Ethical and Social Aspects of Nanotechnology vs. COVID 19

Summary

The methodology of nanomedicine constitutes perhaps the most important “key technology” of the future: no other field is accompanied by so many hopes and will entail comparable social consequences as the expected developments in nanomedicine. And in this context, the use of RNA technologies in the therapeutic, diagnostic and preventive (immunological) fields will certainly play an essential role (be it in the form of mRNA, cRNA or even “free RNA”). The use of mRNA vaccines is merely the prelude to this development. While the ethical problem is still relatively simple here (especially since pure safety risks can only be clarified empirically and therefore do not fall within the focus of bioethics), the circle of (nano-) ethical questions will expand enormously as soon as RNA technology has also gained a foothold in other fields of genetic engineering-based nanomedicine.

Key words/phrases: Bioethics, nanoethics, technology assessment, precautionary principle, social acceptance, safety of mRNA vaccines, data protection.

1. Introduction: Nanotechnology and “Nanoethics”

Nanotechnological processes and products have been playing a considerable role – largely unnoticed by the general public¹  – for many years now. And this also applies to the field of medicine, in which more and more primarily genetically engineered products (such as human insulin obtained via genetically modified bacteria) are being used in diagnostics and therapy. This is even indispensable for so-called “somatic gene therapy”, since here therapeutically effective gene sequences are supposed to compensate for the malfunction of “sick” genes with the help of gene shuttles (mostly viruses rendered incapable of reproduction), for example by coding for vital proteins that the diseased organism itself is either unable to produce or is unable to produce in sufficient quantities. In this case, entities on the nanoscale are even used twice: on the one hand in the form of the “healthy” gene sequence and on the other hand through the use of viral transfer systems (vectors).

But apart from such often rather “exotic” areas of application² , the public has only become aware of the importance of nanotechnology (and here in particular with the means of genetic engineering) through the development of a completely new class of vaccines: namely through the mRNA vaccine to combat the Covid-19 or SARS-CoV2 pandemic. Previously, genetic engineering products had come to general attention mainly in the field of agriculture and food production and were then criticized, sometimes very strongly, because of possible environmental and health risks. It is therefore not surprising that the innovative mRNA vaccines were – at least initially – viewed with great suspicion by many people, since genetic engineering products do not enjoy a good reputation. In addition, little was (and still is) known about the potential side effects of these vaccines due to the lack of long-term clinical studies at the beginning of the vaccination campaigns. Only when the efficacy and relative safety of the mRNA vaccine gradually became apparent in the course of the mass vaccination campaigns did public acceptance of this new procedure also improve. And it is possible that the success of the new vaccines will help to improve the overall perception and acceptance of genetic engineering, so that it could also be trusted more than it has been so far in other (non-medical) fields of application. Nevertheless, by no means all “critical” questions in connection with so-called “nanomedicine” based on genetic engineering have yet been clarified: in particular, not all ethical questions. And the debate on genetic engineering will continue to occupy bioethicists and nanoethicists for a long time to come.

The continuing need for clarification also has to do with the fact that nanotechnologies are applied on a microscopic scale, i.e., they elude immediate visibility, and, moreover, they intervene in the highly complex system of cells and organisms, whose structures and mechanisms are also microscopic in size and are still far from being understood in detail. Above all, proteomics, which describes the dynamic behavior of proteins expressed by genes within the cell, is still in its infancy. Therefore, no one knows for sure whether a DNA or RNA molecule, if introduced into an organism, will really only have the desired effect (if at all) or whether it may also have adverse (unintended) consequences. Outside the laboratory with its safe “containment” conditions, namely tested directly on living humans (as in the case of mRNA vaccination), a clinical or even everyday medical use of genetically engineered remedies resembles a “real experiment” with society [25]. Such real experiments are otherwise only known from the construction of innovative nuclear power plants or unique structures (e.g. bridges, landfills or airports), whose stability and inherent dynamics can often hardly or not at all be simulated under laboratory conditions.

In principle, therefore, extreme caution is always called for here: but in view of the terrible, often fatal effects of the pandemic, there was already very rapid (and sometimes by way of “emergency approvals”) widespread use of the innovative vaccine in order thereby to prevent worse. However, although the overall study situation was very uncertain (especially since long-term data were not yet available), the approval of the new vaccine was of course preceded by a detailed evaluation by the responsible institutions and committees (including national ethics committees), in which above all ethical aspects were also taken into account: in particular, it had to be weighed up whether, in view of the serious pandemic situation, it was permissible to shorten the implementation of clinical studies. However, it cannot be said that the approval was given lightly or completely “blindly”. All in all, the scientific community of immunologists, epidemiologists, infectiologists and virologists, as well as the political decision-makers, can be said to have a considerable ethical awareness. And as it looks at present, the use of the mRNA vaccine can be considered a great success – as well as a breakthrough for nanomedicine as a whole.

On what scale do nanotechnologies operate and what purposes do they serve? To answer this question, we have to broaden our view and look at the entire field of nanotechnological developments. In general, we can say that nanotechnologies describe structures that are 80,000 times smaller than the diameter of a human hair (1 nanometer = 10^-9 meters). However, the classifications of materials as nanomaterials often differ, for example, when the British government assumes a size of up to 200 nanometers, while the USA allows a size of up to 1,000 nanometers [18]. Whatever the case, these technologies will in any case enable fundamental relationships to be explored at the molecular and atomic level and new materials with promising properties to be developed. Nanotechnologies are therefore considered key technologies of the 21st century, which are our “tickets” to the future [16].

In the following, we will again focus more on the field of medically significant nanotechnology. Among the numerous promising applications of nanotechnologies, the field of medicine occupies a special position, as it is particularly associated with high expectations and hopes. New cancer therapies are already being tested in clinical trials³ , and innovative nano-transport systems for drugs make more efficient treatment with fewer active substances possible. Undesirable side effects should thus be reduced. Miniaturized mobile diagnostic units for rapid tests in doctors’ offices and imaging methods for diagnosing diseases that are less stressful for patients are being tested. And innovative surface coatings for implants or new materials in dental technology could help to significantly improve tolerability and durability and thus reduce costs.

