Robert A. Cornell, PhD (Oral Health Sciences)
Our group is interested in the gene regulatory networks (GRNs) that govern the decision of multipotent embryonic precursor cells to differentiate into one or another adult cell type. We study this question in the context of early blastomeres and the neural crest. We are also interested in the GRN that governs the decision of melanocyte stem cells to remain quiescent or to divide and differentiate.
We use zebrafish to explore these questions. We are examining the regulatory hierarchy of transcription factors in the GRN that promotes embryonic precursor cells to become periderm, a tissue that is essential for normal morphogenesis of the face and whose disruption leads to orofacial cleft. In addition, we are exploring how the transcription factors TFAP2 and MITF regulate melanocyte stem cell deployment. Working with colleagues in human genetics, we also have a project to distinguish the functional subset of DNA variants, both coding and non-coding, that are associated with risk orofacial cleft.
Maintenance versus deployment of stem cells is a fine balance: too far in one direction and there can be problems with wound healing and tissue maintenance, too far in the other can lead to cancer. Understanding the GRNs that govern this balance will lead to the development of therapies that can tip the balance one way or the other in patients as needed.
Christine Disteche, PhD (Pathology)
Research in my lab focuses on the regulation of the mammalian X chromosome.
Cecilia Giachelli, PhD (Bioengineering)
My lab is interested in applying stem cell and regenerative medicine strategies to the areas of ectopic calcification, tissue engineering, biomaterials development and biocompatibility.
Marshall Horwitz, MD, PhD (Pathology)
The Horwitz laboratory has a longstanding interest in genes and mechanisms leading to hematological malignancy. More recently, the lab has focused attention on using somatic mutations to infer cell lineage in order to better understand how stem cells contribute to development, tissue regeneration, and cancer.
David Kimelman, PhD (Biochemistry)
This lab dissects the formation of mesodermal progenitor cells in zebrafish as a model organism, focusing on how these cells form the trunk and tail.
Ronald Kwon (Orthopaedics and Sports Medicine)
Our lab is focused on skeletal disease and regeneration. We are understanding the genetic basis of osteoporosis, and identifying new therapeutic targets to combat this massive health burden. We are also understanding why certain organisms such as fish are able to regenerate bony appendages following amputation, and how to mount this response in the digits and limbs of mammals.
The Musculoskeletal Systems Biology Lab comprises engineers, basic scientists, and clinicians. Our focus is on taking bold, innovative approaches to reverse aging-induced bone fragility, and to help realize human regenerative potential.”
Paul Lampe (Fred Hutch)
Our interests in stem cell biology and regenerative medicine mainly revolve around the protein I have spent the last 25-plus years studying, connexin43 (Cx43). Cx43 is the primary protein in gap junctions, a subcellular structure that couples intercellular communication to a cytoplasmic scaffold that coordinates cellular responses to different stimuli including epidermal wounding cardiovascular ischemia and tumorigenesis. Gap junctions are critical at many developmental stages and in response to injury. Specifically, we are interested in understanding the role that Cx43 regulation plays in stem cells and tissue reorganization during epidermal wound repair. Cx43 plays a key role in the initiation of migration and up regulation of proliferation needed to fill in the wound bed – so called re-epithelialization. We study this process using a transgenic mice and human studies. Gap junctions play a key role in regulating sodium and potassium flux between cardiomyocytes and are downregulated during cardiac disease; we have a long-standing collaboration with Mike Laflamme to determine whether modulation of gap junctions can achieve better engraftment of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) post myocardial infarction. We have also studied the role of Cx43 in differentiation of stem cells into definitive endoderm during pancreas development in collaboration in Vincenzino Cirulli. We encouraged and assisted the Allen Institute in the creation of hiPSCs that express one copy of Cx43-GFP that we hope will be useful in further studying the role of Cx43 in stem cell differentiation and cell fate.
