The Emergence of Molecular Biology in the Diagnosis of Cervical Cancer: A Network Perspective by Daniele Rotolo, Michael Hopkins, Ismael Rafols and Stuart Hogarth

The development of molecular biology (since the 1980s) has changed both the research landscape and clinical practices around cervical cancer. Its rise has helped to address the ongoing problems with cytology-based diagnostic technologies (including the Pap test), in particular their well-documented low sensitivity (the Pap test may report 15-50% of false negative cases). In the context of these developments it is important to consider the influence that actors have upon the direction of such emerging technologies. The composition of the network can be crucial in supporting the system of innovation, and in distributing power and control of the network proportionally.

A recent paper presented by Rotolo, Hopkins, Rafols and Hogarth examines the inter-organisational networks in the emergence of molecular biology in the diagnosis of cervical cancer. It draws attention to four different phases of its emergence; exploration, development, adoption, and growth. The sources of innovation are not limited to any one actor, and they are often in the ‘interstices between firms, universities, research laboratories, suppliers and customer’ (Powell 1990: 118). While some configurations favour interaction, others concentrate power among the few (Burt 1992). Some organisations can act as a coordinator (mediating between actors in the same institutional group) or as a gatekeeper (screening and gathering knowledge from another group and distributing it among its own group) -

Cervical cancer’s viral origins have been heavily researched as far back as 1842 by Domenico Rigoni-Stern, which highlighted the link between koilocytes and condylomas and the development of cervical cancer. Later research highlighted that a persistent infection (developing through four stages may eventually evolve into cervical cancer (Schiffman, Castle, Jeronimo, Rodriguez & Wacholder 2007). During initial stage (Cervical Intraepithelial Neoplasia-CIN1), the virus is sexually transmitted, in the second stage (CIN2) lesions are cleared within the first 12 months (however less than 10% are successfully cleared), in the third stage (CIN3) abnormal cells duplicate and thus replace the full thickness of the cervical epithelium, and in the final stage the infection transforms into an invasion where the HPV genome is integrated into the host’s genome.

Using 4,722 scientific articles, and drawing upon the work of Blume (1992), Casper & Clarke (1998), and Hogarth et al. (2012), the paper identified four key stages of the emergence of molecular diagnostic technologies in the cervical cancer screening domain; 1) exploration- 1980-89, 2) development- 1990-99, 3) adoption- 2000-5, and 4) growth- 2006-11. These were all examined through the terms of the bridging roles that different institutional groups played, and then were classified into one of five different institutional groups. These included; Research & Higher Education, Governmental, Hospitals & Care, Industry, Non-governmental, and Other.

The paper concludes that the overall number of ties increases for each group (although they do decrease for the GOV, IND and NGO groups in the last few years). The number of organisations taking on a brokerage role (typically those actors contributing to the diagnosis domain of cervical cancer research), increases in the adoption and growth phases, but decreases in the last three years of observation.

In general it appears that the process of tie formation between groups, and it develops throughout the different phases of emergence. Typically RHE organisations are more active in creating intra-group ties, while GOV, IND and NGOs collaborate more frequently with actors in differing groups.  RHE groups are more likely to take on a brokerage role and to act as a gatekeeper. GOV groups are likely to act as broker in the emergence phase, but as gatekeeper in the adoption and growth phases. The HC, IND, and NGO groups are more active in itinerant broker, and liaison roles than intra-group coordination. These findings are incredibly useful in the development of policies designed to stimulate and support innovation. Using such complex inter-organisational networks will be crucial in this development. 

To read the full paper, click here.

The global market of stem cell research and therapies, ‘stem cell tourism’, and models of innovation – Western and non-Western models

The ‘hype and hope’ of stem cell research and treatments has contributed to the expansion of a flourishing ‘illicit’ global market for stem cell therapies. Patients from all over the world are travelling to places like China, Russia, Japan and India to be treated with - mostly experimental - stem cell therapies. This phenomenon has been coined ‘stem cell tourism’.  

Western models

In the West, a combination of a gap between ‘what was promised’ and ‘what is being delivered’, and the slow pace of traditional Western models of scientific innovations has further stimulated a global supply of ‘illicit’ therapies. The conventional science-based model of innovation (Figure 1) is the considered the most ‘sound’ and ‘safe’ approach, but is also the slowest.  