This small excerpt from the breadth of applications in the field of medicine illustrates the great potential of nanotechnologies⁴ . Quite a few observers even speak here of a “paradigm shift in healthcare”. In the EU, around 100 million euros have been allocated to nanomedicine projects for the period 2007-2013 under the 7th Framework Research Program. The funding volume is likely to increase even more dramatically in the future in view of the success of mRNA vaccines. In the USA, too, the Project on Emerging Nanotechnologies and the National Cancer Institute [24] have also developed comprehensive funding programs for the application of nanotechnologies. National and international policy makers are thus focusing on research and location promotion in the field of nanomedicine.

2. “Nanoethics” as a new bioethical subdiscipline

All this is not just about promoting basic research and product development, because in its new Code of Conduct [12], the EU requires all research projects to take account of possible risks and to be embedded in social and ethical issues. This is because the possibility of exceeding the limits of current forms of therapy simultaneously raises questions about new boundaries. And this brings into play a special field of application of ethics (or practical philosophy), which is generally called “bioethics” and which itself has many subfields.

In connection with the development of nanotechnological processes, a new field of research and reflection has been established within bioethics: so-called “nanoethics”. This field is essentially concerned with monitoring the effects of a new nanotechnology from the perspective of sustainability and evaluating its results with regard to the well-being of society. The focus of nanoethical expertise is thus on the “interest of the common good” in the sense of improving the quality of life of the community.

In order to be able to better classify nanoethics, it is first necessary to understand the goals and tasks of bioethics. For just as nanoethics represents a subfield of bioethics, bioethics for its part can be understood as a subfield of Technology Assessment (TA) in the area of the application of biotechnological processes. This is especially true when TA is related to the application of genetic engineering processes in biomedical, food technology or agricultural fields of application. In this context, the scope of TA includes not only ethical issues in the narrower sense, but also issues of reliability and safety, as well as social and political aspects, by asking, for example, “Are the social effects of a new technology politically and socially acceptable?” For example, if it should one day become possible to extend human life far beyond the normal lifespan with the help of genetic engineering. Would this be desirable at all? Are we not embarking on a fundamentally “slippery slope” that could have devastating consequences for the future of society? And what would it mean for our image of man if we were able to eradicate all hereditary diseases by means of genetic engineering or to shape or optimize the genetic makeup of human beings at will?

In other words, the field of bioethics or bioethically sensitive TA encompasses all ethical, legal and social implications (abbreviated to ELSI) arising from the application of biotechnological processes. And it is only by locating them in the context of the broader ELSI issues of TA that the questions of bioethics can be adequately addressed at all, so that ethical reflection does not take place in a “vacuum”, i.e., detached from other factual issues. There may thus be basic ethical principles that arise in any application of technology, but their meaningful application to particular subject areas (such as nanomedicine) should never be detached from the specifics of the particular field of technology.

However, the aim of bioethics or TA is not to hinder or even prevent new biotechnological developments simply because they are novel and unclear in terms of their hazard potential, but to serve as a kind of “early warning system” that draws attention in good time to undesirable developments or ethically and socially precarious applications of new biotechnological methods. It is therefore important to include bioethical reflections as far as possible from the outset in the research and development of novel biotechnologies (in the sense of accompanying research that is already involved in the research process). This not only prevents ethically questionable developments, but also avoids unnecessary costs and protects the public image of biotechnology. In any case, it would be ideal if ethical reflection would contribute to the design of technology “ex ante” and not only “ex post” [17]. Here, ethical analysis and evaluation would have to focus primarily on (1.) the goals and purposes of the technical innovation, (2.) the instruments and means (e.g., animal or field testing), and (3.) the unintended side effects (i.e., establishing the risk profile, e.g., with regard to possible toxicity, and adherence to the precautionary principle in the face of lack of knowledge).

3. Why do we need ethics in view of the introduction of new technologies?

Every ethics is always based on a certain value system. Without reference to those value determinations and ideals which are decisive for a society, no decisions of action could be made which could be justified before other persons. Every form of responsible action always takes place within a horizon of legitimized value systems that can be invoked as arguments for a particular decision. Many of these values have found their way into legal regulations (laws and regulations), so that they serve the courts as normative criteria for the adjudication of legal conflicts or claims brought before them. In Western culture, it is above all humanistic ethics, often combined with Christian values, that serves as the basis for finding and justifying decisions and that has found expression, for example, in general human rights and in democratic rights to freedom (as rights of defense against the state).

On the basis of the value system, ethics asks what man should do or what he may do in a given situation. This can be about the observance of certain fundamental value principles, which must be adhered to unconditionally (without exception) (thus, according to “deontological ethics”, not even white lies are allowed), or it is about possible undesirable consequences of a certain behavior (thus, “consequentialist ethics” tries to assess the potential effects of actions). In this context, ethics serves primarily to resolve conflicts of values (which, however, is not always successful or possible) by rationally weighing the arguments in favor of or against a particular decision to act. Finally, ethics is that area in which the often only unconsciously valid value concepts are made explicit, so that the establishment of a value standard (or value canon) becomes possible, to which people can orient themselves. Ethics can serve as “ethics of attitude” for the enforcement of ‘ideological’ value attitudes, in which a certain image of man or also a social ideal (a “utopia”) is expressed, or it can attempt as “ethics of responsibility” to do justice to the empirical peculiarities of the respective situation of action by subjecting all circumstances and possible consequences to an evaluation. Either way, ethics is always about answering questions of justice (e.g., about the fair distribution of scarce goods or opportunities and rewards) and about avoiding possible harm (e.g., to life and limb) or a restriction of liberties by weighing different interests, legal claims and expectations against each other.

