“Genetic revolution”, “biotechnological tsunami”, “fantastic tool”: the discovery of CRISPR-Cas9, the new genetic tool, brings both hope and concern, and, for over a year now, has given rise to much debate. At the beginning of it all, the publication of two researchers, Emmanuelle Charpentier and Jennifer Doudna, in 2012.
CRISPR-Cas9 is a tool that enables one to modify the genome by removing or adding genes, or even making them active or mute” explains Pascal Jacob. The idea is to “edit the genome”, i.e., to modify in a controlled manner the sequence of the genome in very specific areas. For the past 15 years, several techniques have been developed in order to modify the genome efficiently. The system CRISPR-Cas9, developed from a bacterial immune system, has stimulated the researchers’ enthusiasm because contrary to the previous tools, it is easy to use, relatively cheap, precise, and fast. Its potential applications are varied: research, a better understanding of the role of genes, but also in therapy in order to correct genetic diseases, improve the compatibility of pigs’ organs with human beings, and even eradicate species, carriers of diseases.
Gènéthique turned towards experts to draw the distinction between the promises and the threats brought up by this new technique: Alexandra Henrion-Caude, research director at Inserm, Marie-Jo Thiel, director of the CEEREat the University of Strasbourg and member of the European Commission on bioethics (EGE), Albert Barrois, scientific blogger, and Pascal Jacob, philosopher.
A revolutionary tool?
Alexandra Henrion-Caude compares CRISPR to a “genetic tippex” because in the same way as with a liquid corrector, the aim of CRISPR sequences is to search for the genetic target that needs modifying. After the DNA is cut thanks to the enzyme Cas9, the next step aims at “bringing the ends together, either after having erased a letter, a word, several words, or after having replaced an entire sentence(s), i.e., gene(s). In our jargon, this change in the genetic information is called edition”. Having said this, she tempers her words: “I believe that though the technique of this new tool is rather nice, rather elegant and easy to implement, it does not revolutionise our knowledge”. The procedure, widely available to any laboratory for a moderate cost, has enabled us to “trivialise” its use for the genetic modification of various species’ information. “However”, adds Alexandra, “for a long time, we have, to a large extent, been applying other insertion or replacement techniques.”
On the contrary, Albert Barrois believes that the rightful place for this toolbox is in research laboratories, and that it is already revolutionising the existing techniques. Indeed, in the field of therapeutics, “it is the first time that we have such a performing toolbox at our disposition, and if its use is controlled by healthy ethical limits, the patients could benefit from it soon”. Associated with the new perspectives of cell therapies brought up by stem cells and IPS cells, the laboratories now have extremely powerful tools at their disposition”. However, any analogy with the “Swiss knife” or the “genetic knife” is too simplistic for Marie-Jo Thiel, who feels that is would be like comparing it to surgical precision, minutely checked thanks to the work of reason, which is not the case here.
A reliable tool?
CRISPR-Cas9 spread at lightning speed throughout the world’s laboratories. Putting fiction behind, this technique is currently used by many researchers. Used for good or ill… “The relative simplicity of this technology makes invention possible for the best and probably, as always, the less good… “, deplores Marie-Jo Thiel. “How could we not speak of those Chinese researchers who moved the whole of the scientific community when they announced in April 2015 that they had carried out “the genetic tippex on human embryos”? Alexandra Henrion-Caude is sorry that “so long as a technique exists, little does it matter if the consequences are known, if the ethical dimension has been considered, and even less if there are sufficient means to follow the consequences of what is carried out. So long as a technique is available, the only preoccupation is to use it”.
However, though more time is still needed in order to perfect the technique and make it even more reliable, Albert Barrois believes that “5 years, maybe less, will probably be sufficient “. Indeed, he considers “CRISPR to be already very reliable”. Because, though there is no such thing as zero risk, it needs to be reduced as much as possible. Marie-Jo, on the other hand, believes that though “the technique is accessible”, it has not yet been “truly mastered”.
