Search Results

Many of the advances made in our understanding of visual mechanisms from one thousand years ago to the present time are discussed. Our knowledge has increased exponentially in more recent years, beginning in the early 19th century when it was proposed that there are elements in the eye that underlie color vision. By the end of that century, rod and cones had been identified, visual pigments discovered and retinal and cortical cells described. How photoceptors and other visual system neurons respond to light was elucidated in detail in the 20th century, and the first genes causing retinal degenerations discovered.But what does the future hold, especially in terms of treating visual disorders and curing blindness? Approaches being tried include gene therapy for inherited disorders, introducing light sensitive molecules into various retinal cells when the photoreceptors have degenerated (optogenetics), stimulating retinal and cortical cells directly to activate the visual pathways (visual prostheses), transplanting photoreceptors or other neurons into damaged retinas, and testing if retinal cells can be replaced by glial cells endogenous to the visual system or by exogenously-applied cells, including stem cells. Progress along these and other fronts is being made, additional ideas explored, and new techniques developed that hopefully will achieve these goals.

After decades of stagnation marked, inter alia, by all too many disappointing failures in costly, late-stage clinical trials, there is hope that new therapies for nervous system disorders are not only possible but also realistic. The advent of new tools and technologies over the last decade has revolutionized our ability to study the nervous system in unprecedented ways. For brain disorders, successful discovery and development of disease-modifying therapies require a “revolution,” not merely incremental progress realized through past approaches. This chapter analyzes past mistakes, takes account of current efforts, and provides a conceptual roadmap to support this revolution in pathophysiology and therapeutics. It reviews tools and technologies that will be needed and discusses the role of genetics and risk-associated loci. A powerful approach found in the combination of genetics and optogenetics is put forth. In addition, animal models based on genetic mutations identified in patients, offer unique opportunities to identify circuits that underlie behavioral abnormalities.

Recent advances in the identification of risk genes for psychiatric disorders have set the stage for functional interrogation of disease related-circuits and underlying mechanisms of pathophysiology. Still, investigators face significant challenges: hundreds of genes may contribute to pathogenesis of a given disorder (polygenicity and genetic heterogeneity); risk alleles may only cause the disease in combination with other factors (reduced penetrance); commonly used rodent models may have significant limitations in studying psychiatric disorders, due to differences in brain structure and function with humans. To address these challenges, high-throughput functional assays should be developed in combination with iPSC technology and novel genome-engineering technologies, as these will help identify common pathways and mechanisms onto which multiple risk genes may converge. To overcome limitations of current animal models, novel genome-editing technologies provide an opportunity to generate better models (e.g., the common marmoset) to dissect disease-relevant circuit dysfunction. Finally, powerful new tools (e.g., CLARITY, dense neural circuit reconstruction, optogenetics) may help identify and test the relationship between distinct circuit defects and abnormal behaviors observed in these animal models. Such approaches are needed to span the gap between emerging genetic information and the symptomatic description of neuropsychiatric disorders.

This chapter tells the story of attempts to turn biomolecules into technologies that were to lead to improved, life-like computing. The history of biochips adds an unexpected dimension to the history of both bio- and nanotechnologies. Far from venture capital and biomedicine, 1980s biotech and recombinant DNA appear here as radical attempts to redesign existing technology through inspiration from life. Such efforts were endorsed by, for example, cell biologist Lynn Margulis and nanotech posterchild Eric Drexler. Projects aiming to tackle life’s molecular machinery for computing existed in US labs and start-ups as well as within the German chemical industry. By analyzing the failed attempt to materialize a biochip, this chapter puts more flesh on the bones of nanotech history, and reveals its interconnections to materials and the life sciences. Moreover, this chapter describes changes in scientists’ discourse on novel technologies in various media of the 1980s, as it follows molecular machinery from the scientific press into novel magazines or newspapers. Finally, 1980s biochips research will be juxtaposed to optogenetics, a recent endeavor to make molecular machinery work within organisms in order to modify their behavior or to create semi-organic prostheses.

We are in the middle of a scientific revolution in the biological sciences. In the 1970s scientists discovered ways to cut and paste DNA in a test tube, and then introduce gene ‘constructs’ into first bacteria and then more complex organisms such as mice. This made it possible to, for instance, produce human insulin artificially in bacteria, but also to create genetically modified mice for medical research. But such genetic engineering methods were expensive, time-consuming, and limited to only certain organisms. In contrast in recent years, new ‘genome editing’ approaches, particularly one called CRISPR/Cas, now makes it possible for the first time to precisely edit the genome of living cells from practically any species. Genome editing looks set to revolutionise medical research, clinical medicine, and agriculture, as the rest of this book will explain. But this is only one of the new technologies discussed In Redesigning Life. Others include optogenetics, which makes it possible to activate nerve cells in the brain using light, ‘organoids’, which are created from human stem cells, and have similarities to human organs like the kidney, intestines, heart, and even brain, and synthetic biology, which seeks to create artificial bacteria and yeast chromosomes from scratch and even reconfigure the genetic code. All of these technologies have great potential for improving human society, but they also raise many ethical and socio-political issues and questions about ways they might be misused, which will be explored in this book.

Visual light, and radiation of other frequencies, are highly important for scientific research. The first light microscopes made it possible for the first time to see that organisms from plants to humans are composed of cells. Electron microscopes have allowed scientists to study the structural components of cells in great detail, and even determine the shapes of individual proteins. Many lifeforms also use light to attract a mate or prey, or deter an attacker. Following the identification of the gene coding for the fluorescent protein that makes certain jellyfish glow green it has become possible to use this to genetically label proteins in a living cell, or even a live animal. This means that now the location of proteins in a cell can be determined exactly. A major recent step forward in neuroscience came with the discovery of protein channels in algae that conduct ions in response to light. By creating transgenic mice that have these proteins in their brain neurons, it is now possible to modulate the activity of these neurons by shining light into the brain though microscopic fibre optic cables. This new science of optogenetics allows neurons to be switched on or off experimentally. The optogenetic approach has been used to uncover the neural circuits involved in memory, pain and pleasure. In the future this technique might be used to treat physical pain or depression in people. Controversially, it might be also be misused, to supress memories, or even create completely false ones in people’s heads.

This chapter provides an overview of the basic methods used in studying vision and the brain. The creation of these methods has played a central role in uncovering how various brain areas work, including those that are engaged in analyzing vision and in generating eye movements. Several Nobel Prizes and other major prizes have been awarded to individuals as a result of having created these methods and having generated major new discoveries with them. The chapter describes seven methods: A: Psychophysics, B: Neuroanatomy, C: Neurophysiology, D: Biochemical Analysis, E: Optogenetics, F: Two-Photon Imaging, and G: Brain Inactivation. Sections H and I provide an overview and a summary.

This chapter discusses human functional neuroimaging findings about how the brain creates true and false memories. These studies have shown that different brain systems contribute to the creation and retrieval of false memories, including systems for sensory perception, executive functioning and cognitive control, and the medial temporal lobe, which has long been associated with episodic and autobiographical memory formation. Many neuroimaging findings provide support for an associative account of false memories, which proposes that false memories arise from associating unrelated mental experiences in memory. At the same time, other neuroimaging findings suggest that false memory creation may depend on states of brain activity during memory encoding. Finally, the chapter briefly provides cautionary notes about using functional neuroimaging as a tool to assess private mental states in individual cases in the courtroom.