What are biomodifying technologies?

‘Biomodifying technologies’ is a term we developed to describe tools and techniques that enable scientists to modify living biological tissue in novel and increasingly customised ways. Our work focuses on three contemporary innovative biomodifying technologies:

1. iPSC technology, which enables ordinary cells of the adult body to be ‘reprogrammed’ so that, like the cells of an early embryo, they can become any type of cell in the body, eye, liver, heart and so on.
2. Gene editing describes the alteration of DNA using molecular tools. This can be applied to human beings in vivo for therapeutic purposes.
3. Bioprinting takes the concept of 3D printing and applies it to living organic biomaterials. Instead of creating objects from multiple layers of plastic or metal, bioprinting requires a specialized printer, a ‘bioink’ with living cells embedded in a supporting fluid; this can include human cells for transplantation.

Much of twentieth century biology, and the biotechnology industry, is based on older biomodifying technologies such as cell culture, recombinant DNA, in vitro fertilization (IVF), cloning (somatic cell nuclear transfer) and the polymerase chain reaction (PCR). While these technologies all derive from different times, places, and avenues of research, they are united in that they all, in different ways, make ‘life’ amenable to being broken down and reformed in new ways through human intervention

What is the significance of biomodifying technologies?

Biomodifying technologies are foundational or ‘gateway’ technologies. They act on such fundamental aspects of biology that they underpin a vast swathe of potential applications in and outside the laboratory. Each of our case study technologies is available as a research tool in more-or-less standardised packages that are comparatively easy to apply, making for a globally distributed ‘experimental space’ in which new potential applications are being explored and developed. They have far reaching implications across a range of sectors. However, the primary focus of our work has been on their translation of iPSC, gene editing and bioprinting for human, medical applications.

 The three technologies stand alone, but can also interact with each other – for example gene-edited iPSC lines are already being developed as research tools and 3D printing is being designed to create bio-structures from differentiated iPSC.  This raises important questions about attempts to translate these technologies into clinical and industrial applications. In particular, the complex interlinking and customisation of these three technologies strongly suggests that the development of new products and services will not follow a simple linear route ‘from bench to bedside’.

Our research

The HeLEX team at Oxford was the lead organisation on two, connected projects examining different aspects of biomodification technologies.

• “Biomodifying technologies and experimental space:  organisational and regulatory implications for the translation and valuation of health research” (2017 to 2020) was funded by the Economic and Social Research Council (ESRC) and led by Dr Michael Morrison
• “BioGOV: Governing Biomodification in the Life Sciences” (2018- 2022) was funded by the Leverhulme Trust and led by Professor Jane Kaye

Both projects were collaborations between the Universities of Oxford, Sussex and York.

Funding was provided by the ESRC through grant number ES/P002943/1 and by the Leverhulme Through grant number RPG-2017-330

Our Research Aims

The two projects complemented each other, each dealing with a specific set of questions relevant to the three case study technologies. The Biomodifying technologies project had a greater emphasis on the social shaping of clinical innovation and the societal implications of the three technologies while BioGOV dealt primarily with the governance and regulation of the three technologies throughout the process of R&D to develop new medicinal products and services.

The core aims of the ESRC Biomodifying technologies project were:

1. To understand and anticipate emerging developments in these three fields and to build an informed and constructively critical social science of biomodifying technologies.
2. To provide insight to stakeholders on likely translational pathways and organisational healthcare models for the selected technologies.
3. To assess the societal and health implications of biomodifying technologies and the processes of valuation at work across different stakeholder groups.

These aims were translated into the following research questions:

1. How could the experimental space which these technologies occupied be characterised? What impact will this have on translational health research and its likely trajectories?
2. What was defined as the benefit or value of these technologies? Which groups benefited or were seen to benefit, and how was benefit and value assessed? How did consensus about their value build? What was the role of patient-centred values here?
3. How could the research contribute towards social science theorisation in this domain that was critical yet constructive?

The core objectives of the ‘Governing Biomodification in the Life Sciences’ project were:

1. 1. To map out the existing landscape of laws, regulations and regulatory bodies, professional standards and guidelines that apply to each of the three case study technologies.  The scope of the study covered statutory law relating to regulation of medicines (for example by the Medicines and Healthcare products Regulatory Agency -MHRA), reimbursement (including cost-benefit analyses by the National Institute for Health and Care Excellence), intellectual property rights, insurance and manufacturing liability for medical products, and professional guidelines and codes of conduct (as issues for example by the General Medical Council).
   2. To understand how this governance framework was influencing which medical applications are taken forward and how they develop as products or services. This meant identifying where existing regulations support and encourage the development of new products and services and also where they may inhibit particular avenues from being pursued. This may be by direct legal prohibition, as for example with ‘germline’ applications of gene editing, or because different regulations impose conflicting or difficult to understand requirements.
   3. To identify ‘pinch points’ where different regulatory frameworks overlap causing complexity and conflicting requirements- especially where combined products incorporating one or more of our case study biomodifying technologies were concerned, and gaps where it may not have been clear which, if any regulations apply (again novel converged products have the potential to fall outside the scope of all existing regulations).
   4. To provide an evidence base to inform the development of appropriate, flexible and responsive governance models for converging technologies in the biotechnology sector. This involved looking at recent developments in the theories of regulation that allow for more responsive management of change by bringing together multiple local stakeholder groups to negotiate and agree consensus frameworks for action. In particular, the idea of ‘adaptive governance’ that has been employed in relation to environmental management.