Indeed, “given the high demand for stem cell therapies, the clear market disadvantage of this model is the time and cost of product development. As with general drug development, including preclinical and clinical safety and efficacy testing, therapies can typically take 12–15 years and approximately EU€1 billion to develop – a difficult business model to sustain” (Salter et al., 2014, p. 355). This has pushed some Western countries to allow for fast-tracked clinical trials (Figure 2) in cases where patients have no alternative treatment. In those cases the authority lies with the clinician.

Model II fast-tracks the clinical development and applications of therapies without upsetting or compromising basic research (i.e. ‘lab’ research) and product development. Model II is a model of ‘medical innovation’, as distinct from ‘scientific innovation’, where generalisable results are the end goal.

Largely in response, non-Western countries have modelled their medical innovation differently, in ways that allow therapies (and stem cell treatments) to reach patients and the market, faster than in the West.

Non-Western models

Non-Western models remain very attractive for those patients who are not eligible for stem cell treatments at home (cf. Model II). These other models of medical innovation (Model III and IV) do little clinical experimentation and have the benefit of going straight from product development to clinical trials.

“Model IV combines elements of medical innovation and scientific innovation in a single business model. Here, some of the profits from stem cell medical innovation are re-invested in the funding of the registered clinical trials” dealing with safety and efficacy required for stem cell scientific innovation, but with regard to different diseases to those addressed by the treatment available through the medical innovation activity” (Salter et al., 2014, p. 357)

There is an irony though: whilst “the vast majority of the stem cell therapy market activity is in the domain of medical innovation (Models II, III and IV), the vast majority of the official policy discourse and public commentary focuses on the domain of scientific innovation (Model I)” (Salter et al., 2014, p. 358). The UK Stem Cell Bank, the International Stem Cell Forum and the International Society for Stem Cell Research (ISSCR), and national funding research agencies, amongst others, have been providing guidance on ‘good practices’ for stem cell basic and applied research, but very little on clinical applications.

This entails that the strong demand and the ever-growing supply in the global market of stem cell therapies is constantly being ignored by policymakers and regulators who continue to support and promulgate the traditional model (cf. Model I) of scientific innovation. There is certainly a case for claiming that the conventional science-based model of innovation is increasingly ill-suited and unsustainable in increasingly global, competitive biomarkets, as is the case for stem cell therapies. 

To read about the models of innovation, click here.

Bioethical ambition, political opportunity and the European governance of patenting: The case of human embryonic stem cell science

Patenting is first and foremost a crucial component of our economic system, today. Yet, patents are also, essentially, an ‘in writing’ definition of ownership. Sheila Jasanoff (2005) notes that, in biotechnology, patents “have the effect of removing the thing being patented from the category of nature to the category of artifice - a profound metaphysical shift” (p. 204).

 “Where the patenting object involves the human embryo either directly or indirectly, this metaphysical shift can generate considerable political emotion through its engagement with a fundamental cultural symbol of human life” (Salter & Salter, p. 287). Hence, when it comes to the human body, patenting may confront significant theological and ethical opposition. In the case of Human Embryonic Stem Cell (hESC) science, the idea of ownership and commodification of the embryo has disquieted certain cultural and religious values.

Unsurprisingly then, in cases like these, the European Patent Organisation (EPO) is finding it increasingly difficult to focus solely on the technical issues of patenting. For instance, the EPO granted the University of Edinburgh a patent entitled “Isolation, selection and propagation of animal transgenic stem cells”, but this was opposed by Italy, Germany, the Netherlands, the European Parliament and Greenpeace on the grounds that it went against “ordre public [public order] and morality”, an important ethical principle of patenting law.

Such situations of cross-national valued-laden conflicts over patenting present a political opportunity for bioethics to intervene as a ‘public spokesman’ and mediator of competing interests. Already, the European Parliament has recognised that “bioethics and biological patenting are inextricably intertwined” (p. 289). Such conflicts between values of individual ownership and communal cultural values will most likely continue to emerge in patenting. There are solid grounds for believing that bioethics committees will not hesitate in seizing such political opportunities and will increasingly become an organic part of biotechnological governance.  

