Can we draw a clear line for regulating CRISPR Cas 9 technology or not?

Introduction

I find the wide-spread application of CRISPR / Cas 9 (i.e., “Clustered Regularly Interspaced Short Palindromic Repeats”, using the CRISPR associated Cas protein 9) intriguing because it evidences innovation[1] in genome engineering technologies[2]. Its technical accessibility as compared with other genome-editing technologies makes it easier for any scientist with molecular biology skills and knowledge of how to work with embryos to be able to do this. [3] In simplified terms, extracting cells from the patient’s blood, disabling genes that holds the immune system in check and can shield the cancer cells, for instance, in the process and reinjecting the modified cells are the steps.[4] If I were to provide a visual representation of this technology, then CRISPR would be a nano-sized sewing kit that is designed to cut and alter DNA at a specific point in a specific gene. Artificial intelligence tools fit in this picture when machine learning is used to predict the off-target effects when editing genes with this system. Tools such as Elevation and Azimuth, available for free to public, are available as cloud based end-to-end guide design service, running on Microsoft Azure as well as via open-source code. The usage of computational tools has enabled researchers to input the name of the gene they want to modify and the cloud-based search engine will return a list of guides that researchers can sort by predicted on-target or off-target effects.[5]

The concept of altering the human germline in embryos for clinical purposes has been debated over many years. This is because germline cells are those that have the potential to be inherited by the next generation. For eg., eggs and sperm. Further, the changes that are introduced to germline cells enter the gene pool of that species. An example of altering human germline is editing of a fertilized egg cell. On the other hand, non-germline cells are referred to as somatic cells. For instance, editing the genome of a child or an adult would be a somatic application. From a simplistic view, any changes that are introduced to somatic cells would not be propagated to future generations. Somatic genome editing is the most familiar in the context of gene therapy, because it rests on the idea of making modifications to correct for those born with a disease-causing genetic variant. It is to be noted that, whereas germline modification is banned in many countries, somatic modification is not.[6] The specific application that I would be focusing on is genetic variation from an outcome perspective. This technology is interesting because of its recent use of turning cells into programmable computers, where researchers have engineered molecular switches to control cell fate to enable them to program conditional behaviors.[7]

In this paper, I want to focus on the normative claims that could form the basis of regulating this technology more uniformly and consistently[8] in the future. I argue that, this claim is different from regulating public health as such, and must not be overtly regulated or overmedicalized. This is because there are deep tensions between the suggested scientific and objective metric of measuring public health as such and the promise of medicine that is truly personalized. Further, I argue that this differentiation plays a critical role in closing the gap that currently exists in the legislative text on gene editing and the market practice in the field of research and development of genome interpretation as a stream.

Analysis

a.      There is a difference between the underlying philosophy between public health and personalized medicine

The traditional approach to healthcare treatments relies on the “on-size-fits-all” approach, wherein one treatment is used for millions of patients. [9] In this paper, I argue that, fundamentally, this traditional approach is different from personalized medicine, which is the basis of this technology. This is because genetic services of any kind are strictly a matter of personal choice, since this flows from reproductive freedom. If there is any government program that would result in pressures that limits this reproductive freedom, it would be unacceptable. On the contrary, the advocates of public health concern might counter-argue that, a mass genetic screening of citizens for detecting high risk for virtually all serious genetic disorders and a broad range of genetic susceptibilities for illness might be justified as a public health matter. The reasoning behind this would be that, people should not be free to inflict avoidable diseases on their children, especially if there is an assumption that, they would never have an affordable health care system that provides coverage for everyone. To substantiate further, insurance plans disregard genetic intervention as an essential medical care that can be covered under the insurance plan. Instead, they cover hospital care and other medical care, operations and treatments performed by doctors and physicians, such as surgeons, pediatricians, cardiologists and oncologists; and emergency medical care abroad.[10]

