genetic engineering

CRISPR: between fear and euphoria, the battle of ethics is in full swing

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Battle stations in the world's scientific academies. The CRISPR/Cas9 technique of genetic surgery is so effective, fast and inexpensive that there are concerns about its use in therapeutics and on the human embryo. But visions differ in Europe, the United States or Asia?
 
Eto avoid a nightmare. Under the vault of the National Academy of Medicine, rue Bonaparte in Paris, there is no attempt to play with genes or human embryos. This Friday, April 29th, about sixty academics from all over the world will share their visions on an explosive subject: how to border human uses - research and therapeutic offers - with the very attractive technique of "genetic correction": CRISPR/cas9. 
This day of hearings is organized by the Study Committee set up by the American Academies of Medicine and Science, in conjunction with the British Royal Society and the Chinese Academy of Sciences. Set up in the summer of 2015, this Committee has already conducted a symposium of four hundred people in December 2015 and is preparing a report by the end of the year on the human use of these so-called "genetic editing" techniques. The term is also problematic for its heuristic effect because it suggests that we can properly "play with words". However, genomic coding is far from being able to be simplified into an unambiguous language. We will have to come back to this unthinking.

Impacts of all kinds

The speakers' interventions questioned a wide range of dimensions. The Swiss Roberto Andorno recalled the principles of the Oviedo Convention (1997 and ratified by France in 2011) which - in its article 13 - bans any intervention on the germ line (the sexual cells that are spermatozoa and ova). Because the transmission of the modification to descendants opens the way to eugenics. "Since these projects concern the whole of humanity, it must be remembered that scientists do not have the independence or democratic legitimacy to decide. he notes. 
The Spanish Monica Lopez Barahona highlighted the potential for unintended effects, including "splashes" inherent in the modification being carried out. "We can unintentionally inherit abnormalities due to genome instability, epigenetic consequences or genotoxic effects, She also points out the immune effects of the Cas9 protein or the risk of mosaicism, i.e. tissues with different cells (mutated or not mutated).
The look of Jackie Leach ScullyProfessor of Social Ethics at the University of Newcastle, engaged the audience in subtle and useful reflections on particularly relevant "interest groups" such as women or disabled patients.. "It is a question of taking the measure of what these steps have as consequences in terms of power, responsibility, involvement over the bodies."she insisted.
 
 
These interventions have shown that there is a consensus that there is no question of genetically modifying the human germ line, i.e. sex cells. The idea of transmission to subsequent generations and thus of the durability of the modification quickly brings back the spectre of eugenics.
 
However, the use of the technique on the human embryo - which also perpetuates the grafted character to its descendants - is not out of the question. For the time being, it is the logic of research that is driving experimentation. In April 2015, the Chinese team of Junjiu Huang (Sun-Yat-sen University, Canton) has published the results of a gene replacement mutated from Beta-globin, which is responsible for thalassemia, to human embryos. The experiment showed many collateral effects (almost a thousand so-called off-target impacts) and many embryos had a mosaic structure, with cells whose DNA had been corrected, but others where the defective gene was still expressed. "This showed how immature these processes are," many scientists have repeated over and over again.
The article moved the international scientific community, as echoed by Bertrand Jordan in the journal Medicine Sciences (Germ therapy, the return?)

The human embryo in the hot seat

In any case, there are different opinions around the world about embryo experimentation.
In the United Kingdom the five main agencies responsible for biomedical research support pre-clinical research using genome editing, including embryo and germ cell research. In Germany, there are strong reservations and the government is sticking to developing the debate... At European level, only genetic editing work on somatic cells is funded: the authorities refuse to support research on embryos, as in the United States, which nevertheless allows more permissive states such as Oregon to carry out experiments involving human embryos.
 
One may wonder about the situations that could lead to a desire to "correct" deleterious genes in the human embryo. According to Pierre Jouannet, who coordinated an inventory for the French Academy of Medicine - entitled Modifications of the germ cell genome and the human embryo - the clinical applications of an intervention on the embryo are conceivable for Huntington's chorea (autosomal dominant alteration) or in cases where both parents carry a recessive alteration (cystic fibrosis, myopathies, amyotrophic sclerosis...).
"Preimplantation screening (PGD) that allows for the re-implantation of mutation-free embryos does not solve everything, as in 20% of cases, all embryos carry the abnormality, underlines Pierre Jouannet. And the couples are at an impasse".
In these exceptional cases, the CRISPR/Case 9 technique could be a solution, once all the risks it induces today have been eliminated.
 
