt University, School of Medicine, Nashville, TN) presented a lecture, titled "Direct Imaging and Profiling of Proteins in Tissues Using Mass Spectrometry to Aid Diagnosis and Treatment of Disease and to Identify Therapeutic Targets" .

     Dr. Homer H. Pien (Managing Director, Center for Biomarker Imaging, Dept. of Radiology, Massachusetts General Hospital, Charlestown, MA) presented a lecture, titled "Using Imaging and Imaging Biomarkers to Accelerate Drug Development". Dieter Hoehn was present for this special Institute event, and we are grateful to him and his wife, Inge, for their continued support of this very informative lecture series.

Richard M. Caprioli, Vanderbilt University School of Medicine

Matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) has been used to determine the spatial distribution of peptides and proteins in tissue sections. Applications range from low-resolution images of peptides and proteins in selected areas of tissue to high resolution images of tissue cross sections. Using a raster of mass spectra from a defined area, images of samples are produced in specific m/z values, or ranges of values. Each spot on the sample irradiated by the laser is approximately 30-50 microns in diameter and typically covers the m/z range 1000-100,000. Individual m/z values can then be assembled from the mass spectra to produce selected m/z images. Sections obtained from any tissue type can be imaged to locate tissue specific peptides and proteins in X,Y coordinates of the tissue. Tumors present in lung, breast, brain, colon, prostate, skin, and head and neck have been profiled and imaged, comparing new proteins (markers) highly expressed in the tumor but not the corresponding normal tissue, and those missing in the tumor that are highly expressed in normal tissue. Major differences in protein expression have been found in tumor subtypes. This is illustrated with studies of human lung non-small cell carcinoma and for human glioblastomas, with correlation of disease specific protein patterns with patient outcomes are shown. Laser capture microdissection has been employed to isolate individual types of cells from heterogeneous cell populations in tissues and these isolated cells profiled for proteins by MALDI MS. Imaging MS has also been applied to drug targeting and metabolic studies with analysis of specific tissues after systemic drug administration. Whole animal sagittal sections have been imaged to measure molecular changes in proteins in multiple organs and correlating this with drug concentrations in these same organs.

Richard M. Caprioli is the Stanley Cohen Professor of Biochemistry and Director of the Mass Spectrometry Research Center at Vanderbilt University School of Medicine. He is also currently Professor in the Departments of Chemistry and Pharmacology at Vanderbilt University. Dr. Caprioli received his B.S. in 1965 from Columbia University in New York, N.Y., his Ph.D. in 1969 in Biochemistry, also at Columbia University with Professor David Rittenberg. He did a one-year postdoctoral fellowship at Purdue University with Professor John H. Beynon. In 1970, he was appointed as Assistant Professor of Biochemistry at Purdue. In 1975, Dr. Caprioli moved to the University of Texas Medical School in Houston where he was Professor of Biochemistry and Molecular Biology and Director of the Analytical Chemistry Center until his move to Nashville in early1998.

Professor Caprioli is interested in the use of mass spectrometry for the analysis of compounds in biological systems. Current work includes the use of electrospray and laser desorption ionization methods with biological tissues and samples. Applications have focused on the development of this instrumentation and associated methodologies to achieve ultra-high sensitivity detection of endogenous compounds (e.g., neuropeptides) in live animal systems. He has published over 300 scientific papers, including three books. Recent work involves the development of Imaging Mass Spectrometry, a technique whereby molecular images of peptides, proteins, drugs and other compounds are localized in tissue sections with molecular weight specificity. This method involves molecular mapping of animal tissue through the production of ion images obtained from the analysis of mammalian tissue. Applications to specific research areas involve questions about certain spatial distributions of molecules within specific tissues, e.g., mapping proteins in cancer tissue. Specific applications include human glioblastomas, aberrant mouse colon crypts, and mouse prostate tumors

Dr. Caprioli has been a member of the American Society for Mass Spectrometry since 1975; he recently served two years each as President of the Society and Vice-President for Programs. He is a member of the American Society for Biochemistry and Molecular Biology. Professor Caprioli has been the Editor-in-Chief of the Journal of Mass Spectrometry since 1990. He is currently co-editing a volume of Encyclopedia of Mass Spectrometry. In 2003, Dr. Caprioli received the Thomson Medal Award from the International Mass Spectrometry Society for "for outstanding achievements in mass spectrometry and for distinguished service to international mass spectrometry."

Using Imaging and imaging Biomarkers to Accelerate Drug Development

Dr. Homer H. Pien, Managing Director, Center for Biomarker Imaging, Dept. of Radiology, MGH, Charlestown, MA

New drugs are estimated to cost approximately $1B and 12-years to reach the marketplace. Concurrently, the number of new molecular entities approved by the Food and Drug Administration has decreased steadily over the past several years. Some have argued that biomarkers may be used to significantly reduce the cost and time associated with new drug development, while simultaneously provide greater insights into the drug's bioactivity. Two major camps of biomarkers have emerged: molecular and imaging biomarkers. While molecular biomarkers may be more familiar to most, considerable evidence has now been accumulated on the benefits conferred by imaging biomarkers. In particular, modern 3-D in vivo imaging methods such as MR, CT, PET, and molecular imaging have undergone revolutionary advances in resolution and specificity over the past decade, and can help address key issues that arise during drug development, including those concerning translational research, efficacy, mechanism, PD/PK, dosing, as well as contribute to registration filings. However, biomarkers in general, and imaging biomarkers in particular, must be used with caution since careless use of biomarkers can lead to erroneous conclusions. The objectives of this presentation were to describe the relationship between molecular and imaging biomarkers, provide specific examples of how imaging biomarkers are utilized in drug development for both animal and human studies and discuss ways in which biomarkers may lead to false conclusions.

Dr. Homer H. Pien

Dr. Homer H. Pien is currently the managing director of the Center for Biomarkers in Imaging at the Massachusetts General Hospital, is on the faculty of Harvard Medical School, and is an adjunct professor in the Graduate College of Computer Science at Northeastern University. Previously, Dr. Pien was a co-founder, CEO, and COO of SRU Biosystems; vice president and technical director of Medical OnLine; leader of the Image Recognition Systems Group and Director of Biomedical Technologies program office at Draper Laboratory; a founding member and Director of Technology at the Center for Integration of Medicine and Innovative Technology (CIMIT), and an assistant staff member at MIT Lincoln Laboratory. Dr. Pien received his BS in mathematics from the University of Illinois, MS and PhD in computer science, focusing on image processing and computer vision, from Northeastern University, and MS in Management from MIT.