This brings me to address the normative claim behind regulating health care in the age of genetic intervention, i.e., helping people live better lives. [11] As per Henrik, Bjorn and Linn, personalized medicine movement is often promoted as “P4 medicine” (predictive, preventive, personalized and participatory). The emergence of systems medicine, which is based on computational modelling of biological systems, in personalized medicine movement tests the theory that, systems medicine would be able to develop a scientific, quantitative metric for wellness that will eliminate its vagueness, ambiguity and incompleteness, i.e., normativity. Henrik, Bjorn and Linn examine the patent that describes a systems medicine method for assessing health and disease, as the most concrete and relevant evidence for such a metric. Henrik, Bjorn and Linn find that, the definition of health in personalized medicine is still normatively based, although the systems medicine is promoted as heralding an era of transformative scientific objectivity. In the light of their findings, Henrik, Bjorn and Linn argue that, the definition of health will be open to influence from various stakeholders and its purported objectivity may conceal important scientific, philosophical and political issues. They also argue that, this is an example of a general trend within biomedicine to create overly hopeful visions and expectations for the future. The fundamental debate between the philosophy of medicine between two main positions, namely, naturalism and normativism, are relevant to the claim about a scientific metric, that would effectively function as a scientific benchmark for health. As per Henrik, Bjorn and Linn, the normative elements of P4 medicine are concealed under the apparently value-neutral professional judgments of agents “skilled in the art” of selecting a healthy reference population. If the method described in the patent is representative of a future metric of health, then this metric would be vulnerable to the influence of various stakeholders. It is a fallacy to assume that providing a quantitative correlate to a construct that is already normatively defined automatically makes it objectively, purely scientific or non-normative. This purported scientific objectivity might obscure influence from stakeholders and important scientific, ethical and political challenges to defining health and disease such as concerns of overmedicalization. The promise of a metric for wellness may be seen as an example of a cultural trend in biomedicine for creating overly hopeful expectations for the future. There are deep tensions between the suggested scientific and objective metric of health and the promise of medicine that is truly personalized. “The mirage of health” [12]is exemplified if one assesses health in each person and seeks to operationalize such concept, invent a method that assess this concept and then patent this method. From a self-actualization perspective, defining or quantifying personal well being is tricky.  I argue that, it is impossible to merge personal well-being into public health, because of the subjectivity attached to the following two criteria:

(a)   Healthy life expectancy of men and women, i.e., average number of years that a person is expected to live in good self-perceived health, assuming that future health and mortality risks remain unchanged; and

(b)   Happiness and life satisfaction of different age groups, in both personal as well as in their professional front.[13]

b.     There is a gap between the legislative text on gene editing and market practice on research and development on gene editing information

Fundamentally, gene editing could be interpreted either as an advanced therapy product, or as biological medicinal product, or as a medicinal product for human use or just as a medicinal product depending on its specific intended use. Law prescribes analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products [14] which obligates clinicians to give information about the therapeutic and toxicological potential of the product.[15]

A biological medicinal product is a product, of which the starting material is a substance of biological origin. Since starting material means all the materials from which the active substances are either manufactured or extracted, thus, the active substance of a biological medicinal product is also a biological substance. Fundamentally, the characteristics and the determination of this active substance, that is used for therapeutic purpose, is dependent on a combination of physico-chemical-biological testing and its production process, without compromising on quality. [16] Gene therapy medicinal product is defined[17] as a biological medicinal product, which has the following characteristics:

(a)   It contains an active substance which contains or consists of a recombinant nucleic acid that is used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a gene sequence;

(b)   Its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.

It is to be noted that, gene therapy medicinal products shall not include vaccines against infectious diseases. However, from an objective perspective, finding a cure for infectious diseases is being tapped into by the entities involved in the study of genetics research. This possibility of devising a finished medicinal product that can be combined with a medical device or active implantable medical device[18], by such entities makes the regime of applicable law on such practices complex, but not unsolvable. Somatic cell therapy medicinal product is defined[19] as a biological medicinal product which has the following characteristics:

(a)   Contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, psychological functions or structural properties relevant for the intended clinical use have been altered, or of cells or tissues that are not intended to be used for the same essential functions(s) in the recipient and the donor;

(b)   Is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues.

However, cell separation, concentration or purification, freezing and cryopreservation, amongst others, would not constitute to be manipulation of cells or tissues[20]. In case of germline cells, the current legal framework identifies germline transmission as a risk, during consideration of a gene therapy medicinal product. Post such identification, the law mandates further studies to be conducted on the potential immunogenic and immunotoxic effects of such medicinal product.[21] Thus, I argue that, this shifts the regulatory challenge from quantifying personalized medicine to countering misinformation or exaggeration that is associated with the clinical trials that are conducted for genome editing, who might under the garb of providing therapy and novel treatment, have merely an intent to profit from the desperate patients and their families. The future regulatory challenge would be a legal climate that does not provide guidance on when and how to allow the compassionate use or expanded access to experimental treatments, that can be availed of by desperate patients. [22] These regulatory challenges crop up during the development process of the gene therapy. To substantiate, I argue that this stage is critical because it influences benefit-risk profile of this novel therapeutic approach, which are not always feasible to overcome.[23] However, the ability to use this knowledge of, how genes function plays an important role in intervening at the appropriate stage and enables concerned healthcare actors to protect the fundamental virtues of the healthcare system, namely, just health care and equality of opportunity in a comprehensive sense of justice[24] for further development of this technology.

