The management of enthusiasm: motives and expectations in cardiovascular medicine



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The management of enthusiasm: motives and expectations in cardiovascular medicine

This version accepted for publication in Health: an interdisciplinary journal.



Final version published as Will, C. (2010) The management of enthusiasm: motivations and expectations in cardiovascular medicine. Health: an interdisciplinary journal for the social study of health, illness and medicine, 14, 6, 547-563.




Biographical note

Catherine Will is a lecturer at the University of Sussex and has worked on technologies for the prevention or management of chronic disease (including pharmaceuticals like statins), as well as the design/organization of clinical trials. Her current research is on the promotion and use of low dose over-the-counter medication for cardiovascular prevention.



The management of enthusiasm: motives and expectations in cardiovascular medicine
Abstract

Debates about appropriate action in medicine often turn on finding the right emotional orientation to new developments. In this paper enthusiasm emerges as a key term in a professional ‘vocabulary of motive’ around innovation, complicating current sociological interest in expectations. The negative associations that adhere to this word among clinical researchers indicate awareness with the difficulty of managing hype and public hopes, but analysis of its use by cardiologists over the past two decades also reveals tensions around more specific professional dangers, including ‘credulity’ and inappropriate activism. An emphasis on clinical trials offers one resolution, but additional narrative strategies can be identified when discussing when to start such trials – here illustrated for stem cells for cardiac repair. In particular, while some suggest delaying trials until there is good knowledge of mechanism gained in the laboratory, others support early clinical research through gestures of therapeutic and epistemic modesty.


Key words: cardiovascular

expectations

evidence

hope


innovation

The management of enthusiasm: motives and expectations in cardiovascular medicine
In 2006, an editorial in the American journal Circulation asked clinicians to ‘curb [their] enthusiasm’ for stem cell transplantation for cardiac repair. The authors surveyed the field, including the latest trial results, concluding that the technique looked less promising than six months earlier. Yet ‘unreasonable expectations of immediate success [might still] lead to disappointment and abandonment of a potentially revolutionary technology.’ (Welt and Losardo 2006: 1273). Researchers should lead ‘a recommitment to preclinical investigation’ before undertaking further human studies.

Debates about appropriate action in medicine often turn on finding the right emotional orientation to new interventions. In this paper I argue that enthusiasm emerges as a key term in a professional ‘vocabulary of motive’ around innovation (Mills 1940), retaining some negative associations from older uses of the word that are largely lost in contemporary use. An investigation of journal literature relating to cardiovascular interventions introduced in the 1980s and 1990s is used to explore the use of this term in more detail, before returning to contemporary narratives around stem cell research. This analysis is used to contribute to an emerging ‘sociology of expectations’.

Studies of recent innovation in health care have made two main arguments in relation to the expectations surrounding new medical technologies. Firstly, case studies have been used to demonstrate that interventions are shaped by the ‘visions’ articulated for them at an early stage (e.g. Hedgecoe and Martin 2003). Secondly it has been suggested that they are increasingly accompanied by attempts to attract and maintain support by influencing a broader distribution of positive and negative forecasts (e.g. Borup, Brown, Konrad and van Lente 2006). This literature has pointed to awareness of the dangers of ‘hype’ among innovators and the strategic reference to past disappointments to reduce these dangers (e.g. Brown 2003), but has also emphasised the growing appeal of ‘hope’ in contemporary society (Brown 2005; Moreira and Palladino 2005; Watson, Moreira and Murtagh 2009). In this paper the idea of ‘managing expectations’ is subjected to further scrutiny. Where the literature has focussed on efforts to control public perceptions of innovation, the paper considers discussions among clinical researchers about efforts to balance their own optimism with realism. In these, enthusiasm emerges as succinct criticism of those who adopt medical interventions based on belief rather than knowledge, as well as a flag for more complex negotiations about appropriate professional action.

The analysis focuses on three different clinical areas: percutaneous (non-surgical) revascularisation using angioplasty and stents; lipid modification, latterly involving the widespread use of statins for cholesterol reduction; and much newer interest in adult stem cell transplantation for cardiac repair. These cases go some way to balance a literature that has focussed on very recent technologies such as pharmacogenetics (Hedgecoe and Martin 2003), genetic testing and banking (Tutton 2007) and xenotransplantation (Brown and Michael 2003). First however, the longer history of enthusiasm and its relationship to medical motivation is briefly introduced.


Enthusiasm as a ‘vocabulary of motive’

The question of motive remains a difficult one for sociologists, who are divided on the weight to give cognitive models of action and actors’ own accounts (Campbell 1996). Mills’ (1940) concept of ‘vocabularies of motive’ suggests an emphasis on the second, and an awareness that such accounts are ‘situated’ – that is they reflect group habits and norms. Sociologists making use of this concept have tended to focus on people’s justifications for their own potentially disreputable actions, but Mills was also interested in discussions of other people’s motivation, which he suggested could work to censure and discipline behaviour. In this paper medical journals are examined as a site for professional reflection, in which enthusiasm works as a specific vocabulary of motive in a wider set of narratives around innovation.

In these medical sources, enthusiasm seems to retain some of the negative sense that it had in the seventeenth century. Then the term was generally used to describe others, particularly members of religious sects who claimed knowledge from divine inspiration rather than observation or reasoning (e.g. Locke 1689). This meaning was gradually extended to cover credulity among other innovators, including medical ones. Rothstein (1972) quotes a nineteenth century critic of homoeopathy, who complained that practitioners credited their own actions with a cure when it was actually due to ‘the recuperative power of nature’ (165). It was ‘both difficult and useless to reason with the enthusiastic and credulous believers in any novel system, whether of medicine, politics or religion…’ (ibid).