This was particularly clear in the case of the political justification of socially drastic “lockdown” measures in connection with the Corona pandemic: the right to freedom of economic activity and freedom of movement was in conflict here with the right to physical integrity and protection against infection, which are among the highest legal rights and the most important tasks of the democratic state. Although there is no ranking of fundamental rights in the constitutions – such as in the Basic Law of the Federal Republic of Germany – a decision had to be made in view of the pandemic as to which fundamental right should be given priority. In the end, it was decided that ethical priority should be given to the protection of health and life, since seriously ill or even deceased persons are no longer able to exercise their other fundamental rights. An additional argument in favor of restricting other civil liberties by imposing a “lockdown” or even the mask and quarantine obligation was that this would not only be a matter of self-protection for individuals, but above all of protecting third parties who could be unintentionally infected. On the other hand, it is more difficult to call for a general obligation to vaccinate in order to be able to include those who refuse vaccination, since such an obligation would seriously interfere with the right to self-determination. The ethical evaluation of the admissibility of the new mRNA vaccines must therefore not only concern the safety aspects of these vaccines, but must also take into account the social context in which these vaccines are to be used: be it voluntarily or be it due to a legal obligation: How could a vaccination obligation be justified if neither the possible vaccination risks nor the long-term protective effect of the new vaccines are already sufficiently known?

4. Nanoethical question areas: Acceptance problems and safety risks

As already mentioned above, more and more nanotechnological methods and their products are finding their way into everyday medical practice. And this is mainly due to the growing importance of genetic engineering in the field of medical diagnostics⁵  and therapy or prophylaxis, with mRNA vaccines falling into the field of preventive medicine, insofar as they are used to prevent the outbreak of a disease. However, the development of these vaccines would not have been possible without the prior molecular genetic elucidation of the viral pathogen, so that genetic engineering carried out on the nanoscale is used here both in the descriptive sequencing of the viral RNA and in the constructive development of the vaccines (especially since the immunologically active mRNA sequence must also be packaged in a shell of nanolipid particles in order to be able to enter the human organism safely and stably). It is therefore not sufficient to consider the new vaccines alone from a bioethical point of view: on the one hand, the entire research and production process and, on the other hand, the totality of the effects of vaccination must be included in the reflection, including not only the possible physiological side effects, but also the social and economic consequences of widespread use of the vaccines. And likewise, consideration must be given to what would be involved in not using these new vaccines. Technology-related ethics must always seek to assess and evaluate the risks, on the one hand, and the opportunities, on the other, of an innovative technology (which is why it is best considered as a subfield of technology assessment, as suggested above).

As a rough approximation, the ethically relevant aspects arising (1) from the application of mRNA vaccines within medical practice in the form of a broad-based vaccination campaign can be distinguished from those ethically relevant aspects of these vaccines arising (2) from the application of genetic engineering procedures in the nanotechnological size range. In the following, both sets of questions will be dealt with in detail, whereby, in the context of our “Nanocode” project, the ethical aspects mentioned under (2) are of particular importance.

4.1. Medical and socio-ethical aspects of the vaccination campaign

There is still much discussion and even dispute in the various societies affected by the covid pandemic about for whom vaccination with mRNA vaccines is useful, i.e. beneficial. There is widespread agreement that especially so-called “vulnerable groups” can benefit from vaccination with mRNA vaccines: this applies especially to elderly people, whose immune system is often already considerably weakened, and people with certain pre-existing conditions, so that a particularly severe (possibly even fatal) course of a corona disease can be expected in them. Pregnant women, on the other hand, are advised against vaccination for good reasons. It is also known that in people with certain rheumatic diseases no or at best moderate vaccination success is to be expected. Finally, one must also evaluate whether there may be adverse “cross-effects” between the vaccine and medications that a patient must take regularly because of his or her current or chronic illnesses. However, all these are not ethical questions, but purely medical or pharmacological questions that can only be clarified empirically as well as in relation to the individual case (anamnesis). Therefore, the usual requirements for clinical testing of any new drug (including vaccines) correspond to this: only when the “candidate” has successfully passed all clinical tests for efficacy and safety, only then can it receive a patent-protected marketing authorization for its use in medical practice. And in the process, it may very well be that a new drug only receives limited approval if it is not effective or safe for every possible patient. For this very reason, clinical trials must always be carried out on different groups of subjects: e.g. on women and men, on adolescents and children, on pregnant women and diabetics, etc., in order to be able to ascertain all possible risks. As a rule, such clinical trials (even carried out on laboratory animals in the first preclinical phase) drag on for many years, with most “candidates” failing and having to be abandoned so that they do not even reach market maturity.

In the case of the innovative mRNA vaccine, however, a shortened clinical trial procedure was chosen due to the urgency and extraordinary danger of the pandemic, in particular by foregoing long-term studies in order not to lose any time. After all, the use of the vaccine was initially restricted to vulnerable groups and the very old in order to gather extensive experience (i.e., data), on the basis of which further vaccination recommendations could then be made for other adults. Such prioritization or differentiation of the patient population (of all potential beneficiaries) is necessary from both a medical and ethical perspective to minimize potential adverse effects. But should, for example, adolescents or even children also be vaccinated? The extent of the protective effect of vaccination in children and adolescents, or the mildness of the course of covid disease in the absence of such vaccination, can of course only be determined by empirical research. This is therefore not an ethical question. Accordingly, it can also only be determined empirically whether, in children and adolescents, the potential side effects of vaccination (the vaccine symptoms) outweigh the possibly severe disease symptoms in the event of infection. Perhaps it is better to leave it to the “nature” of the normally robust immune system of children and adolescents to cope with a Corona infection themselves. On the other hand, children and adolescents can also be carriers of Covid 19 viruses to adults, so that one could be of the opinion that the vaccination of children and adolescents is at least able to reduce the viral load in such a way that a transmission of the pathogens to non-vaccinated adults should relevantly reduce their risk of suffering a severe course of the disease.

From an ethical perspective, it should be noted here that vaccination of children and adolescents, which primarily serves to protect unvaccinated adults (and less their own protection), is only permissible if the possible harmful side effects of vaccinating children and adolescents are not more significant than the health benefits that the children and adolescents themselves can derive from vaccination. It should not be the case that children and adolescents are exposed to unnecessary potential vaccination risks simply to better protect unvaccinated adults from infection⁶ . Instead, it could be argued that an adult who refuses to be vaccinated must bear the risk of infection and thus also of a potentially severe course of the disease on his or her own responsibility.