Even though the regulatory challenges shift, and concepts of harmfulness and therapeutic efficacy would vary depending on the use for which the medicinal product is intended and not intended, however the essence of providing therapy must not change. The particulars and documents which must accompany an application for marketing authorization for such medicinal product must demonstrate that the potential risks are outweighed by the therapeutic efficacy of the product.[25] This risk-based approach is used to assess the extent to which the quality, non-clinical and clinical data, to be included in such marketing authorization application to be filed before the European Medical Agency (“EMA”) and National Competent Authorities (“NCA”), as the case may be, under the centralized procedure, is in accordance with the scientific guidelines relating to the quality, safety and efficacy of medicinal products. This risk analysis may cover the entire development process, and include the consideration of the following risk factors: (a) origin of the cells; (b) ability to proliferate and/or differentiate and to initiate ; (c) level of cell manipulation; (d) combination of cells with bioactive molecules or structural materials; (e) nature of the gene therapy medicinal product; (f) extent of replication competence of viruses or microorganisms used in vivo; (g) level of integration of nucleic acids sequences or genes into the genome; (h) long time functionality; (i) risk of oncogenicity and the (j) mode of administration or use. Further, this risk analysis may also entail considering relevant available non-clinical and clinical data or experience with other, related advanced therapy medicinal products. If there is any deviation from this approach, then there is legal requirement to provide scientific justification. If this risk based approach is applied, then the marketing application would also explain the following aspects, namely (a) nature of identified risks; (b) implications of the risk based approach for the development and evaluation program; (c) nature of the deviations from the formal legal requirements, when such risk analysis is done[26]. I argue that, the main rationale behind this risk-based approach is linked to the specific nature of advanced therapy medicinal products. The essential aim of rules governing their production, distribution and use must be to safeguard public health. However, Regulation on advanced therapy medicinal products[27], which is a lex specialis, to the Directive relating to medicinal products for human use[28], provides explicitly that, advanced therapy medicinal products which are prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient, should be excluded from the scope of this Regulation, whilst at the same time, ensuring that relevant Community rules related to quality and safety are not undermined”.[29] I argue that, the interpretation of this provision and the usage of this provision, might be used to evade compliance of harmfulness and therapeutic efficacy as such, and thus is one of the identified regulatory gaps.