Key findings

Biomodifying Technologies

1) Uptake and utility: The uptake and use each of these technologies was significantly shaped by existing structures. For all three technologies, their most immediate application is as a research tool. Gene editing and iPSCs have been attractive to researchers because they enable them to increase the capacity of a research group- whether in the academic or commercial sector- to carry out experiments. This may be by doing things faster- for example, many respondents reported that gene editing with CRISPR is much quicker to do than with recombinant DNA or older gene editing tools, something that is also reported in the scientific literature. It may also be through making something technically or logistically more simple, such as creating patient specific stem cells from a simple skin or hair biopsy. These altered capacities can translate directly into rewards –a greater experimental capacity can lead to more papers for academic researchers or faster knowledge production, while for commercial firms, being able to produce new knowledge can be captured by intellectual property, or  simply by being able to position themselves as part of new and emerging markets.

3D bioprinting involves components that are more heterogeneous: the printer itself, a bio-ink (a gel-like holding medium in which living cells are suspended), Computer Assisted Design software to design the three-dimensional construct to be printed, and potentially, specialised biomaterials unto which the bio-ink can be printed. As such, 3D bioprinting needs more multi-disciplinary collaboration, even at the level of basic research, to enable it. It is a much younger sector than genetic modification or stem cell science, and to a larger extent new research groups have had to coalesce around the technology, bringing together people with expertise in cell biology, engineering and materials chemistry. Instead of regarding 3D printing as a faster or easier advance on an existing technology, its advantage lies more in adding a previously unavailable capacity- the controlled creation of three-dimensional structures with living cells (in this it is different from, for example existing 3D bioreactors, or bioscaffolds). There is also an ‘open source’ software movement designing freely available software for designing 3D bioprinted constructs, although to date it is mainly in competition with generic CAD software rather than purpose build 3D bioprinting design programmes, which remain rare. This variability, with many competing forms of bioprinting such as laser guided, inkjet, electrospraying and electrospinning, as well as bespoke machines and tools is characteristic of a young, emerging sector where the technology has yet to stabilise into a dominant form or specific form associated with particular applications.

2) Translation: In terms of what makes a good therapeutic target, there is no single determining factor. Rather the range of ‘good targets’ are formed through different sets of justifications and considerations, which sometimes overlap but are also sometimes in competition. Overall, the current criteria for assessing good targets can be summarised as:

• Manageable size of cell population needed to treat
• Speed of production and mode of delivery
• Well-characterised disease
• Vector-selection strategy or characterisation of viable delivery mechanism
• Well-defined subpopulation with unmet need
• Product has capacity to produce clear benefit as defined by QALY or other relevant HTA measure
• Stable product that meets regulatory requirements

Current ‘good targets’  tend to be relatively narrowly defined indications, favouring orphan or rare diseases, or tightly defined subsets of common diseases. These small initial indications can serve as ‘niches’ where current manufacturing solutions demonstrate sufficient utility to be worthwhile. As ‘next generation’ manufacturing solutions come online, increased production speed and scale will support development of biomodifying therapies for larger patient populations. However, it will be important to avoid organisational arrangements, procedures or regulations that unintentionally create ‘lock-in’ to existing techniques.  It is important to consider whether there needs to be a single ‘winning’ therapeutic modality for any one disease (e.g. advanced macular degeneration) or biomodifying technology (e.g. iPS ‘cell therapy’ with a transient effect and limited persistence in the body vs iPS regenerative medicine with long term effects and extensive durability in the body) or whether multiple routes to success can be supported by policy resources.

3) Commercialisation:  It is important to recognise that the acceleration of work- and publishing outputs-  that results from the utility of gene editing, 3D bioprinting and iPSC in the research setting does not translate into a similar speed of translation into practical products. In part this is because the process of application is not an evaluation of the general utility of the technology itself but of the technology as a solution to a particular problem e.g. gene editing for cystic fibrosis or iPSC for macular degeneration. It is not only that the feasibility of applying ‘that technology for that problem’ must be worked out in practice through experimentation, but even when proof of concept is demonstrated in the laboratory, it much then be scaled-up and the manufacturing optimised for human clinical use- for example in Good Manufacturing Practice accredited facilities. This additional level of requirement is something that we do not witness to the same extent in non-medical areas such as agricultural uses of gene editing.  Moreover, scaling up a laboratory-based procedure to an industrial one is not a simple engineering task- it is itself a further round of experimental and uncertain work, that requires time, investment, and above all, trial and error learning. The rate of translation of biomodifying technologies is partly determined by the pace of innovation in supporting technologies such as biomaterials and automation, and in quality management systems (QMS), supply chain management et cetera.