However, the validity of this argument depends on there already being sufficient empirical evidence that vaccination with the novel mRNA vaccines is both sufficiently effective and safe with regard to dangerous long-term effects of the vaccine. The problem in this case is that this is a completely new class of vaccines with which medical science has not yet been able to gain experience. It is therefore ultimately up to clinical research to prove that the protective effect of the mRNA vaccine is high and that (beyond statistically insignificant harmful vaccine reactions⁷ ) no late effects of the vaccination are to be expected (e.g. in that the mRNA molecules could permanently latch onto the human genome, trigger cancer or dementia at some point, reduce fertility or cause lasting damage to the immune system). So far, however, it looks quite encouraging that researchers are able to confirm both the high efficacy and health safety of the mRNA vaccines. And this also includes possible long-term late effects in that no physiological mechanism has yet been discovered that could give serious cause for concern that the mRNA molecule not only serves the immune system as a blueprint for the production of the viral antigen (in order to then generate antibodies against it), but could also stimulate undesirable metabolic processes or cellular tissue changes. This is because the mRNA molecule apparently neither enters the genomic cell nucleus nor remains in the organism for any length of time before it is degraded again, i.e. breaks down into its nucleic bases and thus becomes ineffective.

Furthermore, there is currently a heated debate about how often and at what intervals such a vaccination should be repeated in order to both ensure and increase the protective effect⁸ : again, these are questions that can only be answered on the basis of immunological studies and statistical evaluations of the vaccination success. From an ethical point of view, it can only be said that everything possible must be done to increase the protective effect of an otherwise harmless vaccine as far as possible. This also applies to the further development of the vaccine: for example, its modifying adaptation to new virus variants⁹ .

As already indicated above, questions of efficacy and safety are in principle not ethical but purely scientific questions. The situation is somewhat different with the question of whether the “precautionary principle” should always apply by insisting that the safety of a new drug be tested in advance. But this is already fulfilled by the requirement of multi-phase clinical trials, i.e. regulated in detail in pharmaceutical law. This aspect will therefore not be discussed in detail here, especially as it is dealt with in the training module “Legal and Social Aspects”. There, it is also discussed who (and in what respect) is to be held liable in the event of vaccine damage occurring (the treating physician, the manufacturer or the health authorities).

However, “precaution” also concerns the question of whether larger stocks of vaccines should be stockpiled and whether it should be ensured that the production of vital vaccines is safeguarded within a national framework in order, on the one hand, to be able to monitor the quality assurance of the substances on one’s own and, on the other hand, to be able to contain the risk of a “rupture” of the supply chains. From an ethical point of view, the state’s health care for its population also includes a certain degree of self-sufficiency in the supply of medicines, so it must be considered risky to move production abroad (to India or China, for example) for purely logistical and economic reasons (cost savings). Only within the framework of a national and thus relatively autonomous drug supply can situations of scarcity be prevented, which could force physicians to make ethically highly questionable “triage” decisions (as is familiar from military hospital medicine, where in extreme situations it must often be decided for which wounded patients the drugs that have become scarce can be used most promisingly; and for which patients not, so that they are withheld from them). However, this concerns not only the available quantity of high-quality drugs, but also the other infrastructure of medical care: for example, the number of intensive care beds available in hospitals, or the capacity of the medical and nursing staff needed to operate the apparatus (such as ventilators) and to provide physical care to patients. However, these are general questions of medical ethics that concern the organization of medical care and therefore go beyond the scope of the ethically correct use of mRNA vaccines, so they need not be discussed further here.

Another point concerns issues of distributive justice and access to the new nanomedical possibilities: For example, given the initial scarcity of mRNA vaccines, it could not be overlooked that financially strong countries could obtain them more easily than poorer countries. Although the WHO reserved a certain quota of vaccines for the “Third World”, this proved to be completely insufficient. The majority of the manufacturers of the new vaccines also refused, for reasons of profit, to allow the poorer countries to produce the vaccines themselves without paying patent fees, i.e. to set up their own production facilities. This, too, put the developing countries at a serious disadvantage. In general, there was initially also fierce competition between the richer countries for the purchase of the rare vaccines, which must be viewed negatively from an ethical perspective, since a more concerted approach would also have been possible to ensure fair distribution. Basically, the question arises here how it can be achieved that costly nanotechnologies can also be made accessible to poorer beneficiaries, e.g. to prevent a “two-class medicine”.

In any case, as far as the efficacy and safety of mRNA-based vaccines are concerned, only empirical studies can provide information on this. Ethics has a say in this context only insofar as one can ask according to which criteria the benefit of a vaccine is to be evaluated: the prevention of a serious, perhaps even lethal disease is certainly the decisive criterion here, provided it is actually fulfilled. Against serious diseases such as smallpox and the plague in the past or zika fever or Ebola today, the existing vaccines are certainly the “means of choice”. But there is also a minority view that vaccination is too much and too hasty (e.g., against the seasonal flu), so that our “natural” immune system tends to be overloaded (stressed) and thus hindered in the development of its spontaneous “self-healing power”. Of all things, the great successes of vaccination campaigns – especially in the case of less threatening diseases – could ultimately prove to be “Pyrrhic victories”, since we would rely too much on modern pharmacology and apparatus medicine and accordingly neglect other (“gentler”) ways of maintaining and increasing health. In the case of Covid-19, however, there seems to be no way around vaccination, especially since there are no really effective therapeutics yet, so that a possible infection could be met with some equanimity. In general, there may be many ways to strengthen the innate immune system (such as a healthy diet, sufficient exercise and sleep, and a stress-reducing lifestyle), but against a really serious infectious disease, probably only a suitable vaccination will help in advance.