The sequencing of human genome, understanding of diseases at molecular level advances and the taxonomy of diseases is being re-defined. This has led to understanding that, the diseases which were historically seen as one disease, are in fact a collection of diseases that are influenced by different pathological mechanisms requiring different treatment strategies. [30] In practice, several modifications can be performed simultaneously in one genome, which opens up the possibility of either treating complex diseases or altering traits in humans that are influenced by more than one gene thereby demonstrating easy programmability.[31] John and David argue that, the existing legal gap is in the wordings of Article 3 of The Council of Europe’s Convention on Human Rights and Biomedicine (“ECHRB”), i.e., Oviedo Convention. ECHRB was intended to act as a binding reference for patient rights and general human rights in the context of advancements in biotechnology and medical science. However, in signing the ECHRB, the nations do not necessarily” express their consent to be bound by it, and so, if we are to treat this literally, we may not consider that this act in itself constitutes an accord with the ideals espoused within it. I argue that, this legal gap has direct implications on the newly sovereign states that lack specialist bio-ethical and patient rights legislation. This is because the need for constructing and legislating on the aforesaid areas in a recently democratized state is directly linked to its perceived need for international “legitimization”. Article 13 of ECHRB states provides: “An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants”. The Council of Europe does not explain how any such modification could be made without having the aim of introducing such “modification in the genome of any descendants”. However, Article 1 of the Additional Protocol to the Council of Europe specifically bans cloning. It provides that, “(1) Any intervention seeking to create a human being genetically identical to another human being, whether living or dead, is prohibited. (2) For the purpose of this article, the term human being “genetically identical” to another human being means a human being sharing with another the same nuclear gene set.” Further, I argue that those who endorse “the preservation of the human genome as common heritage of humanity”, have also come to see the present evolved state of the human genome, not only as the common heritage of humanity, but as involving the, almost always un-argued, assertion that the human genome must be “frozen”, as far as is possible, in perpetuity at this particular evolutionary stage. The ethical implications of the usage of this technology flows from its capability to make heritable changes to the human genome. Even though all technologies on germline modification technique are objected because of the questionable “serious and unquantifiable” safety issues, however Collins, the Director of National Institutes of Health[32] argues that, one important difference between this technology and the others is absence of consent. However, it is a reality that, would-be parents do think about what combination of their collective gene would be advantageous or otherwise.  Even if they did not think, unlike Collins, their decisions needed to wait for the consent of the future children. At the core, the advocates of needing consent of non-existent beings, or by those who are not capable of giving consent, assume that, the relevant children would not, or should not, have consented, rather than reverse, and thus those potential children should not be born or should not have been born. However, from a legal perspective, the basis of the decision making of scientists and parents must not for obvious reasons, include the consent of the future children. Rather, the decision must be based on the best available combination of evidence and argument and the application of this technology must be done responsibly, keeping the “best interests of the child” in mind. Further, lack of clarity on the extent to which epigenetic inheritance can occur across generation amplifies the challenge that, the obligation to preserve the “human genome as common heritage on humanity” could consider the epigenetic effects in theory, but in practice there is a possibility of such effects being apparent post hoc. Thus, I argue that, the moral reasons for not considering consent as the basis, could be equated with, as opposed to being an overriding reason, to adopting a more rational and much quicker solution than Darwinian evolution.[33] The acknowledgment of the consequential nature of the scientific matters on the horizon, rapid speed in which this technology is advancing and the existing national and international polarized political environments must alternatively be the basis for developing approaches that enable policy debates around the usage of this technology and take decisions that are based on the best available science and responsible innovation for technologies.[34]

Conclusion

Scientists still have a lot to learn about how CRISPR Cas 9 works in humans. The assumption of people about how cells repair the genome after the Cas 9 enzyme snips DNA are wrong. Gene-editing is super-powerful, with a lot of promise, but, so far, a lot of trial and error. The way it works in human cells has been a black box with a lot of assumptions. [35] At the same time, I also see the prospect of it being considered as a luxury good, instead of public good. Even if pioneered for medical reasons, market forces will inevitably push genome editing towards creating “designer babies” allowing the very wealthy to program desired traits into their unborn children. Social inequality gets written into DNA, once a society in which rich people’s children get biological advantages over other children. At the same time, the potential of gene editing to help children whose conditions are unlikely to have a cure, or whose parents are unwilling to reject a pregnancy might be overlooked. Caution and oversight will be paramount when playing with the very means nature gave us for life. [36] The feature of this technology that makes it inexpensive and easy to experiment amplifies the argument that this technology is democratized. At the same time, with next-generation sequencing (“NGS”) technologies, that provide simultaneous testing of multiple genes and allow either the whole genome or parts of it to be sequenced in hours, at great depth and increasing sensitivity, led to a significant and ongoing decline in consumable costs. Thus there is a widespread expectation that a “ $1000 genome” may soon be available. However, this expectation likely only reflects the consumables component and does not consider the overall costs of the sequencing process. The cost does not include sample processing, including library preparation and sequencing, bioinformatic data processing and analysis, interpretation and reporting of sequencing results and data storage. [37] Thus, I argue that, democratization of this technology should be the cornerstone of regulating or not regulating this technology in the future. I argue that, the synergy between genome editing and genome interpretation would play a critical role in enabling our ability to understand what genetic variation underpins which phenotypic variation, since the observable traits of an organism improves with time as a society. This would establish a direct correlation between substantial advances in genome interpretation and the development of this technology. To move a step further, this would also enrich our understanding of correlating genetic variation with information that may or may not be clinically relevant e.g., sequencing facility in Beijing studies the genetic underpinnings of intelligence. From a moral reasoning perspective, I argue that, the temptation to get lured by falling costs of sequencing would always make us question of what genetic modifications may be desirable and which ones would not be desirable. This would always make us question, if such a genetic modification would be treated as therapy or enhancement, which may or may not be desirable. [38] From a legal perspective, at the member state level, its internal law could reflect constitutional absorption of international non-binding conventions.[39] Further, if a member state is of the view that, a medicinal product is harmful, or lacks therapeutic efficacy, or its risk-benefit balance is not favorable; or its qualitative and quantitative composition is not as declared; or the controls on the medicinal product and/or on the ingredients and the controls at an intermediate stage of the manufacturing process have not been carried out or if some other requirement or obligation relating to the grant of the manufacturing authorization has not been fulfilled, then, such member state can take steps to ensure that the supply of such medicinal product is either prohibited or is withdrawn from the market[40].