4) Patient and public value: To be added

Governing Biomodification

Induced pluripotent stem cells fit most readily into existing regulatory categories designed for cell-based therapies, and they are often seen as a replacement for treatments previously being developed with human embryonic stem cells. Gene editing is also commonly regarded as falling within the EU Advanced Therapy Medicinal Products regulations, but there are questions about how well tools such as CRISPR-Cas9 are actually captured by existing legislation designed to regulate recombinant DNA technology (Mourby and Morrison 2020). 3D printing of cells and tissues is the most ‘disruptive’ of the three technologies in regulatory terms. The potential for localised customisation of bioprinted implants for individual patients raises questions of manufacturing liability that are rarely seen with existing cell therapies or transplants and it has been more appropriate to look to recent regulatory debates around ‘point of care’ manufacturing at hospital sites.

A number of ‘pinch points’ where gaps, lack of clarity or excessive complexity in existing regulation might inhibit innovation or direct it along socially undesirable paths were identified during the project:

1. 1. Some in vivo gene editing products may not fall within the current definition of a Gene Therapy Medicinal Product (GTMP) under the ATMP regulations. A GTMP is defined as containing, or consisting of, ‘recombinant nucleic acid’, but it is far from clear that nucleic acids within the CRISPR gene editing tool will always be produced by genetic recombination, and protein-based gene editing tools such as zinc finger nucleases or TALENS could be out of scope altogether if they do not include any nucleic acid. If therapeutic gene-editing compounds fall outside the definition of a GTMP, they would have to be reviewed outside of the specialised scrutiny of the ATMP regulation, which was intended to ensure a high level of scientific evaluation of these medicinal products. The narrow definition of GTMPs currently embodied in the ATMP regulation may therefore not be fit for purpose when it comes to gene editing.
   2. The complexity and many components involved in bioprinting mean that the production and application of a bioprinted construct could potentially fall under the ATMP regulations (for the cells), the Medical Device Regulation (for the software), the Machinery Directive (for the bioprinter itself), and the Computer Aided Design (CAD) file might also contain sensitive personal data as defined by the GDPR if it matches features of the patient’s biology and/or anatomy. This complexity also affects issues of product liability, where there remains a need for clarity about what constitutes ‘product’ in bioprinting (whether it is the 3D bioprinted material; the bioink, the CAD file etc) and who the producer is (the patient from who cells are harvested; the laboratory technician generating the 3D bioprinting; the hospital/treatment facility itself). Moreover, bioprinting projects use a mixture of proprietary or open-source software, but in both cases the majority of software licences or terms and conditions explicitly disavow clinical use and any liability that might result from use to create a clinical product, leaving academic and SMEs with the liability for errors, bugs or inherent flaws in the software code itself if used to 3D print a cellular construct.
   3. The potential existence of viable bioprinted organs also raises intellectual property rights questions. Natural occurring human organs are not eligible for patent protection as they are ‘products of nature’. Reviewing existing case law pertinent to bioprinting, Lim and Li (2022) conclude that “3D bioprinted human organs may be excluded [from patent eligibility] if it is a claim for a method of treatment by surgery, diagnosis or therapy in the United Kingdom and New Zealand, where legislation provides for an explicit medical treatment exception. However, if a method claim is construed under the non-surgical aspect of making and printing of a 3D bioprinted human organ, (in contrast with the surgical implantation of a 3D bioprinted organ) it could be patentable and not fall under the medical treatment exclusion”. Whether or not a bioprinted organ that was identical to a naturally occurring organ would be patentable will be for the patent office, and potentially the courts to decide in each jurisdiction but there are a number of precedents that would suggest that a product claim or composition of matter claim on the organ itself would not be valid.

However, in addition to these regulatory ‘pinch points’ our analysis also identified a number of other, often broader and less clearly defined challenges posed by the clinical application of biomodifying technologies:

1. The issue of how to regulate (and indeed the very moral permissibility) of heritable or reproductive gene editing. This was not originally a core part of the project but was brought into sharp and inescapable relief by the actions of He Jiankui, at whose clinic, the world’s first genetically edited babies were born in 2018. A further challenge is the difficulty of securing any meaningful ‘societal consensus’ on reproductive gene editing, especially at a global level.
2. Several applications of iPSC, gene editing and bioprinting challenge our understanding and definition of ‘foundational’ concepts that underpin regulatory frameworks, and also often have a more general societal meaning as well, such as ‘natural’, ‘donor’ or ‘product’. Societal framings of ‘nature’, ‘products’ and ‘donors’ may be tentative and heterogeneous, and will find expression outside academic, policy or regulatory discourse - for example in popular culture and on social media. Tracing these developments with sufficient accuracy to provide a reliable barometer for the law is thus a complex proposition and may require new forms of governance.
3. Mechanisms such as the patent system favour “logic of experimentality whereby social and political issues are overshadowed by a market rationale”. As a result, control over the innovation trajectories and accessibility of biomodifying therapies tends to lie with a limited number of powerful well-resourced actors in the private sector and tends to operate through transactions that are neither transparent nor accountable except to shareholders.

These findings point to a different kind of challenge to the regulatory ‘pinch points’ as defined above. Specifically, they make it clear that regulation, at least as conventionally understood, is only one factor among many shaping the innovation trajectories of biomodifying technologies.