On the other hand, especially in the case of Corona, one could consider whether epidemics and pandemics originating in animals could not also be prevented by limiting the occasions when a virus (or any other dangerous pathogen: a bacterium or a parasite) can jump from animals to humans. Indeed, the covid-19 pathogen is, after all, a “zoonosis” (at least, there is little to suggest that it escaped unintentionally from a Chinese laboratory¹⁰ ) that was probably facilitated by the fact that pangolins or certain bats were offered for consumption at a market in Wuhan, which are excellent hosts for numerous viruses that can be potentially dangerous to humans if transmitted. This is to say: Changing our dietary habits can also prevent the outbreak of serious infectious diseases. The idea is that in the exchange area of human civilization and nature, we should limit or at least control the risk of transmission as much as possible. Indeed, the (illegal) wildlife trade, for example, as well as new forms of technology-intensive forest management, increase the likelihood of human contact with previously unknown pathogens through intrusion into previously largely untouched wilderness areas. Of particular sociological interest, moreover, are the often domestic cohabitation with farm animals (such as poultry) and the often inadequate local hygiene standards (e.g., in drinking water quality control or waste disposal). In general, human settlements and the associated road construction are apparently expanding further and further into the wilderness; just as, conversely, wild animals (incl. birds and insects) are increasingly being displaced from their ancestral natural habitats and settling in the settlements.

Thus, in order to avoid zoonotic diseases, the “epidemiological management” of the diverse human-nature relationships in the border area to wilderness becomes more and more urgent. In addition to scientific monitoring of the possible spread of wild species with zoonotic potential, legal and practical measures are thus also required: e.g. in the area of settlement and infrastructure development, economic exploitation of rainforests, improvement of hygiene, (nature-oriented) food production and health education. This is where medical bioethics meets environmental ethics. But these are all broader issues that are, to a certain extent, in the forefront of mRNA strategies against the Covid 19 pandemic: because once a pandemic has broken out, all considerations of preventive measures against zoonotic risks come too late, so that we must now try, on the one hand, to contain the further spread of the infectious event as far as possible (e.g., by wearing protective masks, by using a protective clothing, etc.). (e.g., by wearing protective masks, disinfecting hands and surfaces, ventilating indoor areas, temporary quarantine, and even a temporary “lock down”) and, secondly, through broad-based vaccination campaigns. And in the case of the latter, we are fortunate that the mRNA vaccines could be developed to operational readiness so amazingly quickly, which has certainly saved countless lives.

4.2. Nanoethical Aspects of mRNA Vaccines as Genetic Engineering Products

After briefly discussing the general medical and socio-ethical implications of the practical use of the novel mRNA vaccines, we will now consider the possible problems that could arise from the genetic engineering character of these vaccines: i.e. from the fact that these agents are, on the one hand, the result of constructive operations (so to speak, “RNA engineering”) on a molecular genetic scale; and that, on the other hand, they are intended to intervene in the biological functions of cells or in the immune system of a living organism (i.e. the human organism). in the immune system of a living being (namely the human organism). As already mentioned above, the field of nanoethics will be limited to the field of human medicine in the context of this training unit. Whereby – narrowing down the field even further – nanoethics will be related mainly (but not only) to the development of mRNA vaccines. In fact, all “manipulations” of RNA and DNA molecules, i.e. also all constructions of gene sequences (and the mRNA molecule, after all, also codes for a specific spike protein on the envelope of the covid-19 virus, i.e. for a viral gene) can be considered nanotechnical procedures. The development of mRNA-based vaccines is only a special case here. However, since ethical questions also arise in this special case, which arise overall for genetic engineering procedures or for the medical application of the products of these procedures, it makes sense to broaden the focus of ethical reflection accordingly, i.e. to include the entire spectrum of genetic engineering-based developments in the field of human medicine in the ethical assessment. Indeed, it will become apparent that in this special case, too, virtually all the ethical questions that arise in connection with genetic engineering in the health sector will come up¹¹ .

It can certainly be disputed that a special “nanoethics” as a special discipline is necessary, insofar as it would be merely a further application of “bioethics” or “gene ethics” and thus the questions raised by nanobiotechnology are already very well-known from other contexts of ethical reflection. Indeed, one should not misjudge the cross-cutting nature of ethical reflection, since even (nano-) technologies that are completely different in substance often face quite similar ethical and social challenges.

In principle, the use of genetic engineering methods to combat (infectious) diseases is certainly to be welcomed. However, in connection with the genetic engineering production (construction) of mRNA vaccines and with their handling during transfer into the human body, there are not only safety issues, but also, e.g. However, in connection with the genetic engineering production (construction) of mRNA vaccines and their handling during transfer into the human body, not only safety issues arise, but also questions of social acceptance, insofar as genetic engineering (both as a process and in terms of its products) does not enjoy a particularly good reputation: it is often argued that man would interfere with “God’s creation”, even “play God”, by changing the “blueprint of life” (which, however, is hardly the case in the case of mRNA molecules, since they merely provide the human immune system with templates for its own activity). Even the environmental compatibility of genetically engineered drugs is sometimes doubted (although, for example, human insulin obtained via genetically modified bacteria is readily accepted by diabetics). In any case, it is difficult to be dismissive of the construction of mRNA molecules to fight serious infections, since their advantages obviously clearly outweigh any concerns. One would have to be a fundamental opponent of technology, or at least an “ideologically” convinced enemy of genetic engineering, not to be able to see and appreciate the health benefits of precisely this application of genetic engineering. In the case of the agricultural use of GM plants, this may be somewhat different, since the safety situation and the environmental compatibility under “field conditions” are not yet clear in the last consequence; and also, in the case of the reproductive cloning of farm animals as well as the “reconstruction” of organisms with the help of “synthetic biology” or “genome editing”, not all risk and ethical questions have yet been cleared up (we will come back to this later).

Interestingly, in the case of the “tailor-made” mRNA vaccines, we are actually dealing with two nanostructures: on the one hand, the mRNA itself, i.e. the active substance, and on the other hand, the lipid nanoparticles into which the mRNA is “packaged” and subsequently introduced into the human organism. The nanotechnological procedure thus takes place on two different levels of construction, thus forming an exceedingly complex process.

