Thomas Lufkin

Research Interests Our research is in the novel area of Developmental Genomics and Regenerative Medicine with a focus on the molecular mechanisms controlling vertebral column development and an emphasis on early embryogenesis and embryonic stem cell commitment to specific differentiation pathways, but from a novel Systems Biology point of view. We use both mouse and zebrafish as model animals. In particular we are working on understanding the gene regulatory networks (GRNs) that govern normal embryonic development of the vertebral column and intervertebral disc (IVD). We are investigating the role of transcriptional regulators in the restriction of pluripotent embryonic stem cells into specific lineages that in turn comprise functional pre and postnatal vertebral elements with the goal of applying this knowledge to regenerative medicine using patient- specific induced pluripotent stem (iPS) cells and adult mesenchymal stem cells. The incidence of lower back pain (LBP) is extraordinarily high and is a cause for societal and fiscal concern world wide. In the USA alone, LBP’s economic impact shows that it is the number one reason for people under 45 to restrict their life style, 2nd highest complaint seen by physician’s, 3rd leading cause for surgery and the 5th most common requirement for hospitalization. The economic impact of LBP is striking, and is in excess of the costs of coronary artery disease and the total costs of stroke, respiratory infection, rheumatoid disease and diabetes combined. Direct medical costs in the USA annually exceed USD $30 billion. Most often, LBP is due to degenerative changes in the disc, spinal disc herniation, trauma and fractures. Surgeons have an arsenal of procedures for repairing the damaged disc. The most common strategies provide pain relief, but fail to prevent further disc degeneration, or completely restore disc function. Thus these surgical procedures are less than ideal, as they do not prevent further degeneration of the impaired vertebral column. Our current focus is on the Pax, Sox, Bapx and Runx GRNs in the commitment of cells to the chondro/osteoblast lineages which builds the fetal skeleton. Our goal here is to build a unified GRN for embryonic skeletal development as it pertains to the vertebral column and use this knowledge to direct iPS cells to fates of clinical significance and to provide a resource to reverse trauma and age-associated spinal degeneration. In particular the IVD. Our approach is multidisciplinary, collaborative, and technology-driven. We have been highly successful at developing novel experimental strategies that combine modern molecular genetic and transgenic approaches in mouse and zebrafish with the latest bioinformatic and genomic technologies such as comparative genomics, microarray, Ditag-Seq, ChIP-Seq, RNA-Seq and others. By applying these approaches in developing embryos, we show how relevant biological data can be generated to explain pleiotropic effects in organogenesis and finally by combining these approaches simultaneously with multiple interconnected genes, we have shown how a detailed network map can be elucidated for the developing vertebral column, reiterating the importance of building gene regulatory networks in complex processes. In recent decades developmental biologists have been successful in determining some molecular level mechanisms controlling vertebral column development, such as the genes governing cell fate decisions, but have made comparatively little progress in other equally important areas such as patterning, morphogenesis, size control and regeneration. There is a major reason for this failure. These questions cannot be answered using the reductionist logic of one gene, one mutant, one phenotype, one function. Understanding these phenomena will require a more systems biological approach looking at multiple genes and their integrated activity in their native in vivo context using genomic approaches.

2chapters authored