CRISPR / Cas9 – Abiological revolution between almighty cure and nightmare

Even heralds of an ever accelerating scientific and technological progress are sometimes forced to follow with awe how fast results from basic scientific research every so often find their way into the developmental dynamics of our society. Just a year ago the biotechnical method bearing the difficult name “CRISPR/Cas9”,itself only three years old,was known only to specialist in biotechnology (see here). Even after the controversial experiments performed by Chinese scientists last spring (see here), who genetically modified human germ cells (which is illegal in Western countries)with the help of this method, the public reaction was rather contained. We have been forced to realize that major scientific events do not nearly receive as much public interest as the presentation of the new iPhone, the soccer World Cup, or the annual rendezvous of a self-proclaimed world’s elite in Davos. Once again we can observe this typical reaction pattern with “CRISPR/Cas9”: Right in front of all our eyes anew technology is developing which more than almost anything else has the potential to change the field medicine in the 21st century, and potentially even mankind itself, and we continue to discuss the dullness in the statements of an American presidential candidate (or his European counterparts), or the obscurityof some politicians demanding to use firearms to keep refugees from our borders.

However, the discussion about this particular scientific development has recently received an extraordinary amount of – albeit short-lived – public attention. With the decision of the British authorities to allow the new CISPR/Cas9 method to be used in experiments on human germ cells(at first to examine “what genes are needed for an embryo to develop into a healthy baby”), Western regulator snow seem to no longer want to stand behind the Chinese unscrupulousness when it comes to bio-scientific research. “A slippery slope” say some, “necessary for the development of new health-promoting technologies,” others claim. The layman does no longer seethe forest for the trees in this argumentative thicket. The only certainty, as it appears, is that within a surprisingly short time of less than one year a massive shift seems to have occurred in the bioethical discussion – towards the Chinese line. Thus more and more biologists now support the use of CISPR / Cas9 in embryonic research (even if the genetically modified cell clumps are not to be used to induce a pregnancy). This is predominantly due to the incrediblepotential of this new technology. In the scientific community CISPR is already regarded as the main medical breakthrough of the century. Whether in plant, animal, or human cells, this new technique allows genes to be precisely replaced, changed, or removed –in a fast, accurate and very cheap manner. What untilrecently took weeks, months or years and was very error-prone, can now be performed with CISPR/Cas9in hours and days with very high accuracy (see here for a detailed description). For some medical application, the technology is already developed thus far that in just a couple of yearsclinical trials appear possible. Among others this includes many inherited diseases, but also plagues such as HIV or malaria.

Significant new opportunities also arise in the area of plant breeding. Unlike previous methods of genetic engineering such as the creation of transgenic plants, CISPR/Cas9 allows organisms to be modified such that these can hardly be distinguished from natural mutations: they are only subject to individual selective and specific genetic changes which can potentially (albeit with much lower probability) equally arise naturally by mutations. Thus biologists could for example implant specific resistances against fungi and other specific pathogens into the genome of particularly profitable rice or wheat varieties that would then differ only in that particular characteristic, respectively gene,from the original varieties. This form of genetic engineering might be more acceptable to consumers, as the interventions would be much more precise and controlled and would in principle correspond to a naturally occurring point mutation. Such resistances could also be reached by means of conventional breeding, i.e. the crossing of appropriate varieties. But it would take years to remove less desired properties that would unavoidably accompany these varieties. Especially in poor countries CISPR promises to createsignificantly higher yield for crops. Some European countries (for example Sweden) have thus approved first field trials with CISPR-modified plants,specifically noting that these do not fundamentally differ from those created by breeding or even natural mutation. Potentially CISPR gen-edited plants may no longer be considered “genetically modified” and would thus not be regulated accordingly.

However, despite (or maybe because of) its huge technological power the new methodraises some serious questions and should by no means considered harmless. The main concern of bioethicists is that with CRISPR it will be significantly easier to introduce new modified DNA into the germline of living beings and thus to permanently change their properties. For years, researchers in life science have strived to achieve biased inheritance of particular genes to alter entire populations of living organisms, e.g. in order to change wild populations of harmful organisms to be less dangerous.This is referred to as “gen-drive”. Through corresponding genetic mutations “gen-drive”has been occurring in an entirely natural way in the evolution since the beginning of life on earth. However, CISPR/Cas9 now provides biotechnologists with new, almost limitless possibilities to steer this process:Normally (advantageous) mutations – whether they occurredcoincidently or were created by purpose – spread in free populations only over the course of many generations, asaccording to Mendel’s law they are inherited only to half of the descendants. But with the help of the CISPR technology the biologists last year managed to develop a way to simply copy the genetic modification on one chromosome to the other chromosome in the cell. It is thus possible to raise the number of the hereditary transmission of altered genes from 50% to 100%. The desired genetic modification can then manifest itself within a very short time in an entire population. And all this requires nothing that cannot be performed in any genetic lab, maybe soon even in a high school classroom.

The CRISP technique appears like a genie, which promises to fulfill biologists all their wishes. And the new gene-drive method is seen as one of its most powerful applications. But it is probably also its most problematic one: It could abruptly change the structure ofan entire ecosystem. With the eradication of diseases that are transmitted by insects, such as malaria or the Zika virus, this technique may be very helpful and would probably be welcomed by many. But already with its application in the agricultural sector the power of this method appears quitescary. And a technology that has the potential to eradicate entire species, even if these are initially pathogens, raises ethical and regulatory issues that scientific and government agencies are only beginning to consider. At the same time the CRISPR technology is moving so rapid that the reaction by political decision makers- also in view of their anyways underdeveloped awareness of scientific developments -will likely not be enough to cork the bottle before the genie escapes. It seems thus be primarily up to the scientists themselves to keep the genie under control. In view of the foreseeable multi-billion-business opportunities (or even military applications) the new method promises, this not only appears very difficult but quiteunrealistic, as the history of nuclear fission teaches. It took less than seven years from its scientific discovery to the mushroom clouds appearing over Hiroshima and Nagasaki. But can we really afford that a broad and democratic discussion about the applications of this new technology (if at all) only starts when biologists start messing with the human germ line?Biologists should be very carefully about what they want from the genie. “Making a wish” should entail “be careful what you wish for”.

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