Although the focus of this training module is the search for vaccines against the Corona virus in its different variants (as well as their ethical evaluation), the medical use of tailor-made mRNA hosts is capable of more than just combating infectious diseases: there is justified hope that artificial mRNA products can also be successfully used for innovative approaches in the field of gene therapy; or in the treatment of cancer as well as cardiovascular diseases. However, in order to be able to intervene in the genetic material of diseased cells in a targeted manner using mRNA, suitable insertion procedures (“erase and paste”) are required. And this is where the CRISPR-Cas technology of “genome editing” comes into play. Finally, in an at least indirect way, mRNA sequences could also become important in the development of diagnostic methods in the future (for example, in genome analysis, in the detection of tumor markers, etc.). Therefore, these areas of application will also be addressed subsequently, because a full assessment of mRNA nanotechnology can also only be made from an ethical perspective if this technique is considered in the broader context of other RNA- and DNA-based genetic engineering applications. This broadening of the scope of reflection is also justified by the fact that RNA technology is likely to soon open up further fields of application: such as in cancer or gene therapy, but also in diagnostics. And at the latest when this happens, the focus of ethical consideration will also have to expand, as ethical aspects will then become relevant that do not only concern the use of this technology for vaccination purposes: because only then will the enormous potential of this method become apparent. However, since any ethical reflection on the social implications of a new technology should take place as early as possible, it makes sense to try to evaluate these implications in the various fields of application of RNA technology already today. The advantage of a “prospectively” pursued nanoethics also consists in preparing a “proactively” oriented technology policy, in that nanoethics draws attention to possible risks or disadvantages of the new technology at an early stage.

In any case, the expected different medical applications of (RNA-based) genetic engineering raise particular scientific (empirical) and ethical problems, depending on the scope of construction and the depth of intervention in the organism, or depending on their objectives. The variation and weight of these problems depend, for example, on the level of construction reached by the manipulation of those molecular structures or organisms that are intended either to produce pharmacologically valuable proteins (e.g. in the bacterial production of human insulin) or to serve as “ferries” (vectors) for the introduction of therapeutic agents into the human body. However, even genetic medical procedures already applied at the nanoscale for purely diagnostic purposes produce data that are often very personal (e.g., genetic data that are characteristic of a particular person, making that person partially “genetically transparent”) and that could therefore be misused (e.g., by insurance companies if the data collected indicate future illnesses due to certain genetic dispositions; or also by government authorities to identify certain individuals even though there is no law enforcement connection). In this case, appropriate precautions must be taken under data protection law: e.g. by means of suitable procedures for anonymization or at least pseudonymization of the data (or also by means of high access barriers or by holding the data for a limited period of time). Also, the use of genetic data, for example for epidemiological purposes, must not take place without the express consent of the data donor (an “informed consent”) (this applies, for example, to clinical tissue collections or research biobanks in which genetically meaningful tissue samples are stored and evaluated).

Thus, it can be seen that the development of mRNA techniques should be viewed in the broader context of the development of molecular genetic tools, all of which are, or will be, effective at the nanoscale: be it

(a) for diagnostic purposes (e.g., in genomic analysis for the detection of inherited disease predispositions);

(b) or for therapeutic purposes (e.g., in the performance of somatic or even germline-interfering gene therapy);

(c) or for immunological purposes (e.g., in the construction of mRNA sequences that are “tailored” to combat specific pathogens);

(d) or for bioconstructive purposes, where the aim is to design whole organisms (single-celled organisms) in such a way that they can be used for the production of diagnostically or therapeutically effective drugs (e.g. by means of “genome editing” in the field of “synthetic biology”, for example, in order to incorporate new metabolic pathways “top down” into a given organism; in addition, however, the completely new construction of a living organism would also be conceivable “bottom up”, which could even have nucleic bases in its DNA or RNA that do not occur in nature).

Unfortunately, it is not possible within the limited scope of this paper to present here all the relevant areas in which genetic engineering is used within medicine. Therefore, in conclusion, we will only take a look at the vectors with the help of which the mRNA vaccines are introduced into the human organism.  In addition to the vaccines themselves, these transport systems represent the second application of nanotechnological methods in the context of combating covid-19.

5. “Nano Delivery Systems”: Functions and Risks

Since the safe transport of the mRNA agent into the human immune system is crucial for vaccination success, this aspect will first be considered in some detail. It has already been mentioned above that the mRNA active ingredient must be packaged in a shell of lipid nanoparticles in order to be able to enter the human immune system in a stable manner so that it can serve there as a template (antigen) for the production of antibodies against covid-19. However, this is only one example of a large number of so-called “delivery systems” at the nanoscale that can perform very different transport functions.

Nanomaterials are used in a wide variety of ways in the human body. Two particularly promising areas of application will be discussed in the following section: First, the group of various nano-transport systems (“nano delivery systems”), which serve to distribute active substances in the body. On the other hand, various metallic nanoparticles are used in cancer therapy, where alternating magnetic fields provide heating and destruction of tumor cells (hyperthermia process). Here, only the first case will be considered in more detail.

Nanoscale systems are used to transport active ingredients in the body (drug delivery). The nanomaterials enclose the active substance with tiny protective shells, which are then referred to as encapsulated systems or micelles. They enable the active substances to be protected or disguised by biological mimicry [6] in such a way that they can be transported to specific areas of application. Depending on their structure, they can overcome biological barriers such as cell walls, the gastrointestinal wall or the blood-brain barrier [19]. It is precisely the blood-brain barrier that has so far prevented a readily usable pharmaceutical approach to effectively treat diseases such as Alzheimer’s disease. Accordingly, the hopes associated with the use of nanomaterials are high. Depending on the objective and the desired site of application, the nano-transport systems fulfill different tasks. For example, they envelop poorly water-soluble or fat-soluble vitamins and active ingredients [2], making them more readily available to the body.

Other processes allow the release of active ingredients to be timed or substances that would decompose too quickly in the body to be released only at the point of use or evenly distributed over a very long period of time. There is a whole range of encapsulation systems, e.g. for cosmetics, for new pharmaceutical products or for contrast agents. Many systems use natural materials that are easily broken down by the body, but their nanoform gives them more stability or makes them more easily absorbed by the body. These include tiny fat droplets (nanolipid structures), natural protein compounds such as those that can be obtained from the extracts of shellfish (chitosan), or gelatin. Many systems copy nature, such as degradable polylactogluconates (protein-sugar compounds) or dendrimers (tree-like polymer structures), which are to be used in cancer therapies, herpes and difficult-to-treat fungal diseases.