Ghayda Mirzaa, MD (Pediatrics)
The broad goal of our research is to understand the causes, mechanisms and outcomes of human developmental brain disorders, including brain growth abnormalities (megalencephaly, microcephaly), malformations of cortical development and associated co-morbidities including autism, epilepsy and intellectual disability. Our work has led to gene discovery for several disorders associated with brain growth dysregulation including megalencephaly (e.g. PIK3CA, PIK3R2, AKT3, MTOR, CCND2) and microcephaly (e.g. STAMBP, CENPE, KIF11, CDC42), among several others (Mirzaa et al., Neuropediatrics 2004; Mirzaa et al., AJMG 2012; McDonnell et al., Nature Genetics 2013; Mirzaa et al., Pediatric Neurology 2013; Mirzaa et al., Human Genetics 2014; Martinelli et al., American Journal of Human Genetics 2018). Our work on the PI3K-AKT-MTOR related brain overgrowth disorders has led to the identification of several genes within this pathway that cause brain growth dysregulation and focal cortical dysplasia, with important therapeutic implications using PI3K-AKT-MTOR pathway inhibitors (Rivière et al., Nature Genetics 2012; Mirzaa et al., Nature Genetics 2014; Jansen et al., Brain 2015; Mirzaa et al., Lancet Neurology, 2015; Mirzaa et al., JAMA Neurology, 2016).
Our lab is focused on identifying the molecular and cellular mechanisms of developmental brain disorders and translating these genomic discoveries to molecularly-guided therapies using high throughput genomic, transcriptomic, and proteomic methods in relevant human tissues, combined with functional validation of genetic variants using human reprogramming and genome editing via CRISPR-Cas9 methods. Our lab houses the first human stem cell tissue culture facility at the Seattle Children’s Research Institute (SCRI) solely dedicated to generating human induced Pluripotent Stem Cells (iPSCs), Neural Progenitor cells (NPCs), cortical neurons and cerebral organoids to model genetic variants that are of high relevance to neurodevelopmental disorders, and to be used as a platform for future pre-clinical high throughput drug screening.
David W. Raible, PhD (Biological Structure)
We are interested in the development of the peripheral nervous system using zebrafish as a model. Current research focuses on two areas: sensory neurons derived from neural crest and the mechanosensory lateral line system.
Jeff Rasmussen, PhD (Biology)
Our lab uses zebrafish to gain insights into neuronal and tissue plasticity, both during development and following injury. The skin is our largest sensory organ and is densely innervated by somatosensory nerve endings that sense pain and touch. Nerve regeneration is often incomplete following skin injury, and sensory loss is a major complication associated with diabetes and chemotherapy. Using the imaging advantages of the zebrafish system and novel remodeling assays developed in the lab, we have identified interactions between somatosensory nerve endings and several specialized cell types (including osteoblasts, resident macrophages, and sensory cells) within the skin tissue environment. Our long-term goals are to understand: (1) the molecular basis for these axon-tissue interactions; and (2) how these interactions regulate tissue form and function, both during development and in disease states.
Jay Shendure, MD, PhD (Genome Sciences)
The primary mission of our lab is to develop and apply new technologies at the interface of genomics, molecular biology and developmental biology.
Most genetic variants that contribute to the risk or severity of common and rare diseases fall in regions of the human genome that control the expression of genes, rather than in the genes themselves. Although we have learned the hallmark characteristics of such “enhancer” regions, it has been exceedingly difficult to pinpoint which genetic variants within them are disease-contributory and which gene(s) they act through.
We have been working on implementing and advancing stem cell models of development, including gastruloids and embryoid bodies, and implementing multiplex CRISPR-based screens in them in order to identify regulatory elements and variants that may impact development.
Cory L. Simpson, MD, PhD, FAAD (Medicine/Dermatology)
Our lab studies the skin, which serves as a protective shield between the human body and its environment. This critical barrier tissue is tasked with sealing the body to prevent water loss, excluding pathogens like bacteria to avoid infection, and withstanding damage from environmental insults like ultraviolet radiation to resist cancer formation. The epidermis is made up of multiple layers of cells called keratinocytes, which must continually replicate themselves to replenish the skin tissue as it is naturally shed every month. While keratinocytes slowly move outward toward the skin surface, they must undergo a unique process of maturation to harden and strongly adhere to one another to protect the body and resist wounding. Unfortunately, keratinocyte maturation is disrupted in many human skin diseases like eczema and psoriasis or in rare genetic disorders like ichthyoses. These diseases can cause widespread flaky, itchy, painful, and wounded skin.