 
The most optimistic academics have repeatedly asked for opinions: "If the method is made safe in three or five years, what could prevent the characteristics of unborn children from changing at will? "For beyond the cures sought, everyone knows that these genetic interventions can be used to improve performance or to meet aesthetic criteria. And parents will do anything to bring their dream child into the world, as the following statement shows the published report in February by Erika Check Hayden (Should you edit your children's genes).
In the United States all DPI centers offer sex selection. It is conceivable that other criteria are proposed such as eye colour or resistance to diseases. "If the first baby Crispr was conceived because his parents dreamed of blue eyes, it would be a disaster.", says Jennifer Doudnaone of the inventors of the method.
It is very rare for a trait to be carried by a single gene - this is not the case for blue eyes or intelligence! - but it happens! We were able to identify a mutation in a Finnish ski champion with an above-average number of red blood cells. Modifying the erythropoietin receptor gene (well known by its acronym EPO), this mutation gives him a real advantage. This case, reported by Jean Gayon and Simone Bateman in the chapter Human improvement (Human enhancement) published in Nature et artifice. Man facing the evolution of his own essence, coordinated by Edgardo Carosella (Hermann, 2014) shows that proposals for improvement of all kinds are likely in the years to come. "My fear is that we'll fly too fast and make mistakes, recognizes J. Doudna. But also that some people are racing to commercialize this technology, promising parents a baby with this or that characteristic when we cannot afford to do so".

New gene therapies

At the heart of industrial expectations and strategies are new therapeutic solutions for sick children and adults. CRISPR/Cas9 techniques facilitate gene therapy constructs. They can in fact cut off faulty (deleterious) genes and replace them with unaltered copies. Although the copy and paste image is simplistic and makes people believe in "miracles", researchers are nevertheless considering correcting mutations in human clinics in the case of monogenic diseases, in cancerology or to induce a protective effect (against viral infections such as AIDS or hepatitis B for example) or against diabetes or hypercholesterolemia (PCSK9 gene).
 
 
The therapeutic potential of this technique has been shown in cell lines or animal models for genetic diseases (Duchenne muscular dystrophy, tyrosinemia - incurable liver disease - haemophilia).
 
However, progress is still awaited before seeing the arrival of the CRISPR/Cas9 tool as a gene therapy drug. Indeed, the fears about its use in the clinic focus on the safety of this tool, which could induce other lesions on the DNA, and on its effectiveness in correcting a sufficiently large number of cells to obtain a therapeutic benefit in humans. The company Editas Medicine created by J. Doudna and which has just been listed on the stock exchange designs tools for human therapies, in particular for eye diseases: these tissues, like blood, are among the easiest to reach with CRISPR/Cas9. Similarly, Intellia Therapeutics (still founded by J. Doudna), located in Cambridge, near Boston, is also developing genetic tools for therapeutic purposes.

CRISPR/Cas9 in the kitchen

The testimony of Bethan Wolfenden, founder of Bento BioworksThe first time he came from London to talk about the experiences of the bio hacker community, he suddenly put pragmatism at the heart of ethical considerations. As an advocate of biology accessible to all, she works to facilitate people's autonomy by providing them with the tools they need to become self-sufficient. ad hoc in the spirit of DoYBio. "On the internet today, you can get your molecular surgery kit for 69.49 $ ", she explained, pointing out that demands are exploding to transform yeasts into "insulin factories" (see the site Lab counterculture in Oakland, California). Networks are passionate about modifying the intestinal microflora... or offering paternity tests. The irruption of these uncontrollable realities however leaves academics a little sceptical...
 
 
Everyone was able to appreciate the clarity of vision of Bartha Knoppers from McGill University (Montreal) who dared to point out the cleavage of points of view between Europe and the rest of the world. The old continent is hiding behind principles and the status quo of prohibition when we see Asia's rush into the bio-economy. The gap deserves to be made more widely known through presentations by Xiaomei Zhai, from the Beijing Union Medical College, and Jacqueline Chin, from the University of Singapore. Another indispensable perspective was provided by Rahman Jamal of the University of Malaysia, who explained the Muslim references that organize ethics.
 
Among the speakers, the figure of Nick Bostrom in this debate is not surprising. Founder of the Institute for the Future of Mankind and Director of the Centre for Strategic Research on Artificial Intelligence, this Oxford philosopher is an expert in probability and opinion analysis. He introduced his remarks to show how Americans are gradually showing themselves to be in agreement with technical proposals that they could refuse twenty years earlier. And to explain what weighs on change: fear of risk, transition costs, evolutionary adaptation, emotional impacts. It is easy to understand why people are calculating the efficient way to get the crowds moving quickly. This is an interest he shares with William Sims Bainbridge, his colleague from the Transhumanist World Association (TWO). To border on genetic ethics, he's a strange guest ... under the dome.
 
 

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