Other systems work with materials such as carbon. These form non-degradable, nanometer-sized football-like structures (fullerenes) or tiny carbon nanotubes in which the active substances can be transported [7, 22]. Another development step that researchers are working on is targeted delivery systems, which can be equipped with specific receptors for cell types, viruses or other pathogens to “recognize” their target location [30, 13]. This would ensure that active substances act at the intended site of action, e.g. at specific organs such as the liver or at specific tumor cells, but not in other regions of the body. Monoclonal antibodies, which attach themselves to the tumor cells, are usually used. What the different types of delivery systems have in common is that improved or more targeted uptake could significantly reduce the amount of drug and undesirable side effects [1].

The societal benefits of drug delivery systems are seen primarily in improved medical cures and increased quality of life for patients [11]. Other benefit aspects include the potential reduction in health care costs and the expected positive economic development. Various attempts to quantify these benefits are summarized below.

First and foremost are approaches to cancer treatment. Cancer represents one of the leading causes of death worldwide, with approximately 7.6 million deaths in 2005. In industrialized nations, cancer is the second leading cause of death. The WHO predicts that cancer-related deaths will rise to 9 million in 2015 and increase to 11.4 million by 2030 [32]. Any therapeutic advances could mean cures or time delays for millions of sufferers and their families, and the greater efficiency of treatment methods could potentially lead to a reduction in healthcare costs.

In the research report “Nanotechnology pro Health: Opportunities and Risks”, written in 2004 for the German Federal Ministry of Education and Research [3], the authors refer to American studies [14] which, using the example of virial carcinomas, calculated possible cost reductions through the use of nanomaterials, since the lower side effects required fewer follow-up treatments. This was especially true for older female patients with a higher susceptibility to side effects. However, the BMBF study advises that the estimates of potential economic savings should be viewed with caution because of the poor comparability of the various international treatment methods and health care systems, as well as possible price trends for drugs and procedures [3].

Overall, undesirable side effects are a serious problem. In the USA, for example, they were responsible for an estimated 100,000 deaths within one year, making them the tenth most common cause of death [33].

Most quantitative estimates of the benefits of nanomaterials in the pharmaceutical industry relate to projections of market growth. They predict an increase of about 50% per year within the period from 2005 to 2012. At the same time, a steadily increasing share of nanotechnology in the overall pharmaceutical market is forecast. The forecast of a market volume of 4.8 billion US dollars in 2012 shows the optimistic assessment of the market potential of nanotechnology in this area [23]. The question would then remain open as to whether the high growth figures are associated with high drug prices, which would cancel out some of the cost savings in the health care system.

A general risk assessment of nano delivery systems is not possible in view of the wide range of applications and materials used as outlined above. Statements on the hazardousness or non-hazardousness of nanomaterials in this field of application should always be related to the individual case. Not only the forms of nanomaterials used, but also their possible bonding or decomposition processes (agglomeration and deagglomeration) must be taken into account [4].

When used in the medical field, specific safety tests apply before a product is approved. Of course, this also applies to products containing nanomaterials as active ingredients or as excipients, or to medical devices. Active ingredients are understood to be natural or synthetically produced chemical elements, their compounds, and mixtures or solutions that produce a pharmacological effect. They must be tested in preclinical trials to determine whether they have a long-term toxic effect on animals or humans (acute and chronic toxicity), whether they cause cancer (carcinogenicity), affect genetic material (mutagenicity) or have negative effects on unborn children (teratogenicity). As a rule, an additional risk assessment for environmental effects is required. Excipients, on the other hand, refer to substances that are necessary to give the drug a certain form, to make it durable, to flavor it, to color it, or to otherwise improve it with regard to its use. The pharmaceutical association Interpharma lists starch, sugar, gelatine, fats, oils, water and alcohols as examples of excipients [20].

Depending on the context of application, nanomaterials can fall under active substances as well as excipients if they are only used as a transport system. The German Medicines Act (AMG; 14th amendment AMG) and the Ordinance on the Application of Good Clinical Practice in the Conduct of Clinical Trials of Medicinal Products for Human Use (GCP Ordinance) specify precisely the extent to which safety tests must be carried out for active substances and excipients. This concerns the consultation procedures and clinical trials prior to approval, the approval procedures themselves, and the ongoing monitoring and reporting (pharmacovigilance) after approval, which documents the occurrence of side effects. Included in the review procedures for approval are consultations by ethics committees, which must approve clinical trials.

Currently, a discussion is taking place in expert circles on the extent to which nanomaterials as transport systems are sufficiently tested by approval procedures for excipients. Since 2002, however, the Notice on Marketing Authorization under Section 21 of the German Medicines Act has been in effect, requiring information on the bioavailability and bioequivalence of medicines. The improved bioavailability resulting from the use of nanomaterials in excipients must therefore be stated in new approvals, even if existing formulations are modified.

In the various scientific papers on drug delivery systems, there are usually detailed descriptions of functions and benefits, but only a few references to possible risk potentials. A distinction is made between degradable and non-degradable delivery systems. The majority of experts assume that degradable nanotransport systems such as the fat, protein or sugar compounds described above are processed by the body in the same way as larger compounds and do not pose a nano-specific risk [7]. At the heart of the concerns expressed are the possible overdose and entrainment effects of toxic substances from the environment, which could enter the organism with the drug delivery systems virtually by piggyback principle. However, these are all questions that need to be answered empirically and are only indirectly of ethical relevance.

Non-degradable (persistent) nanomaterials have been assessed as far more problematic. Various studies show negative health effects, e.g., for fullerenes [26] and carbon nanotubes, which do not recommend their use for transport systems in medicine [34]. However, again, recent studies on nanotubes indicate that a risk assessment is highly dependent on the form and application chosen and can only be made on a case-by-case basis. For nondegradable, persistent nanomaterials, questions also arise about environmental risks-even if they should be harmless to humans. Here, it is necessary to examine how they behave after excretion in the environment, i.e., what effects they might have on water, soil, and air. However, research in this area is still in its infancy.

