Frederick Coffman, Ph.D.

In an extensive series of studies with Dr. Stanley Cohen, Dr. Coffman investigated the regulation of DNA replication initiation in leukemia cells, and in the process developed an in vitro DNA replication system utilizing plasmids containing DNA replication origin regions from the human ribosomal RNA gene. DNA replication in these plasmids initiated from the same origin regions as are used in vivo, without relying on a viral replication origin and a viral replication initiation protein (such as an SV-40 replication origin and the SV-40 large T antigen, which were commonly used to study human DNA replication proteins in vitro. His group also identified which origin region was preferentially utilized early in S phase when DNA containing actively transcribed genes is replicated, and which origin region was preferentially utilized late in S phase when DNA containing transcriptionally silent genes are replicated. His group also demonstrated that the RNA splicing factor SF2/ASF (now more commonly called SRSF1, or serine and arginine-rich splicing factor 1) bound to specific origin-related sequences near one of the replication initiation sites, which was the first demonstration of DNA binding by this RNA splicing factor and raised interesting questions regarding both the potential utility of this interaction in the integrated regulation of cell proliferation and RNA processing, as well as evolutionary implications reflecting the transition from the earliest RNA-based life forms to more current DNA-based life forms.

While investigating gene expression patterns in soft tissue tumors, Dr. Coffman became interested in the chitinase family protein CHI3L1 (also called YKL-40), which was significantly upregulated in these tumor samples. CHI3L1 had previously been implicated in tissue remodeling processes, and Dr. Coffman and his collaborators showed that it can also act as a biomarker of stem cell differentiation, as a prognostic biomarker in breast cancer, and potentially as a tumor cell survival factor. This is a unique member of the chitinase gene family, as it has no chitin hydrolytic activity due to several point mutations in the enzyme active site, but it appears to be significantly involved in a number of processes relevant to tissue remodeling, angiogenesis, tumor survival and regulation of immune responses (more recently it has been shown to be involved in the development of asthma and has been used as a prognostic biomarker of more severe asthmatic responses).

Dr. Coffman has also applied his early interests in chemistry and biophysics toward the identification of differences in the biophysical properties of low grade and highly malignant cancer cells, using impedance measurements and laser Raman micro-spectrophotometry. Since cell phenotypes (and cell behaviors) are based on cell genotypes, examining cell phenotypes in this manner may offer another way to identify more dangerous cancers. Prognostic molecular classifications of cancer cells are based primarily on a number of key established genomic alterations, and while some DNA mutations, such as those in BRCA1 and APC, have been shown to have clear clinical consequences, in many cases the combinations of genetic variations which create the clinical tumor phenotype are not well understood. Biophysical approaches can show the direct results of complex and varied combinations of genetic variations, and identifying biophysical “fingerprints” of more aggressive tumors would facilitate the earlier identification of more dangerous diseases. The laser Raman studies revealed an interesting phenomenon within a number of different tumor cell lines – the presence of highly ordered lipids within the cell nuclei. These highly ordered lipids co-localize with nuclear chromatin, are present throughout the nuclear volume, and appear to remain co-localized with chromatin through mitosis, when the nuclear envelope has dissociated. Phosphatidylinositol is a major component of the highly ordered lipids, which is intriguing due to the involvement of this lipid in intracellular signaling pathways. While the roles of these ordered lipids remain to be elucidated, their presence enveloping nuclear chromatin does add another layer of complexity to how transcription factors which translocate from the cytoplasm locate and subsequently bind to specific DNA sequences.

In his current role in the Health Informatics Department, Dr. Coffman has continued his interest researching human diseases, especially cancers. He has collaborated with Dr. Antonina Mitrofanova on several of her projects involving pathway analysis of the development of treatment resistance in breast and prostate cancer cells, and has worked with a number of his own students on projects focused on cancers of the breast, cervix, stomach, head and neck, leukocytes, and melanocytes. He has worked with students in developing research projects focused on non-cancerous diseases, such as ischemic stroke, celiac disease, systemic lupus erythematosus, asthma, osteoporosis, early onset Type II diabetes, renal failure and schizophrenia. He has also worked with students whose projects focused on effectors and predictors of patient procedural and post-procedural outcomes. He is involved in Dr. Scott Parrott’s project analyzing respiratory disorders in US military veterans who have served in Iraq and Afghanistan and were exposed to toxic fumes from burn pits. He is also developing bioinformatics projects based on previous laboratory projects, to take advantage of his experience in those areas as well as the current availability of growing molecular databases and analytical tools. Of particular interest is CHI3L1, which shows computational linkages with anti-inflammatory cytokines and asthma regulatory proteins, as well as a large cluster of electron transport system-linked genes, which offers tantalizing new clues about the role of this protein in a number of biological processes.