[1] Steffi Friedrichs and others, 'An overview of regulatory approaches to genome editing in agriculture' [2019] 3(2) Biotechnology Research and Innovation <https://www.sciencedirect.com/science/article/pii/S2452072119300371> accessed 14 April 2020.

[2] Genome engineering refers to the process of making targeted modifications to the genome, its contexts (e.g., epigenetic marks) or its outputs (e.g., transcripts). Patrick D Hsu and others, 'Development and applications of CRISPR - Cas9 for Genome Engineering' [2014] 157(6) Cell <https://www.sciencedirect.com/science/article/pii/S0092867414006047?via%3Dihub> accessed 14 April 2020

[3] Sarah Polcz and Anna Lewis, 'CRISPR-Cas9 and the non-germline non-controversy' [2016] 3(2) Journal of Law and the Biosciences <https://academic.oup.com/jlb/article/3/2/413/1751234> accessed 14 April 2020.

[4] Heidi Ledford, (Quest to use CRISPR against disease gains ground , 6 January ) <https://www.nature.com/articles/d41586-019-03919-0> accessed 15 April 2020.

[5] John Roach, 'The AI Blog' (Researchers use AI to improve accuracy of gene editing with CRISPR, January 10, 2018) <https://blogs.microsoft.com/ai/crispr-gene-editing/> accessed 14 April 2020.

[6] Sarah Polcz and Anna Lewis, 'CRISPR-Cas9 and the non-germline non-controversy' [2016] 3(2) Journal of Law and the Biosciences <https://academic.oup.com/jlb/article/3/2/413/1751234> accessed 14 April 2020.

[7] AdamP Cribbs and SumethMW Perera, 'Science and Bioethics of CRISPR-Cas 9 Gene Editing: An analysis towards separating facts and fiction' [2017] 90(4) Yale Journal of Biology and Medicine <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733851/#> accessed 14 April 2020.

[8] Guido Wert de and others, 'Responsible innovation in human germline gene editing : Background document to the recommendations of ESHG and ESHRE' [2018] 2018(1) Human Reproduction Open <https://academic.oup.com/hropen/article/2018/1/hox024/4797562> accessed 14 April 2020.

[9] European commission, 'Use of "-omics" technologies in the development of personalised medicine' (Commission Staff Working Document , 25 October 2013) <https://ec.europa.eu/research/health/pdf/2013-10_personalised_medicine_en.pdf> accessed 15 April 2020.

[10] Zorgwijzer, <https://www.zorgwijzer.nl/zorgvergelijker/english#/search> accessed 14 April 2020.

[11] Allen Buchanan and others, From Chance to Choice: Genetics and Justice (Cambridge University Press https://books.google.nl/books?hl=en&lr=&id=P9vLCgAAQBAJ&oi=fnd&pg=PP1&ots=ztLvoAW0mJ&sig=mlvKxRHJUelO8pghWoE-Ih3sjRY&redir_esc=y#v=onepage&q&f=false).

[12] Henrik Vogt and others, 'Personalized medicine: Evidence of normativity in its quantitative definition of health' [2016] 37(NA) Theoretical Medicine and Bioethics <https://link.springer.com/article/10.1007/s11017-016-9379-3> accessed 14 April 2020.

[13] Trends in the Netherlands, 2017 – CBS; Eurostat, 'Healthy life years statistics' (Statistics explained, March 2020) <https://ec.europa.eu/eurostat/statistics-explained/index.php/Healthy_life_years_statistics> accessed 14 April 2020.

[14] Annex I, “Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products”, Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, hereinafter referred to as Directive on medicinal products for human use.

[15] Module 4, “Non-clinical reports”, 4.2. (1)(b), “Content: Basic principles and requirements”, Annex I, “Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products”, Directive on medicinal products for human use.

[16] Module 3, “ Chemical, Pharmaceutical and Biological Information for medicinal products containing chemical and / or biological active substances”, 3.2.1.1. (b), “General Information and information related to the starting and raw materials”, Annex I “Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products”, Directive on medicinal products for human use.

