Vision is of key importance for humans and losing vision has a major effect on day-to-day life. Vision starts in the retina, where an image captured by photoreceptors is processed by retinal circuits built from more than hundred cell types. Information flows from the retina via the thalamus to a number of cortical areas. Despite the large number of cortical neurons involved in vision, most blinding diseases originate in the retina and are cell-type specific. Although the vertebrate retina has a conserved cellular architecture, only a few animal models of visual diseases reproduce the pathology found in humans. Therefore, there is a major need for understanding the healthy and the disease-affected human retina. Recently my laboratory developed a set of new technologies that enable us to study the human retina, to understand its functional architecture and disease mechanism in its cell types, and so to develop therapies. Using these technologies, we first aim to describe the functional diversity as well as the function of ganglion cell types and their circuits in the human retina. Second, we aim to reveal mechanisms of cell-type vulnerability in human and mouse retinas. Third, we aim to provide proof of principle for cell type-targeted near infrared vision restoration in the human retina. Taken together, this study will provide insights into the structure, function, and mechanisms of disease of the cell types in the human visual system and will investigate a new approach to restore vision in patients with blinding diseases.

Humans diverged from our closest living relatives, chimpanzees and other great apes, 6-10 million years ago. Since this divergence, our ancestors acquired genetic changes that enhanced cognition, altered metabolism, and endowed our species with an adaptive capacity to colonize the entire planet and reshape the biosphere. Through genome comparisons between modern humans, Neandertals, chimpanzees and other apes we have identified genetic changes that likely contribute to innovations in human metabolic and cognitive physiology. However, it has been difficult to assess the functional effects of these genetic changes due to the lack of cell culture systems that recapitulate great ape organ complexity. Human and chimpanzee pluripotent stem cells (PSCs) can self-organize into three-dimensional (3D) tissues that recapitulate the morphology, function, and genetic programs controlling organ development. Our vision is to use organoids to study the changes that set modern humans apart from our closest evolutionary relatives as well as all other organisms on the planet. In ANTHROPOID we will generate a great ape developmental cell atlas using cortex, liver, and small intestine organoids. We will use single-cell transcriptomics and chromatin accessibility to identify cell type-specific features of transcriptome divergence at cellular resolution. We will dissect enhancer evolution using single-cell genomic screens and ancestralize human cells to resurrect pre-human cellular phenotypes. ANTHROPOID utilizes quantitative and state-of-the-art methods to explore exciting high-risk questions at multiple branches of the modern human lineage. This project is a ground breaking starting point to replay evolution and tackle the ancient question of what makes us uniquely human?