Two difficulties still need to be overcome for its application in gene therapy: correcting a sufficient number of cells in a given organism, and making sure that the genome will be modified only in the intended area. First of all, when modifying the genetic heritage of an individual, “we notice that there is a cellular mosaicism, much greater than foreseen, which causes some cells to be modified and not others”. Albert Barrois concludes by saying that “we cannot exclude the fact that we may have corrected only certain cells and not others, which could be disastrous”. Besides, CRISPR-CAS9 “causes a certain number of non-desired, non-intended mutations”, explains Alexandra Henrion-Caude. “A bit like a bad pupil would make unwanted tippex stains on his paper, as well as the intended modification. It is called the off-target effect. Thus, we should be so much more careful than we are today”.
This call to vigilance and prudence is also relayed by Marie-Jo, who questions the appropriateness of the applications of the technique. All living organisms, “including human embryos in their zygote stage, are potentially concerned, but for what advantages? Paradoxically, it may be that instead of listening to the ethics specialists, people will turn towards the market performance which, when it is low, abandons a given practice”. Thus, the eradication of embryos genetically “abnormal” identified through preimplantation genetic screening, could be chosen over their correction thanks to CRISPR-Cas9. “It is always easier to identify the embryos without a given gene (in order to implant them) rather than modify the Zygote!“ observes Marie-Jor Thiel.
The emergency of ethical supervision
The two researchers, conscious of the impact of their discovery, recommend “a step by step progression” because, “as soon as you start manipulating the genetic heritage, there is a risk”.
“As for all techniques of intervention on the living, the power held inside CRISPR is something we need to master, “explains Pascal Jacob, who then adds, “Though it is obvious that we should not deny ourselves a technique capable of healing, we should also guard ourselves from the way technique can cause us to look at sick people: they are subjects at the service of which technique is only a means, and never an object”.
Thus, for Albert Barrois, the use for men of CRISPR-Cas9 comes with two different ethical levels “that have already been subject to conferences and reports in the US as well as in Europe and in France”. The first level concerns “the question of knowing whether the modifications will be transmissible or not: the modifications of somatic cells that will not be transmitted to the next generations do not pose any major issues; on the other hand, the germ line alterations that will be transmitted could have much more serious consequences, apart from the fact that they usually concern an embryo of a few cells, and therefore IVF and selection stages, because any mistake would be transmitted also to all the descendants”. The second level has more to do with the “alteration in itself”; will the aim simply be to correct in order to restore a normal function, or will it be to enhance certain capabilities? Putting the in vitro fertilisation aspect aside, as indeed the embryonic alteration via CRISPR-Cas9 can only be imagined today within the framework of in vitro fertilisation, one could judge it fairer on an ethical point of view to want to eradicate a disease through germline therapy rather that modifying the genome through somatic therapy, but with the aim of increasing a sportsman’s muscle mass.
The question is all the more relevant as, to this day, “this technology offers no security guarantee”, as reminded by Marie-Jo Thiel. She believes that, for this reason, it should not be used, particularly on gametes and embryos since any alteration is, in those specific cases, transmittable.
According to Alexandra Henrion-Caude, awareness concerning all these issues thus needs to be increased on an international level so that the “limits may be defined through an objective and consensual analysis of the global consequences of all the genetic modifications that have been carried out since Asilomar, in 1975”. She believes that we would probably learn a lot about those which were truly beneficial for man and its environment, and those which were not. In other words, let science and its applications be tested by history and a virtual international court, in front of which, detached from any financial conflicts of interest, all past genetic modifications on the living would be analysed to determine their suitability”. She asks herself, “Do we not owe it to society to carry out such an intellectual exercise to see clearer what we should and shouldn’t do? Shouldn’t the logic that leads one to measure one’s actions be applied to scientists?”
Necessary questions because, as explained by Pascal Jacob “the time of technique, very short, is not that of politics, always longer. That is why researchers must give politicians enough time to discern”. The danger of CRISPR, which is not a new one, is to enter man into the commercial system. Applied to the gametes, the risk is great also because there is the possibility of provoking hereditary genetic mutations, of which we are far from controlling the consequences. In the background, still lingers the transhumanism ideology that sees man as being actor of his own evolution. So, without throwing out the baby with the bath water, we must be cautious.
 European Centre for Teaching and Research in Ethics.
 Somatic cells are all the cells of a body that do not belong to the germline (gametes and germ cells).
 In vitro fertilisation.
 Conference organised by the scientist Paul Berg, who called for a moratorium concerning genetic manipulation, in order to prevent genetically modified bacteria being dispersed into the environment.