[17] Part IV, “Advanced Therapy Medicinal Product”, Point 2.1, Annex I, “Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products”, Directive on medicinal products for human use.

[18] Point 3.2.1.1. and Point 3.2.1.2, Part IV, “Advanced Therapy Medicinal Product”, Point 2.1, Annex I, “Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products”, Directive on medicinal products for human use.

[19] Part IV, “Advanced Therapy Medicinal Product”, Point 2.2, Annex I, “Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products”, Directive on medicinal products for human use.

[20] Annex I, “Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products”, Directive on medicinal products for human use.

[21] Point 2.3. (g), Part IV, “Advanced Therapy Medicinal Product”, Point 2.1, Annex I, “Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products”, Directive on medicinal products for human use.

[22] ArthurL Caplan and others, 'No time to waste - The ethical challenges created by CRISPR' [2015] 16(11) EMBO Reports <https://www.embopress.org/doi/abs/10.15252/embr.201541337> accessed 15 April 2020.

[23] Mohamed Abou - el- enein and others, 'Human Genome Editing in the Clinic: New Challenges in Regulatory Benefit-Risk Assessment' [2017] 21(4) Cell Stem Cell <https://www.sciencedirect.com/science/article/pii/S1934590917303740> accessed 15 April 2020.

[24] Allen Buchanan and others, From Chance to Choice: Genetics and Justice (Cambridge University Press https://books.google.nl/books?hl=en&lr=&id=P9vLCgAAQBAJ&oi=fnd&pg=PP1&ots=ztLvoAW0mJ&sig=mlvKxRHJUelO8pghWoE-Ih3sjRY&redir_esc=y#v=onepage&q&f=false).

[25] Recital 7, Directive on medicinal products for human use.

[26] Part IV, “Advanced Therapy Medicinal Product”, Point I “Introduction”, Annex I, “Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products”, Directive on medicinal products for human use.

[27] Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance), hereinafter referred to as Regulation on advanced therapy medicinal product.

[28] Recital 6, Regulation on advanced therapy medicinal product.

[29] Recital 6, Regulation on advanced therapy medicinal product.

[30] European commission, 'Use of "-omics" technologies in the development of personalised medicine' (Commission Staff Working Document , 25 October 2013) <https://ec.europa.eu/research/health/pdf/2013-10_personalised_medicine_en.pdf> accessed 15 April 2020.

[31] Le Cong and others, 'Multiplex Genome Engineering Using CRISPR/Cas Systems' [2013] 339(6121) Science <https://science.sciencemag.org/content/339/6121/819> accessed 15 April 2020.

[32] Francis S Collins, 'Statement on NIH funding of research using gene-editing technologies in human embryos ' (National Institutes of Health - The NIH Director, April 28, 2015) <https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-nih-funding-research-using-gene-editing-technologies-human-embryos> accessed 15 April 2020.

[33] John Harris, New Technologies, Old Attitudes and Legislative Rigidity. in Brownsword and others (eds), The Oxford Handbook of Law, Regulation and Technology ( 2017).

[34] DietramA Scheufele, Conclusion - On the Horizon : The Changing Science Communication and Environment . in Jamieson and others (eds), The Oxford Handbook of the Science of Science Communication ( 2017).

[35] University of California, 'DNA repair after CRISPR cutting not at all what people thought' (Phys.org, 30 July, 2018) <https://phys.org/news/2018-07-dna-crispr-people-thought.html> accessed 15 April 2020.

[36] Geib Claudia, 'Expert argues that gene editing will widen economic class gap' (Neoscope, 15 April ) <https://futurism.com/neoscope/expert-argues-that-gene-editing-will-widen-economic-class-gap> accessed 15 April 2020.

[37] Katharina Schwarze and others, 'The complete costs of genome sequencing: A microcosting study in cancer and rare diseases from a single center in the United Kingdom ' [2020] 22 Genetics in Medicine <https://www.nature.com/articles/s41436-019-0618-7#citeas> accessed 15 April 2020.

[38] Sarah Polcz and Anna Lewis, 'CRISPR-Cas9 and the non-germline non-controversy' [2016] 3(2) Journal of Law and the Biosciences <https://academic.oup.com/jlb/article/3/2/413/1751234> accessed 14 April 2020.

[39] John Harris, New Technologies, Old Attitudes and Legislative Rigidity. in Brownsword and others (eds), The Oxford Handbook of Law, Regulation and Technology ( 2017).

[40] Article 117 (1), Directive on medicinal products for human use.