Dr. Conklin’s research focuses on human genetics that lead to cardiovascular diseases, such as cardiac arrhythmias and cardiomyopathy. His uses genome engineering methods to test the role of specific genetic changes in induced pluripotent (iPS) cell-derived models of disease. Dr. Conklin began his research career by working for two years with Julius Axelrod, Ph.D., (Nobel Laureate) at the National Institutes of Health. He then completed his residency at Johns Hopkins Hospital and a postdoctoral fellowship in the laboratory of Henry Bourne, M.D. at UCSF. In 1995 Dr. Conklin joined the Gladstone Institutes and the UCSF faculty where he has advanced to become a Senior Investigator at Gladstone, and a Professor at UCSF. Dr. Conklin is also the Gladstone Scientific Officer for Technology and Innovation. Dr. Conklin is the founder of several public stem cell and genomics projects including BayGenomics, GenMAPP, AltAnalyze and WikiPathways. Dr. Conklin pioneered the field of using designer G protein coupled receptors (RASSLs) for tissue engineering. He was the founding director of the Gladstone Genomics Core and the Gladstone Stem Cell Core. Dr. Conklin leads the Gladstone Stem Cell Training Program, is the principal investigator on multiple research grants from NIH and serves on multiple advisory boards. He is a member of several honorary societies, including the American Society for Clinical Investigation, and is a Fellow in the California Academy of Sciences. Dr. Conklin’s expertise in the field of stem cell biology, genomics, regulatory signaling and bioinformatics is essential for the success of his research projects.
Human Cardiac Disease Models We use induced pluripotent stem (iPS) cells to model human cardiac genetic disease. We focus on genes associated with heart failure from cardiomyopathy or abnormal heart rhythm resulting in “sudden death.” The heart provides an ideal system to determine the molecular basis of human genetic findings. Hundreds of gene loci have already been associated with heart disease, yet, until recently, modeling these gene variants in human cardiac tissue has been difficult. Human iPS cells now allow us to produce many cardiovascular tissues that have already been used to successfully uncover disease phenotypes. Our first studies focused on iPS cells from patients who have genetic diseases and, more recently, the lab as focused on engineering iPS cells to have specific mutations since they allow more in-depth studies of disease mechanism in a controlled background.
Genome and Tissue Engineering
The late Richard Feynman once said, “What I cannot create, I do not understand.” Although this is well known in the field of engineering, we are just beginning to apply the principle to human biology. Up until recently, human genetics was primarily observational, but newly developed genome engineering tools now allow us to directly test the cellular consequences of discrete genetic changes. We have developed efficient methods to edit one residue at a time in living human iPS cells, resulting in “isogenic” iPS cell lines that are identical except for a single alteration. These isogenic iPS disease models are now yielding phenotypes that are helping to explain the molecular basis of several human diseases. In addition, we are constructing collections of isogenic disease cell lines that carry a range of disease mutations, from the most severe (rare) to the moderate (common) forms of cardiomyopathy. We are currently focused on the most severe cardiomyopathies to develop cell-based assays. We are hopeful that these severe cardiomyopathies will allow us to understand the molecular basis of the more common cardiomyopathies as well.
The heart is a complex tissue that is tightly integrated via chemical and electrical coupling. We are working with tissue engineers to recapitulate these complex tissues so that we can better model cardiac disease. The disease cell lines we are making help to provide a “yard stick” to measure robustness of engineered tissues. The cardiac tissues that best reflect human cardiac contraction, and electrical coupling are most likely to provide insights into specific human disease genes.
Miyaoka Y, Chan AH, Judge LM, Yoo J, Huang M, Nguyen TD, Lizarraga PP, So PL, Conklin BR, Isolation of single-base genome-edited human iPS cells without antibiotic selection, Nature Methods, 2014 Mar;11(3):291-3.
Conklin BR. Sculpting genomes with a hammer and chisel (2013) Nat Methods. Aug; 10(9):839-40.
Spencer CI, Baba S, Nakamura K, Hua EA, Sears MA, Fu CC, Zhang J, Balijepalli S, Tomoda K, Hayashi Y, Lizarraga P, Wojciak J, Scheinman MM, Aalto-Setälä K, Makielski JC, January CT, Healy KE, Kamp TJ, Yamanaka S, Conklin BR. (2014) Calcium transients closely reflect prolonged action potentials in iPSC models of inherited cardiac arrhythmia. Stem Cell Reports, 3(2):269-81. PMC4175159.
Salomonis N, Nelson B, Vranizan K, Pico AR, Hanspers K, Kuchinsky A, Ta L, Mercola M, Conklin BR. (2009) Alternative splicing in the differentiation of human embryonic stem cells into cardiac precursors. PLoS Comput Biol, 5(11):e1000553.
Conklin BR, Hsiao EC, Claeysen S, Dumuis A, Srinivasan S, Forsayeth JR, Guettier JM, Chang WC, Pei Y, McCarthy KD, Nissenson RA, Wess J, Bockaert J, Roth BL. (2008) Engineering GPCR signaling pathways with RASSLs. Nat Methods, 5(8):673-8.