FONDATION-IPSEN

A new method for making precise changes in selected genes is taking the world of biomedical research by storm. Known by the rather inelegant name of CRISPR-Cas9, it is a rapid, efficient, versatile and relatively cheap tool for dissecting the molecular pathways that are the basis of life, as well as for investigating and potentially rectifying faults in these pathways that result in disease. During this Colloque Médecine et Recherche in Neurosciences organized by the Fondation Ipsen, an international panel of speakers reviewed how this and other genome editing techniques are advancing understanding of the development and functioning of the nervous system. A special focus has been on the combination of genome editing with recent developments in stem cell technology, which is proving particularly powerful for uncovering the mechanisms of, and developing treatments for, a range of neurological disorders. The scientific committee included Rudolf Jaenisch (MIT, Cambridge, USA), Feng Zhang (MIT, Cambridge, USA), Fred Gage (Salk Institute for Biological Studies, La Jolla, USA) and Yves Christen (Fondation Ipsen, Paris, France).

Genes are the blueprints for making proteins, the complex molecules that provide both the structural and functional organisation of all forms of life. A mutation in a gene may result in the protein being misshapen, shortened or absent, causing a hiccup in a biological process that may cause disease or death. The roles of healthy or mutated proteins have been investigated for many years by studying what happens in the organism when single genes are silenced or their activity enhanced. Although used extensively and productively, these methods are cumbersome, expensive and not very reliable. In the past five years, a new generation of techniques have been developed that use enzymes known as endonucleases to make precisely positioned cuts in DNA. Harnessing the natural mechanisms for repairing breaks in DNA found in every cell, these ‘molecular scissors’ can be used to remove, alter or replace small sequences of DNA; the changes resulting from the operation can be examined either in single cells in culture or in whole organisms. The most effective of these editing tools, known as CRISPR-Cas9, is derived from a natural immune defence mechanism found in bacteria and in the past two years has been adapted for use in a variety of organisms and with wide applications in research, medicine and crop breeding (Emmanuelle Charpentier , Max Planck Institute, Berlin, Germany). It provides a rapid way to examine the sea of variations in gene sequences between individuals and to identify those that cause problems, which will be of fundamental importance in personalised medicine (Zhang ).

The rest of the presentations focused on the applications of CRISPR-Cas9 and other editing methods in nervous system development, function and disease. In development, gene editing is enabling the study of the dynamics of gene regulation in real-time in single cells as they become differentiated into specific functional types (Jaenisch ). Rapid genomic screening of neural stem cells is giving an insight into vulnerability to mental illness: genes associated with establishing neural connections and synaptic function contain breaking regions in the DNA that are susceptible to stress (Frederick Alt , Children’s Hospital, Harvard Medical School, Boston, USA). The study of fish brains is contributing to understanding how nervous systems regenerate. Because they grow throughout life, these brains contain populations of active stem cells, which can be manipulated with tools such as CRISPR-Cas9 to provide information about the conditions controlling cell division in the generation of new neurons (Jean-Stéphane Joly , CNRS/INRA, University Paris-Saclay, Gif-sur-Yvette, France).

Much has already be learned about synaptic function with the now-old-fashioned methods of gene silencing but use of CRIPSR-Cas 9 is allowing a far more refined dissection of molecular mechanisms. Molecules previously thought to be active only when synaptic function changes during memory formation are now being found also to have an essential role in the on-going maintenance of the synapses of some neurons (Salvatore Incontro , University of California, San Francisco, USA). The CRISPR-Cas 9 method is also being applied on the whole-cell level in zebra fish to study how neural circuits become hooked-up during development. Specific types of neurons can be identified by genetic targeting of protein markers, which can be visualised in real time as the fish larva are almost transparent (Filippo del Bene , Institut Curie, Paris, France).

Genome editing adds an extra layer of sophistication to another already powerful biomedical research tool, induced pluripotent stem cells (iPSCs have been the topic of two previous Fondation Ipsen meetings: Programmed cells : from basic neuroscience to therapy, Paris, April 2012 and Stem cells in neuroendocrinology, Paris, December 2015. Skin cells taken from a patient can be made to revert to undifferentiated stem cells in vitro and now CRISPR-Cas9 is being used to correct disease-related genetic defects before the stem cells undergo differentiation into particular cell types, with the ultimate goal of replacing the patient’s damaged cells. Such stem cells are being used for investigating the effects of specific, disease-related mutations by creating isogenic cell lines: colonies of cells with identical genomes except that one has the normal copy of the gene, the other the mutated one. Application include determining the effects of genes that increase the risk of developing Parkinson’s disease on neuron function (Jaenisch ); examining the deficits in neuronal function related to mutations linked to autism (Neville Sanjana , Broad Institute, Cambridge, USA); investigating why myelin production is disrupted by the mutation that causes the fatal congenital Pelizaeus-Merzbacher disease (Marius Wernig , Institute for Stem Cell Biology and Regenerative Medicine, Stanford, USA); and determining why only certain types of neuron are susceptible to the mutant protein that causes Huntington’s disease (Lisa Ellerby , Buck Institute for Research on Aging, Novato, USA). Genetic screens of single cells are also being used to analyse how this mutant protein affects cell function (Myriam Heiman , MIT, Cambridge, USA).

A proof-of-principle experiment to bypass the gene defect causing Duchenne muscular dystrophy is having some success in mice, using a specially designed CRISPR-Cas9 to modify the mutant gene, a taste of future therapies for presently intractable genetic diseases (Amy Wagers , Joslin Diabetes Center, Harvard Medical School, Boston, USA). Bringing animal models closer to humans, the common marmoset, a primate that is both easy to breed and has close similarities to humans than the more commonly used macaque monkeys, is now being genetically modified to mimic symptoms of various human neurodevelopmental and neurodegenerative diseases (Hideyuki Okano , Keio University, Tokyo, Japan).

The meeting provided a snapshot of this fast growing field, a taste of the wide range of creative ways in which these genome-editing tools are being applied, and a look to their future use in the development of personalised medicine.

About the Fondation Ipsen
Established in 1983 under the aegis of the Fondation de France, the mission of the Fondation Ipsen is to contribute to the development and dissemination of scientific knowledge. The long-standing action of the Fondation Ipsen aims at fostering the interaction between researchers and clinical practitioners, which is indispensable due to the extreme specialization of these professions. The ambition of the Fondation Ipsen is to initiate a reflection about the major scientific issues of the forthcoming years. It has developed an important international network of scientific experts who meet regularly at meetings known as Colloques Médecine et Recherche , dedicated to three main themes: neurosciences, endocrinology and cancer science. Moreover the Fondation Ipsen has started since 2007 several meetings in partnership with the Salk Institute, the Karolinska Institutet, the Massachusetts General Hospital, the Days of Molecular Medicine Global Foundation as well as with the science journals Nature , Cell and Science . The Fondation Ipsen produced several hundred publications; more than 250 scientists and biomedical researchers have been awarded prizes and research grants.
www.fondation-ipsen.org

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