From Molecular Insights to Patient Stratification for Neurological and Psychiatric Disorders Proceedings of a Workshop (2022) / Chapter Skim
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5 Identifying and Validating Molecular Pathways Using New Technologies for Human Biology
5 Identifying and Validating Molecular Pathways Using New Technologies for Human Biology
Pages 37-50
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From page 37... ...
. • Human brain organoids, derived from pluripotent stem cells, enable studies of diverse cell types found in developing brain, allowing investigation of the genetic causes and mechanisms of human neuropathology (Arlotta)
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From page 38... ...
To assess the functional consequences of genetic variants, human models of disease are essential, particularly when studying a combination of rare and commengenetic variants, said Dimitri Krainc. Not only is the effect size small for many of these variants, but effects may also vary across different genetic backgrounds, he said.
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From page 39... ...
For example, in autism spectrum disorder, genetic studies have implicated common genes with small effect sizes as well as many rare variants with large effect sizes, said Willsey. Each one of these genes represents an opportunity to answer questions regarding relevant cell types, brain regions, and functions as a precursor to rational drug design.
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In induced pluripotent stem cells– (iPSC-) derived neural progenitor cells, they recapitulated the proliferation defect of four autism risk genes; in addition, in human cortical organoids, they showed that estrogen rescued the inhibition of the autism risk gene DYRK1A, which contributes to decreased forebrain size in Xenopus.
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From page 41... ...
MODELING IN NON-HUMAN PRIMATES As Willsey demonstrated, some aspects of deeply conserved biology are relevant to human disorders that can be studied in evolutionarily distant animal models. However, when there is a lack of deep conservation, or where in vitro models may be inadequate, non-human primate models are valuable, said Fenna Krienen, postdoctoral fellow in Steve McCarroll's lab at Harvard Medical School and The Broad Institute.
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From page 42... ...
Single-cell sequencing also provides readouts for demonstrating cell-type specificity and enables the screening of poten tially dozens or hundreds of enhancers in a single animal, thus minimizing costs and animal use, said Krienen. HUMAN BRAIN ORGANOIDS Integrating and leveraging genetic information about neurological and psychiatric illnesses is essential to understanding disease mechanisms, said Paola Arlotta, chair and Golub Family Professor of Harvard's Department of Stem Cell and Regenerative Biology.
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From page 43... ...
This work, published as a preprint, demonstrates how they used the organoids to identify affected cell types and biological process, determine when cells were affected during development, examine whether and how these three genetic mutations converged to produce a phenotype, and assess whether and how the genetic background in which the mutations acted influenced the disease phenotype.1 What they found was that through largely different molecular mechanisms, all three of these genes converge on asynchronous development and maturations of two neuronal populations of the cerebral cortex, GABAergic neurons and deep layer projection neurons, said Arlotta. They also showed that the genetic background of the donor stem cell line affected the phenotype, indicating that individual genomes can modulate the effect of even highly penetrant risk genes.
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From page 44... ...
Kampmann and colleagues have developed scalable, high-throughput, and quantitative functional genomics technologies that perturb genes using a variation of CRISPR-Cas92 technology. Their approach controls the expression of genes targeting transcriptional activators (CRISPRa)
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From page 45... ...
The insights derived from human data are then used to build in vitro cellular systems that recapitulate the complex polygenic architecture of human disease, said Koller. Machine learning then takes the data obtained from these cellular systems to build phenotypic manifolds that inform pre dictive disease models, she said (see Figure 5-3)
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"The idea is to use this approach to identify a conserved pathophysiology across heterogeneous genetic causes where we can discern coherent subsets of patients that are likely to respond to a single treatment, and then screen for high-impact genetic modifiers of disease in those subgroups," she said. ARTIFICIAL INTELLIGENCE Leveraging the huge amount of human genetic data generated over the past decade, integrating it with other types of human data, and extending it to larger diverse patient populations will increase the probability of clinical success, said Alice Zhang, CEO and co-founder of Verge Genomics.
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From page 47... ...
They also showed that these compounds down-regulated the C9 disease signature in patients with sporadic ALS. Although the Verge drug discovery platform is what Zhang calls an "all-in-human platform," in that it combines data from human genetic studies, human tissue, human-derived neuronal cells, and human clinical studies, she said they also employ mouse models to develop a panel of biomarkers that can be translated to early clinical studies to demonstrate target engagement and effects on the downstream biology.
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From page 48... ...
"As a field, we have to move from developing multiple models to assuring that the models are actually reproducing endogenous biology, and to making sure there is reproducibility," she said. Next-generation organoids will likely contain a better representation of cell types and structures, including vasculature, to model higher-order, more complex events, she said, "I think it's just a matter of time." Steven Hyman agreed about the need to match questions with models, noting that for many questions, a living brain, and thus animals are needed, but that many human disease-relevant processes cannot be recreated in animals, even in nonhuman primates given the need for human genes, including human genetic backgrounds.
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From page 49... ...
"To me, human genetics is a form of ground truth, so if we can look at the effect of human genetics on a cellular phenotype and use what we see in that cellular phenotype to predict a human clinical outcome that we care about, that is a ground truth test for whether our cellular system is predictive of the human clinical outcome," said Koller. She added that genetics may also be useful to understand which environmental exposures and other stressors that may be disease relevant.
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From page 50... ...
Koller agreed, noting an example from her work with polygenic liver disease where a subset of patients with a particular genetic variant, who exhibit characteristic morphological and histopathological features, may be separately treatable using a precision therapeutic. Moving away from highly penetrant genetic variants that affect only a small subset of patients and into a larger patient population that has a disruption in the same pathway is, what Koller called, "the holy grail" in the field.
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