What is CRISPR? A molecular-biological method to cut and modify DNA in a targeted manner. This allows individual DNA building blocks to be inserted, removed or modified. In principle, the procedure works for all organisms. It is also used in animal and plant breeding, and in biotechnology.
The CRISPR/Cas system (“programmable gene scissors”) is a precise instrument that enables targeted, selective changes in the genome (genome editing). This essentially takes place in three steps:
Finding the target: With the help of the RNA ( guide RNA ) integrated into it, the CRISPR system recognizes the respective target, a specific DNA sequence that is to be “transcribed”. The guide RNA and the target DNA match exactly.
Cutting: The Cas9 protein coupled to the CRISPR section cuts the DNA double strand exactly at the predetermined point in the genome. This creates a “double strand break”.
Repair: Now the cell’s own repair systems come into action and reassemble the severed DNA strand. This can be random (non-homologous) or targeted (homologous). In the case of non-homologous repair, individual DNA building blocks are removed or “wrongly” assembled at the point of breakage. As a result, the gene in question can no longer be read correctly. In the case of homologous repair, a new gene section or a modified variant of a short DNA sequence (mutation) can be inserted at the point of break.
If no new gene sequences are inserted, these processes – breakage of the DNA strand and subsequent repair – correspond to natural mutations that occur randomly and in large numbers with each reproduction or are triggered in breeding by radiation or chemical substances.
The CRISPR/Cas system is derived from a natural mechanism by which bacteria protect themselves from harmful viruses, like an immune system. It works not only with bacteria, but in principle with all organisms. Both elements – CRISPR-RNA and the cutting protein Cas9 – are produced synthetically and then introduced into a cell. This can be done using known genetic engineering methods – in the case of plants, for example, transformation with agrobacterium. It is now also possible to introduce the relevant DNA or RNA directly. When the CRISPR tools have served their purpose and induced the intended mutation, they are no longer needed and are no longer present in the offspring.
Compared to other genome editing methods, the CRISPR/Cas_Elements can be produced much easier, faster and cheaper. In addition, they work much more precisely than other cultivation methods: unintentional cuts in the DNA strand outside the target region (off-target effects) are very rare.
In basic research, CRISPR/Cas plays a major role in switching off individual genes and subsequently clarifying their functions. Today, gene scissors are also increasingly used in animal and plant breeding.
Since the establishment of CRISPR technology around two years ago, there has been an exponential increase in new research strategies and results that allow researchers to carry out or realistically plan things that they would hardly have dared to dream of just a few years ago.
Potential uses
In the field of tumor diseases, a decisive milestone towards precision medicine is emerging. The shortage of organs in transplantation medicine could be overcome if, for example, pig organs modified by CRISPR-Cas9 would no longer be rejected or cause the most serious side effects. Additionally, somatic gene therapies in humans or even germline interventions to treat severe hereditary diseases, or to prevent their development from the outset (a possibility, but the targeted improvement of the genetic makeup also appears on the horizon leaves), are on the life sciences menu.
In addition to such potential applications, the reason for rejection of “green” genetic engineering, namely the introduction of foreign genes into a plant, seem to no longer exist as a justification with the new genome editing methods. For example, a point mutation is carried out using CRISPR genome of a plant, the change cannot be distinguished from changes that can occur in the wild type. If one follows the approach of product evaluation of biotechnological interventions, the intervention in the product would no longer be detectable and accordingly classified as particularly precise, even relatively gentle breeding. Whereas, in some cases, the biotechnological process is the focus of the assessment, it is to be expected that CRISPR-Cas9 and co-modifications will be classified like the genetically modified organisms (GMO) that are desired and will be subject to high regulatory hurdles. For a globally active agricultural industry, such regulatory differences represent crucial location considerations with consequences that may cost billions.
