Our group studies pancreas developmental biology and cancer biology in several models, including fruit flies, mice and humans. We have innovated methods for studying pancreas biology in these models, and discovered cellular, molecular and genetic mechanisms governing islet β-cell growth, development and function in mouse and human pancreas. Based on our findings, we have several active clinical collaborations to investigate translational implications of our work. My training in internal medicine and oncology helps frame and inform studies in my group. One goal of our work is to translate our studies into novel diagnostic and therapeutic strategies for common pancreatic disease states in humans, particularly diabetes mellitus and pancreatic cancer. I have also contributed to science education in multiple ways over the past two decades as a PI and mentor in several graduate and post-graduate training programs at Stanford and a high school program in New England. We are committed to training the next generation of biomedical researchers.
1. Deconstructing and reconstituting pancreas development with purified cells
Functional restoration of diseased solid organs is a broad goal motivating intensive effort in modern biomedical research. Replacement or regeneration of pancreatic islets of Langerhans, endocrine organs that secrete insulin and glucagon, has emerged as a paradigm for organ restoration in recent years. Deficiency of insulin-producing islet β-cells underlies the pathogenesis of diabetes mellitus, a disease with devastating autoimmune and pandemic forms I have managed as a physician. However, islet replacement in diabetes is ultimately limited by our inadequate understanding of mechanisms controlling islet formation and growth. Thus, islet replacement is a specific challenge to the consensus that knowledge about solid organ development and expansion can be used to restore organ function in human diseases.
To meet this challenge, we have been devoted to generating new experimental approaches to create, expand, and regenerate islets. We have discovered cell interactions and signaling pathways that regulate pancreas development in vertebrates (Kim et al 1997). We identified new FACS-based methods to purify specific classes of cells that generate the pancreas and islets, including definitive endoderm and multipotent progenitor cells from fetal pancreas that self-renew, and recapitulate pancreatic endocrine and exocrine cell development in vitro (Sugiyama et al 2007; 2013). These approaches provide powerful platforms to accelerate use of pancreatic and embryonic stem cells for islet studies and replacement. To decode the global logic of genetic and epigenetic regulatory networks controlling pancreas development, we have combined cell-sorting strategies with other modern genome-scale methods to produce and analyze expression profiles from pancreatic stem/progenitor cells and their progeny (Benitez et al 2014). We have used these experimental strategies to investigate human pancreas developmental genetics (Pauerstein et al 2015; Arda et al 2016).
Arda HE, Li L, Tsai J, Torre EA, Rosli Y, Peiris H, Spitale RC, Dai C, Gu X, Qu K, Wang P, Wang J, Grompe M, Scharfmann R, Snyder MS, Bottino R, Powers AC, Chang HY, Kim SK. 2016. Age-dependent pancreatic gene regulation reveals mechanisms governing human beta-cell function. Cell Metabolism. 23(5):909-920.
Pauerstein PT, Park KM, Peiris HS, Wang J, Kim SK. 2016. Research Resource: Genetic labelling of human islet alpha cells. Molecular Endocrinology. 30(2):248-253.
T. Sugiyama , Benitez CM, Ghodasara A, Liu L, McLean GW, Lee J, Blauwkamp TA, Nusse R, Wright CVE, Gu G, and S.K. Kim 2013. Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation. Proc. Natl. Acad. Sci. USA 110:12691-12696
C.M. Benitez, K. Qu, T. Sugiyama, P.T. Pauerstein, Y. Liu, J. Tsai, X. Gu, A. Ghodasara, H.E. Arda, J. Zhang, J.D. Dekker, H.O. Tucker, H.Y. Chang, S.K. Kim. 2014. An Integrated Cell Purification and Genomics Strategy Reveals Multiple Regulators of Pancreas Development. PLoS Genet 10:e1004645.
Pauerstein PT, Sugiyama T, Stanley SE, McLean GW, Wang J, Martin MG, Kim SK. 2015. Dissecting human gene functions regulating islet development with targeted gene transduction. Diabetes. 64(8):3037-49.
2. Discovery of mechanisms regulating pancreatic islet β-cell proliferation and function
Once viewed as post-mitotic and incapable of significant proliferation, β-cells in the pancreas are now recognized to have a significant capacity to replicate, and thereby maintain or expand β-cell mass. For this reason, expansion of islets in culture or in the pancreas may become a therapeutic option for diabetes. However, prior attempts to expand cultured islets with mitogens have been bedeviled by the loss of key β-cell features, like insulin expression, that accompanies proliferation. Thus, it remains elusive how adult β-cells 'remember' their differentiated fate while proliferating. To decode the mechanisms controlling β-cell proliferation, we sought to identify signals, and genetic and epigenetic pathways that govern expression of hallmark β-cell factors and cell cycle regulators. This led to identification of several regulators, including Menin, Wnt, PDGF, and NFAT signaling in β-cell proliferation. This includes discovery of mechanisms underlying age-dependent declines in β-cell proliferation (Chen et al, 2009, 2011; Goodyer et al 2012; Zhou et al 2013; Banerjee et al 2016).
Banerjee RR, Cyphert HA, Walker EM, Chakravarthy H, Peiris H, Gu X, Liu Y, Conrad E, Goodrich L, Stein RW, Kim SK. 2016. Gestational diabetes from inactivation of prolactin receptor and MafB in islet beta cells. Diabetes. In Press.
S.K. Karnik, C.M. Hughes, X. Gu, O. Rozenblatt-Rosen, G.W. McLean,
Y. Xiong, M. Meyerson, and S.K. Kim. 2005. Menin
regulates pancreatic islet growth by promoting histone methylation
and expression of genes encoding p27Kip1 and p18INK4c. Proc.
