Nancy Allbritton, MD, PhD (Bioengineering)
Research in my laboratory focuses on the development of novel methods and technologies to answer fundamental questions in biology & medicine. Much of biology & medicine is technology limited in that leaps in knowledge follow closely on the heels of new discoveries and inventions in the physical and engineering sciences; consequently, interdisciplinary groups which bridge these different disciplines are playing increasingly important roles in biomedical research. Our lab has developed partnerships with other investigators in the areas of biology, medicine, chemistry, physics, and engineering to design, fabricate, test, and utilize new tools for biomedical and clinical research. Collaborative projects include novel strategies to measure enzyme activity in single cells using microelectrophoresis innovations, to build organ-on-a-chips particularly intestine-on-chip, array-based methods for cell screening and sorting. An additional focus area is the development of software and instrumentation to support these applications areas. The ultimate goal is to design and build novel technologies and then translate these technologies into the marketplace to insure their availability to the biomedical research and clinical communities to enable humans to lead healthier and more productive lives.
Charles Alpers, MD (Lab Medicine & Pathology)
Our research involves studies of kidney disease consequent to immune responses to foreign pathogens and as a consequence of diabetes.
Benjamin Freedman, PhD (Medicine/Nephrology)
Our laboratory has developed techniques to efficiently differentiate hPSCs into kidney organoids in a reproducible, multi-well format – a prototype ‘kidney-in-a-dish’. In addition, we have generated hPSC lines carrying naturally occurring or engineered mutations relevant to human kidney diseases, such as polycystic kidney disease and nephrotic syndrome. The goal of our research is to use these new tools to model human kidney disease and identify therapeutic approaches, including kidney regeneration.
William R. Henderson, Jr., MD (Medicine/Allergy and Infectious Diseases)
Study aims of the Henderson laboratory are to address the role of progenitor cells in lung repair in mouse models of pulmonary fibrosis and asthma. For this, stem cells (embryonic and adult bone marrow-derived mouse and human cells) will be isolated and manipulated ex vivo in culture prior to in vivo administration in mice with fibrotic lungs. Important goals are to determine if engrafted cells proliferate and repair/regenerate damaged lung tissue. The effect of small molecule inhibitors of key signaling pathways in the airway fibrotic process will also be examined in these studies that may lead to novel therapies for patients with airway injury and fibrosis.
Edward J. Kelly, PhD (Pharmaceutics)
Utility of embryonic stem (ES) cells as a source of human hepatocytes.
Gustavo Matute-Bello, MD (Pulmonary and Critical Care Medicine)
Our laboratory is interested in the role of resident lung stem cells in the response of the lung to injury. Ultimately we want to determine whether therapeutic strategies involving lung resident stem cells could be useful for the treatment of acute lung injury and repair.
John K. McGuire, MD (Pediatrics)
My laboratory work is directed at understanding how epithelial responses to acute injury and infection regulate lung repair and resolution of inflammation. Our work has specifically focused on understanding the role of matrix metalloproteinases in controlling lung epithelial regeneration and lung epithelial cell interactions with inflammatory cells.
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.
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.
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.
Kelly R. Stevens, PhD (Bioengineering and Pathology)
Our research is focused on developing new technologies to assemble synthetic human tissues from stem cells, and to remotely control these tissues after implantation in a patient. To do this, we use diverse tools from stem cell biology, tissue engineering, synthetic biology, microfabrication, and bioprinting. We seek to translate our work into new regenerative therapies for patients with heart and liver disease.
Valeri Vasioukhin, PhD (Fred Hutch)
Our laboratory studies the mechanisms and significance of cell polarity and cell adhesion in normal mammalian development and cancer.