To read the full paper click here

Bioinformatics in the UK, China and India

Bioinformatics has recently been recognised in the UK as a ‘huge priority for government’ with the ‘potential to drive research and development, increase productivity and innovation and ultimately transform lives.’ (UK Medical Research Council, 2014). While there is wide agreement among nations regarding the importance of bioinformatics, there is little consensus over possible pathways for maximising its contribution to the life sciences. A recent paper by Salter, Zhou and Datta (2015) explores the extent to which bioinformatics have become a strategic priority for India, China and the UK, and how these efforts are shaping or are in turn being shaped by the existing norms, rules and institutions in the global lifesciences.

Bioinformatics is the combination of knowledge, skills and techniques of biology made 'readable' with computer science, statistics and mathematics. The traditional view of the role of mathematics and computer science in bioinformatics was that of a 'means' to the end of capturing and understanding increasingly data-intensive biological knowledge production e.g. as with genomic data. However, in the last few years a more balanced view has emerged that considers computer science and mathematical tools as both the object and instrument of knowledge production. Leonelli’s (2012: 2) comment that ‘data-intensive methods are changing what counts as good science’- is perhaps nowhere more relevant today than in bioinformatics where the tug-of-war for primacy between two disparate branches of science (mathematics and biology) has become increasingly polarized.

For nations, in particular emerging economies, these spaces of rapidly advancing technology, uncertainty and political tensions that sit uncomfortably within the hegemonic norms, rules and institutions in the global lifesciences increasingly represent spaces of future growth and opportunities for catching up with the west. For emerging economies, the ensuing shift from ‘developmental state’ into what has been described as the ‘adaptive state’ and the ‘transformative state’ signals the opportunity to shape global lifesciences according to their national interests (Kim, 1999Salter, 2009aWu, 2004; Wong, 2005). For the west, the changing nature of ‘science’ and simultaneously the changing role of emerging economies’ participation in global sciences, questions the established mutually beneficial relationship between ‘state and science’ – where science supplies the state with a flow of knowledge, and the state supplies science with the resources to pursue research interests – the fundamental question being how to accommodate transnational science with national interest?

Yet, it would be mistake to presume that the changing nature of science presents only opportunities and few challenges for emerging economies. From a political perspective, the mutually beneficial state-science relationship at the heart of western domination of global lifesciences since WWII never really developed in India, China or Brazil. Simply put, science in the BRICS lacked political value – until now; thus today, for science to progress the key need is to forge and nurture the ‘science and state’ relationship. Furthermore, while a scientific elite is emerging in the BRICS, their experience in negotiating the key science-state relationship to take the national scientific ambition forward is lacking - although the reverse influx of seasoned diaspora (to the BRICS) from elite western scientific communities is helpful. Similarly, the institutional tools generated by more than sixty years of western domination of global lifesciences is reflected in the hegemonic dynamic of today's global bioinformatics governance and in turn disadvantages new entrants like the BRICS whose establishment of similar institutional strengths is still in its nascent stages. For instance, the Bermuda rules of 1996 enabled the development of bioinformatics self-regulation in western nations, but at the exclusion of China and India.

In the case of China, a top-down style of innovation governance has been adopted with the State Council setting the 'science' agenda with its Five Year Plans. Similarly, India’s Planning Commission’s (recently dissolved) has so far used a similar mechanism of Five Year Plans to set the agenda for the Ministry of Science and Technology (MOST) and the Department of Technology (DIT). In contrast the UK's bottom-up approach with funding from both public and private sources is strengthened by a state apparatus that collaborates closely with a science-led (and scientific elite led) agenda. Neverthless, the Chinese or Indian state's committment to becoming global players cannot be doubted. For instance, between 2005 and 2014, China invested a whopping £303 million in bioinformatics compared to India’s £18 million and UK’s £163.9 million. However, a close study reveals that the bulk of China’s funding of £216 million while earmarked under the broad category of ‘bioinformatics’ was further earmarked under the sub-category ‘New Drug Creation and Development (2009-2010)’ – implying that states differ in their interpretation of what constitutes or differentiates bioinformatics from biomedical innovation.

That western hegemonic domination of global lifesciences has extended into bioinformatics is an accepted fact. However, the extent to which this status quo will be retained given the changing nature of science and the spaces of opportunity it has created for the BRICS to climb ever higher in the global lifesciences value chain, is worth questioning.

To read the paper in full, click here. 

Has bioethics matured to the point where it is capable of re-orienting the relations between science, state and bioethics in the governance of science?