Various ethical and social issues arise for nanotransport systems in medicine. In general, applications in medicine are considered a special case in the social risk assessment of nanomaterials. The core question of how much risk a society is willing to take when using new technologies in view of still existing knowledge gaps is considered in a very individualized way in the field of medicine [17]. Here, the health of the individual and the potential benefits from the use of nanomaterials are weighed against the individual risks of side effects. Depending on the severity of the disease and previous failures in therapy, the risk tolerance is very high if therapy with nanomaterials is seen as a promising method or “last resort”. This certainly applies in particular to cancer therapies, but in a broader sense also to the other applications where nanomaterials increase the efficacy of drugs and reduce side effects.

Ethicists are paying particular attention to the crossing of the blood-brain barrier and the resulting potential fields of application [21, 15]. The possibility of positively influencing brain performance in the case of Alzheimer’s disease could be used to increase performance in healthy people. An important topic of the ethical debate is therefore the possibility of misuse of this application for non-therapeutically indicated improvement of humans (human enhancement) by drugs. In its Code of Conduct, the EU excludes research on procedures or materials to improve healthy humans and makes reflection on ethical and social aspects of research projects mandatory for all EU projects [12].

The problem of misuse is also addressed in connection with military applications. Here, the main issue is the medication of soldiers to increase concentration or for continuous use without the need for sleep, as well as, in a broader sense, the use of nano delivery systems in the development of biological warfare agents [15]. What is problematic about the debate on military use or misuse of nanomaterials is that it remains predominantly in the realm of speculation due to the secrecy surrounding the actual projects.

In addition to the individual risk assessment and the possibilities of misuse, the critical question for nano-transport systems is the possible entry into the environment. Environmental organizations and ethicists alike address the open questions of risk assessment for the environment [29]. This concerns research, production and disposal of the products as well as possible entry into the environment through human or animal excretions. As there are currently no long-term studies on the use of nanomaterials in medicine, it is difficult to assess possible hazards. Until reliable findings are available, the principle of avoiding contact between humans and the environment with nanomaterials throughout the entire product life cycle applies in both the pharmaceutical and chemical industries. Particular attention is being paid to the use of non-degradable carbon-based nanomaterials (fullerenes and carbon nanotubes). Ethicists therefore appeal for a responsible approach to nanomaterials and focus on a critical debate about necessary approval criteria [15].

*

In the training unit 6.2 on the “legal aspects” of Covid 19 molecular genetic strategies, we will then see how some of the ethical issues are addressed by the legislation of different states as well as by the EU.

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¹ The fact that nanotechnology still takes place largely in the shadows can certainly be viewed critically: for although nanomaterials are not infrequently a component of marketable products, the manufacturer has so far almost nowhere been required to provide information (in contrast, for example, to the duty to notify in the case of additives in foodstuffs). A labeling obligation – such as applies within the EU for products with genetically modified ingredients – would therefore be desirable for cosmetics and textiles containing nanoparticles, for example [9].

² The application potential of RNA vaccines is enormous: in the future, for example, it could be possible to use them to effectively combat such recalcitrant diseases as tuberculosis, AIDS and malaria; as well as to significantly improve the annual flu vaccination [10].

³ Some of the hopes here go very far: molecular machines introduced into the body will one day be able to make autonomous diagnoses and then take action, for example, to remove detected deposits in the arteries or to reconstruct damaged tissue in a targeted manner. However, it is precisely such ideas of serviceable “nanorobots” that frighten many people. What would happen if these robots got out of control? Could they then be deactivated again or “recalled” from their own bodies? There is obviously a considerable trust deficit here.

⁴ It should not go unmentioned that the relatively easy-to-produce mRNA active substances could also contribute to opening up healing opportunities for rare (and often hereditary) diseases, the so-called “orphan diseases”. These diseases in particular often receive little attention from the pharmaceutical industry, as it is hardly profitable to combat them.

⁵ For example, a blood test for expectant mothers has recently been developed which, with the help of “free” RNA, makes it possible to determine the risk of a dangerous pregnancy complication (the “pre-eclampsia”) at an early stage.

⁶ But a recommendation to vaccinate children (around the age of 6 to 11 years) can of course already be made: and this applies especially to children who have contact with vulnerable older adults. After all, what child wants to put his or her grandparents at risk? However, the decision to vaccinate always ultimately rests with the parents with parental authority.

⁷ For example, with the Moderna vaccine, occasional attacks of fatigue, fever, and muscle pain occur.

⁸ Here it is not decisive that the vaccination against Corona is not able to protect absolutely (i.e. to ensure long-term immunity): it is sufficient to prove that the vaccination can significantly attenuate the symptoms of the disease in case of infection.

⁹ It is extremely helpful here that RNA vaccines can be developed and modified very quickly. As Ron Renaud, CEO of the company Translate Bio, said: “You can change the sequence almost in the blink of an eye and adapt it to the currently circulating pathogen strains” (quoted from Dolgin, 2021 [10])

¹⁰ It is curious, however, that Wuhan, of all places, is home to a laboratory that has the world’s largest collection of coronaviruses [5].

¹¹ The references of coronavirus research to “synthetic biology” and to so-called “gain-of-function” (GoF) research, in which an organism is endowed with new capabilities, will not be discussed in detail here. It is worth noting, however, that in 2015 a team of researchers led by biologist Ralph Baric produced an artificial coronavirus by combining spike proteins from a bat pathogen with a Sars-CoV derivative: Such constructive research projects are not harmless unless there is absolute assurance that the modified organisms cannot escape into the environment and perhaps cause a pandemic there. On the other hand, GoF experiments can also help prevent widespread epidemics by showing which modifications of a potential pathogen could become dangerous. According to German GoF expert Silke Stertz, “In the current pandemic, we are also benefiting from the fact that researchers have been studying Sars-CoV and other coronaviruses for decades and exploring ways to vaccinate against them” (quoted from Spektrum der Wissenschaft, 2022[27]).

¹² The importance of these lipid nanoparticles should not be underestimated. As the Norwegian expert Nick Jackson put it: “Lipid nanoparticles have finally allowed RNA molecules to be used against a broad spectrum of diseases” (quoted from Dolgin, 2021 [10])

¹³ In the future, for example, mRNA-based cancer therapies should specifically block signals and signaling pathways by making so-called “small molecules” on the surface of tumor cells effective as receptor blockers. It would be advantageous here that the sequence of the mRNA could easily be individually adapted [28].

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Test LO 6.1

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