The possibilities of CRISPR-Cas9, is exciting because precision genome editing represents a bioscientific innovation, which some even call a revolution, which comes along quietly, yet disruptively preparing to radically change the world and our living environment. In light of this such changes should not take place without ethical reflection. In this context, neither undifferentiated skepticism nor subsequent moral consecration of long-established procedures – commonly referred to as “acquisition of acceptance” – is the task of ethical reflection.
Ethical reflection
Ethics can be defined as a reflexive distancing from moral attitudes towards actions, decisions and social arrangements. Therefore, it must be a question of examining what we as a society are getting involved or not wanting to get involved in with precision genome editing processes.
In order to tackle this task in a theoretically ambitious way that is practically feasible under the conditions of modernity, a multidimensional methodology is required. This initially includes – in the words of Rabinow and Bennett – a “first-wave assessment”: the assessment and weighing of intentions, opportunities and risks. When evaluating such considerations, ethics is initially based on the technology assessment and asks: “How high is the probability and damage potential of possible errors, unintentional release and, in return, fast and effective countermeasures (biosafety problem)?” The higher an insufficiently calculable or controllable residual risk is classified in error management, the higher the additional risk of misuse of such technologies by criminals or even terrorists (biosecurity and dual-use problem). The advertising message for CRISPR is the procedure is proportionally effective, efficient, easy to learn, easy to use and inexpensive compared to comparable methods.
On the question of moral and legal prohibition
Beyond the assessment of the consequences of technology, many people are faced with the fundamental question of whether certain uses of the new gene scissors are morally reprehensible or not. The question of the moral and legal ban on modifying the human genome has provoked an intensive debate worldwide in the last two years. Although, unsurprisingly, no agreement was reached on the moral assessment of this question. Despite the ideological differences, the time gained should be used to consider whether such a de facto moratorium on hereditary genetic manipulation in humans should not be extended. The knowledge gained in recent years about epigenetic effects, which can only be clarified after many years, gives reason for further reluctance to carry out such human experiments in accordance with the principle of caution, which must be used carefully.
In order to avoid throwing the baby out with the bathwater, it is necessary to avoid assessing the gene editing process in general terms, but rather taking into account criteria such as networking, preservation of biodiversity and the retrievability of the respective processes according to domains (microorganism, plant, animal, human), the directly or indirectly announced level of complexity (cell, tissue, organism), the intended application context (basic research, research and/or application for medicines, food, military) and the actors involved (private individuals, public research, industry, military).
Self-reflexivity of ethical research
In order to proactively counter the suspicion that the evaluation of new technologies tends to be downstream, reactive, and to create acceptance (“informing the public about science”), the approach of second-wave bioethics has been established beyond the processing of ethical criteria. The aim is to establish a further self-reflective process of ethical research – if only to eliminate one’s own blind spots. It is postulated that such reflection of the accompanying ethical research can succeed with an “up-streaming process”. However, when research projects are being carried out – as far and as intensively as possible – the dialogue with the public is sought in a transparent and participatory manner (“public engagement with science”). In this way, the proponents of this approach want to confront critical questions of biotechnology with publicly expressed hopes, expectations, and fears from the outset, and help shape the research decision-making process more actively from a broad public.
Organizational and social ethics
In order to promote a strategy of responsible governance, a third branch of responsible-ethical reflection has been developed on the threshold of science and society. Empirical studies show that many people welcome scientific progress, but at the same time the high complexity of scientific research processes may be hard to understand. Trust in research has therefore shifted to trust in institutions. The trend is evident – public institutions are trusted more than those organized by the private sector. This trust remains precarious because it is quickly withdrawn in the event of abuse or scandals. Whole branches of research, not just the respective culprits, can be affected. Regaining such lost trust is difficult, sometimes hopeless.
What does this trend mean for the ethics of genome editing? I avoid taking such observations into account as purely moral psychology or sociology. Instead, scientific ethics in this and other areas of emerging biotechnology must be organizational and include social ethics if we want to reflect and shape the challenges of the discourse between science and various publics in a responsible manner.