To answer these questions authors Brian Salter and Alison Harvey looked at the case of the production of human/animal chimeras (i.e. genetic hybrids) in scientific research. It is not a new practice: “cytoplasmic hybrids fusing human and non-human (mouse or hamster) cells were developed in the 1960s and were used in early studies mapping the human genome” (p. 688). Yet it has only recently come under ethical scrutiny. In 2011, the UK Academy of Medical Sciences (AMS) released a report entitled: ‘Animals containing human material’ (ACHM). The report had the ambition of shaping future regulation and governance of chimera use in biomedical research.  

Whereas traditionally states have used bioethics to legitimise policy-making, the case of chimeras illustrates how bioethics is becoming more of a proactive player in the mediation of state, society and science. In the case human/animal chimeras, public bioethics (distinct from academic bioethics) is actively framing the problem, the debate, and hence its solutions. Bioethical bodies in Denmark, Germany, Sweden, and in the EU, at large, have already expressed concern and interest in the issue.  

What makes current and future trends in the use of human/animal chimeras even more ethically problematic is the fact that it combines existing controversial features of scientific research: genetic modification (GM) and human embryonic stem cells (HESC). Although the introduction of human elements in animals - such as mice - are unlikely to raise issues of animal welfare, there remains the everlasting conflict of values over the ‘natural’ and the ‘unnatural’. Combined with the ethical dilemma of using of embryonic stem cells, human/animal chimeras become rather problematic.

As a solution the AMS report puts forward the concept of ‘human dignity’, arguing that respect for ‘human dignity’ may serve as the ultimate guideline in the production of chimeras, by neatly addressing both the issue of GM and HESCs. It also assures that a tight leash is kept on science and the extent to which chimeras can be made ‘human-like’. Finally, such a solution welcomes bioethics, but continues to preserve its political neutrality.

To read the full paper click here. 

Should Regenerative Medicines be Awarded 'Special Treatment' in Regulation?

Regenerative medicine is one of the rapidly developing areas of healthcare. However, due to the unique character of such medicines, questions have arisen regarding regulation. These tensions are intensified by the technical novelty, evidential uncertainty and high promise of such technologies. Therefore many have placed forward the argument for regenerative medicine to be granted special treatment with respect to regulation.

A recent paper by Alex Faulkner examines how such medicines can be more readily available to patients, whilst exploring whether or not they should be accorded special treatment. Faulkner assesses how regenerative technologies can be made more readily available to patients by looking at the roles of the market/practice entry regulators and the healthcare system assessment and adoption agencies on the other.

In the UK, ‘gatekeeping’ of regenerative medicines is largely shaped by its role in the EU, although this has become more relaxed in recent years. In turn, three key licensing flexibilities have been introduced in order to provide greater incentives to medicine developers. One of the key flexibilities is conditional approval which essentially allows a product to jump to Phase 4 study as long as its safety has been proven through Phase 1 and Phase 2 clinical trials. This conditional marketing license thus bypasses Phase 3 study. However, this flexibility is typically only allowed for life-threatening diseases. A second flexibility is Exceptional Circumstances which is designed to meet the circumstance where sufficient data can never been generated, for instance disease is rare, research is limited or it is unethical to subject seriously-ill patients to long and intensive testing. The final flexibility is Accelerated Assessment which takes into account the rapid progression of science and responds the expectation of patients. All the three flexibilities have been integrated into the adaptive licensing programme launched by European Medicines Agency (EMA) in early 2014.

The UK has introduced the Early Access to Medicines Scheme (EAMS) cohering with Medicines Adaptive Pathways to Patients of the EU Committee for Advanced Therapies. Unlike above flexible licensing strategies, the EAMS operates outside of marketplace if a clear unmet medical need is perceived. In this regards, the EAMS recognised not only the early role of patients in the process but also the changes driven by genomics, data and personalised medicines. However, there are still conflicts and a need to find a balance between commercial interests, clinician decision-making and national system-level evidence appraisal.

While these incentives and flexibilities are presented as solutions to the issue of ‘special treatment,’ they appear to be lacking. Such relaxations in regulation are often unable to increase incentives, and many do not create faster approval times. Furthermore, the limited number of disease exemptions is preventing such initiatives from having an impact across the board. The rise of regenerative medicine is thus constrained due to existing institutional regimes, epistemologies and methodologies. 

To read the full paper click here.