Our understanding of the biology of keratinocyte maturation is limited and this has prevented development of effective therapies to promote regeneration of the epidermis after wounding and limits our ability to treat inherited skin disorders. To address this knowledge gap, I have optimized a laboratory “organoid” model of the epidermis in which human keratinocytes form a multi-layered tissue in just 1 week. We can engineer the keratinocytes to express fluorescent proteins that are visible using a high-magnification (confocal) microscope. This technique permits us to visualize changes in the live tissue model at the level of single organelles (e.g., mitochondria) to better understand how the epidermis forms. As well, we can use genetic engineering to alter the DNA of human keratinocytes to make them harbor mutations found in human skin disorders in order to model those disease in the lab. These skin tissue models can then be treated with chemicals that might serve as new medications. Ultimately, we aim to use our lab’s findings to identify novel treatment strategies to promote epidermal tissue regeneration after skin injuries and to restore skin barrier function in inherited and currently incurable dermatologic diseases lacking effective therapies.
Alec Smith, PhD (Physiology & Biophysics)
My lab’s research is focused on understanding the mechanistic pathways that underpin muscle and nervous tissue development in health and disease. To achieve this, we are developing human stem cell-derived models of neuromuscular diseases, such as amyotrophic lateral sclerosis (ALS). By analyzing the behavior of these cells, we aim to better define how the causal mutation leads to the development and progression of neurodegenerative disease. Ultimately, identification of pathways critical to disease progression will provide new targets for therapeutic intervention, leading to the development of new treatments for patients suffering from these debilitating and life-threatening conditions.
Jason G. Smith, PhD (Microbiology)
Our laboratory cultures enteroid “mini guts” from adult intestinal epithelial stem cells to study the genetics of inflammatory bowel disease (IBD), Paneth cell development and function, and host pathogen interactions in the gut.
Valeri Vasioukhin (Fred Hutch)
Our laboratory studies the mechanisms and significance of cell polarity and cell adhesion in normal mammalian development and cancer.
Claudia G. Vásquez (Biochemistry)
Our research is focused on understanding the molecular and physical rules that cells use to build and shape functional organs. The goal of our lab is to dissect the emergent properties progenitor cells use to build complex higher-order tissue structures, like our organs. We take a multidisciplinary approach, using a combination of quantitative light microscopy, genetics, and biochemistry on the developing renal system of the fruit fly (Drosophila melanogaster Malpighian tubules) as an in vivo model for organogenesis. The developing fly renal system involves the generation and extension of two pairs of tubes that fold on themselves in a stereotypic manner providing an ideal model in which to isolate the parameters that generate specific cell and tissue shapes while keeping the cells in an in vivo context. Work in our lab will leverage the known conserved pathways and molecular mechanisms at work in studying cells at an individual basis to uncover how progenitor cells collectively integrate these features into highly regulatable 3D tissue forms with physiological functions.
We expect that cells and tissues will use a diversity of strategies to generate 3D folding patterns – and that understanding of how cellular shape feeds into tissue form will inform us how organ form informs its physiological function. Understanding these strategies will bring us closer towards recovering organs that are in dysfunction or regenerating organs.
Li Xin (Urology)
We are interested in using the prostate as a tissue model to study the molecular and cellular mechanisms that regulate development, tissue homeostasis and carcinogenesis. Currently, there are two major research focuses in the lab. The first research focus is to characterize the prostate epithelial lineage hierarchy. We seek to investigate how individual prostate epithelial lineages are maintained in adults by prostate stem cells or progenitors, and to identify master regulators that control adult prostate homeostasis. Cells of origin for tumor can dictate the clinical behaviors of the resulting diseases. Investigating the normal prostate lineage hierarchy serves as a prerequisite to understanding the cells of origin for prostate cancer, which will ultimately help understand the cellular basis for the aggressive prostate cancer. The second focus of the lab is to investigate the molecular mechanisms underlying the initiation and progression of the prostate related diseases including prostate cancer and benign prostatic hyperplasia. We are interested in determining the function of genetic changes or altered signaling that are associated with these diseases using genetically engineered mouse models. This work will inspire novel prognostic markers and therapeutic targets for these diseases.