Natl. Acad. Sci. USA 102: 14659-14664.
J.J. Heit, Å.A. Apelqvist, X. Gu, M.M. Winslow, J.R. Neilson,
G.R. Crabtree and S.K. Kim. 2006. Calcineurin/NFAT
signaling regulates pancreatic β-cell growth and function. Nature, 443: 345-349.
Chen H, Gu X, Liu Y, Wang J, Wirt SE, Bottino R, Schorle H, Sage J, Kim SK. 2011. PDGF signalling controls age-dependent proliferation in pancreatic β-cells. Nature. 478(7369):349-55
W. Goodyer, X. Gu, Y. Liu, R. Bottino, G.R. Crabtree, S.K. Kim. 2012. Neonatal β-Cell Development in Mice and Humans Is Regulated by Calcineurin/NFAT. Developmental Cell 23: 21-34.
Z.X. Zhou, Dhawan S, Fu H, Snyder E, Bottino R, Kundu S, S.K. Kim, and A. Bhushan. 2013.Combined modulation of polycomb and trithorax genes rejuvenates β cell replication. J Clin Invest 123:4849–4858.
3. Establishing the cellular and hormonal basis of metabolic regulation in Drosophila
We discovered Drosophila endocrine cells that secrete insulin in collaboration with my colleagues Roel Nusse and Eric Rulifson, and showed this hormone is crucial for regulation of fly growth and glucose homeostasis. We demonstrated that Drosophila cells secreting a glucagon-like hormone called AKH are also essential for glucose regulation. We showed that glucose-sensing and responses by AKH-secreting cells are governed by KATP channels, which also regulate stimulus-secretion coupling in mammalian islets. We have also generated methods to measure circulating bioactive insulin in fruit flies. These discoveries have created new opportunities to use the powerful experimental advantages of Drosophila for genetic, developmental and lineage studies of ancestral islet-like cells to identify new regulators of pancreatic islet development, growth and function.
E.J. Rulifson, S.K. Kim, and R. Nusse. 2002. Ablation
of insulin-producing neurons in flies: growth and diabetic phenotypes. Science, 296:
S.K. Kim and E.J. Rulifson. 2004. Conserved
mechanisms of glucose sensing and regulation by Drosophila corpora
cardiaca cells. Nature 431: 316-420.
Park S, Bustamante EL, Antonova J, McLean GM, S.K. Kim. 2011. Specification of Drosophila Corpora Cardiaca Neuroendocrine Cells from Mesoderm is Regulated by Notch Signaling. PLoS Genetics. 7(8):e1002241.
S. Park, R.W. Alfa, S.M. Topper, G.E.S. Kim, L. Kockel, S.K. Kim.2014. A Genetic Strategy to Measure Circulating Drosophila Insulin Reveals Genes Regulating Insulin Production and Secretion. PLoS Genet 10:e1004555.
4. Discovery of a decretin hormone
Decretins are hormones induced by fasting that suppress insulin production and secretion, and have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila ortholog of Neuromedin U receptors (NMURs), in insulin-producing cells phenocopied limostatin deficiency and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insu- lin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output. This work illustrates the potential of the Drosophila systems developed in our group to make discoveries about important conserved hormone pathways likely relevant to human biology. We are pursuing the implications of these findings in mammalian systems.
R.W. Alfa, Park S, Skelly KR, Poffenberger G, Jain N, Gu X, Kockel L, Wang J, Liu Y, Powers AC, S.K Kim. 2015. Suppression of Insulin Production and Secretion by a Decretin Hormone. Cell Metab. 21:323-333.
N. Gough. 2015. Finding the decretin hormone. Sci. Signal 8, Issue 363, ec29 DOI: 10.1126/scisignal.aaa8672
5. Contributions to science education
I have contributed to science education in multiple ways over the past 17 years as a PI and mentor in several graduate and post-graduate training programs at Stanford. Our group has trained 8 PhD students, 2 MS students, 23 postdoctoral fellows, 10 high school students, and 20 undergraduates over the past 17 years at Stanford. Our group has a growing track record of career achievement in its graduates. As of this writing (2015), 8 previous technicians from the Kim laboratory have entered MD/PhD, PhD or MD programs. Of 10 PhD or MS students, 6 remain in training and 2 hold assistant professor positions at Stanford. 8 post-doctoral fellows from the Kim lab now hold assistant, associate or full professorships in academic institutions, 7 are currently in our group, and several others lead biomedical research teams in industry. For 14 years I directed or co-directed the Stanford Medical Scientist Training Program (MSTP), a dual-degree MD/PhD program. For the past several years, I have taught graduate and post-graduate students ‘how to write grants’ in a well-received course. In 2012 we created a course designed to expose advanced high-school students to biomedical research and open-ended discovery at Phillips Exeter Academy, my high school. In this Stanford-Exeter course, now in its third consecutive year, and in partnership with instructors at Exeter, we aim to introduce students to biomedical research by creating and characterizing new strains of fruit flies (Drosophila melanogaster) that can be used by a worldwide community of investigators. We are now exploring expansion of this model to other high schools.
Farming Fruit Flies for Science
Our efforts have created unprecedented opportunities for harnessing knowledge about the molecular and cellular basis of pancreatic development and growth to restore pancreas islet function and to diagnose pancreas cancers. Our work with Drosophila, mice, human islet organogenesis and diseases, cell purification, and chromatin regulation has revealed mechanisms underlying islet development, adaptations and disease pathogenesis. We trust that our discoveries will provide the tools and expertise needed to produce islet regeneration therapies for type 1 diabetes, improve treatments and tests to mitigate or prevent type 2 diabetes, and generate new therapeutic strategies for endocrine or exocrine pancreas cancers.