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The CRISPR/CAS9 genome editing system and humans

The CRISPR/CAS9 genome editing system and humans

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This is a brief introduction to the CRISPR/Cas9 genome editing technique and a quick review of two articles that have to do with potential applications in humans. There is a draft for an ethical reflexion.

This is a brief introduction to the CRISPR/Cas9 genome editing technique and a quick review of two articles that have to do with potential applications in humans. There is a draft for an ethical reflexion.

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The CRISPR/CAS9 genome editing system and humans

  1. 1. What is the CRISPR/Cas9 Targeted Genome Editing System? What is Publicly Known about the Use of this System in Humans? Ignacio Monge and Maurits Vissers (Fribourg, Switzerland)
  2. 2. Plan • Maurits: Origin and explanation of the CRISPR-Cas9 system • Ignacio: - One "ethically questionable" application in "human embryos" in China - One interesting development (in mice) without apparent ethical problems - Some quick general ethical ideas
  3. 3. CRISPR-Cas9
  4. 4. Bacteria can be attacked by viruses
  5. 5. Bacteria have developed a protection mechanism (“a bacterial immune system”)
  6. 6. The basic concept: the bacterium keeps a copy of part of the viral genome Bacterial DNA DNA Viral- Bacterial DNA
  7. 7. What is CRISPR-Cas9? The copied sequence from the virus is used to guide the CRISPR-Cas9 complex to the complementary viral DNA and to cut it! Clustered Regularly Interspaced Short Palindromic Repeats Bacterial Defense Mechanism
  8. 8. CRISPR-Cas9 system becomes an instrument for genome editing: example in mice
  9. 9. Tests on human embryos in China (1)
  10. 10. Tests on human embryos in China (2) • Published in May 2015 (not in a big journal) • They use tripronuclear zygotes (artificial fecondation of an egg cell with 2 sperm cells) => they are not viable • Use of the genome editing CRISPR/Cas9 approach • Aim is to test the editing of the endogenous human ß-globin gene
  11. 11. Tests in China (3) : results • They manage to "reach", to cleave, the ß-globin gene • BUT Ø There is mosaicism = embryos with different genetically modified tissues Ø Notable off-target effects (=mutations in other unwanted places) Ø Embryo cells also use other endogenous homologous genes/sequences to repair the targeted gene (7 cases) Ø In 4 cases, embryos with the targeted mutation (based on designed injected ssDNA) • Still far away from a secure clinical application !
  12. 12. Use of CRISPR/Cas9 for clinical purposes without gene editing (1)
  13. 13. Use of CRISPR/Cas9 for clinical purposes without gene editing (2) • Salk Institute (California), Izpisua-Belmonte's lab • Idea: activate the target genes without creating genetic modifications Ø recruitment of Cas9 and transcriptional activation complexes by guide RNAs Ø proof-of-concept: treatment of mouse-models of diabetes, molecular dystrophy and acute kidney disease Ø measurable phenotypes and amelioration of disease symptoms Ø new avenues for developing epigenetic therapies against human diseases
  14. 14. The "Oviedo Convention" (1) • Agreement from 1997 • A reference in the field of bioethics • From the European council Ø 34 out of 47 member countries have signed it Ø Germany, Ireland, Malta and Monaco did not sign because they refuse every manipulation of the human embryo (and) abortion Ø UK and Belgium neither, because they found it too restrictive Ø 28 have ratified and applied it • Not so easy to change
  15. 15. The "Oviedo Convention" (2) • Article 13 – Interventions on the human genome An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants. • Article 18 – Research on embryos in vitro 1 Where the law allows research on embryos in vitro, it shall ensure adequate protection of the embryo. 2 The creation of human embryos for research purposes is prohibited.
  16. 16. Possible mid- and longterm purposes of gene editing • CLINICAL 1: genetically heal embryos from parents that are carriers of genetic diseases? => this is rather unrealistic, because in vitro fertilization (IVF) is being used and healthy embryos can be chosen by genetic diagnosis anyway (which is already a problem, ethically speaking) • CLINICAL 2: genetically heal tissues from an adult patient, or stem cells, and reintroduce them back to the patient, avoiding to cause heritable genetic changes if possible (this is ethically less of a problem, if the stem cells do not come from embryos) • CLINICAL 3: "epigenetic approach" for illness treatment • GENETIC DESIGN: "sculpturing" of humans to a lineage that is physically and intellectually "stronger and smarter"
  17. 17. Some general ethical reflections • The question of tolerance towards handicapped persons • Kant: the universal principle for ethics Consider the other person as an "aim in his/herself" and not as an instrument that I use, that I manipulate = as a mean (for my profit) => Consider other human beings as persons, having rights, and not reducing them to an object, that has no rights
  18. 18. Programmed molecular robots and automation of genomic modification • The CRISPR/Cas9 system allows to direct through the guide RNA a "genomic editing machine" or a "gene activating machine" to target genes • After the genome sequencing era (genomes of humans and many organisms have been read through automated mechanisms), a new era of genome modification could be opened, in the mid or long term, also through automated processes
  19. 19. Bibliography • 2 cited scientific articles • Wikipedia • Website "Genethique" • Aceprensa

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