Other nineteenth century debates about medicine also reveal concern with degrees of clinical intervention, speaking to the term’s ability to convey zeal or ardour. Jacob Bigelow, a prominent medical commentator, portrayed homeopaths as unduly ‘expectant’, but attacked blood-letting or blisters as ‘active practice, carried to the extreme usually called heroic, [which] is alike chargeable with evil to patients,’ (ibid. 167). Taking inspiration from French reformers, Bigelow proposed that clinicians should focus on scientific investigation to seek a balance between such extremes. Later the diagnostic movement in Vienna professed more radical doubt about the ability of contemporary medicine to assist patients, contrasting their thirst for knowledge (caricatured as ‘therapeutic nihilism’) with unjustified enthusiasm (Lachmund 1998).

Allegations of therapeutic enthusiasm therefore have the potential to signify two dangers: credulity linked to poor scientific understanding of specific interventions and over-optimism about the value of medical action in general. Research on contemporary stem cell science has identified both with clinicians. In one example laboratory scientists working on embryonic stem cells in diabetes are quoted as saying that clinicians indulge in unrealistic hopes of the field with the exception of small numbers involved with the work of the laboratory (Wainwright, Williams, Michael, Farsides and Cribb 2006: 2056). The authors argue that these accounts should be seen as strategic attempts to mark ‘to clinicians especially, but also to regulators and funders, that this research programme is highly vulnerable,’ (2062): a classic case of attempts to dampen expectations around a new field. I will argue in the rest of the paper that such tensions are acknowledged within the clinical community, and that discussion of the relationship between ‘enthusiasm’ and ‘evidence’ offers one way for clinical researchers to define an emerging field.
Cardiovascular innovation debated

Credulity as a professional problem

The analysis in the following two sections is drawn from articles identified through the National Institute of Health’s database of biomedical literature: PubMed Central.i From an initial search of the term ‘enthusiasm’ in relation to cardiovascular disease and its treatment, only those articles relating to the three cases listed above were included.ii Almost all articles in this sample occurred in review articles or editorials of some kind. This supports Hedgecoe’s (2004) suggestion (drawing on Myers 1991) that review articles function as a particular ‘discursive space’ (18) in which the future of a field is constructed along with accounts of its past and present. Analysis was carried out in a number of ways. The particular meaning of the term ‘enthusiasm’ itself was investigated with reference to its use and position within the article. The narrative structure of each individual piece was also explored alongside their manifest content. Contextual information was gathered, especially on the author and expected readership, and any responses in subsequent editions were also retrieved.

The term ‘enthusiasm’ was most commonly used in generalist and specialist journals to signal the author’s discomfort with the adoption of new technologies without evidence of effectiveness. This was particularly clear in an early article on percutaneous transluminal coronary angioplasty (PTCA), a technique in which a catheter is fed through an artery and a balloon used to relieve blockage [stenosis]. PTCA was spreading rapidly in the 1980s at the expense of the surgical technique of coronary artery bypass grafting (Jones 2000), yet an editorial in the generalist BMJ presented a cautious account of the new technique.

No prospective randomised trial has yet been undertaken... of the efficacy and safety of coronary angioplasty when compared with medical or surgical treatment [however]... enthusiasm for the procedure is such that patients with multiple vessel disease are now being considered for treatment by dilatation of all the affected arteries. (Silverton 1985: 955).

The author further suggested that such credulity presented a risk to patients since clinicians were not able to predict who would suffer acute blockages or damage to the vessel during the procedure and did not understand the mechanism by which angioplasty offered either relief or a risk of recurrent stenosis.

As this example illustrates, writing for a generalist audience was not necessarily linked to greater optimism about innovations, despite Collins’ (1985) suggestion that distance from a core set of scientists working on something would increase certaintyiii. If this spatial or social distribution of expectations was not apparent, a temporal distribution certainly was referenced in professional discussion. As Brown (2005) suggests, this pattern may be used to suggest the need to restrain early expectations. For example, an article in the British Heart Journal commented:

As non-invasive techniques have improved the focus has shifted to their use in assessing valve stenosis. These techniques usually evoke an initial enthusiasm that is followed by disappointment until some middle ground is found. (Odemuyiwa and Hall 1986: 117).

Such narratives might occasionally provide the backdrop to more positive accounts, by contrasting tried and tested techniques with earlier failures, but the term enthusiasm was almost always reserved for the disappointing approach. Thus though Garbe (1987) recommended angioplasty in single vessel disease as one of several ‘recent advances in invasive cardiology’ he dismissed the use of lasers for removing the blockage in the following terms: ‘initial attempts at directing a laser beam at atherosclerotic plaque have been found extremely hazardous and initial enthusiasm has waned,’ (955). Very similar language was used about the technique in the more specialist Texas Heart Institute Journal two years later (e.g. Skolkin and Toombs 1989).

Referencing past disappointments – what Brown and Michael (2003) describe as a strategy of ‘retrospecting prospects’ – was not the only way of using the vocabulary of enthusiasm to articulate doubts about an intervention. These accounts also started to explore the problem of appropriate motivation, by linking false hope in the past with the absence of knowledge. In a piece on cholesterol published in the British Heart Journal in 1987, Oliver - a key figure in research on this area internationally - started by noting that early studies were not based on controlled observations and hinting that lipid research had suffered from too much exposure in its early years.

During [the 1960s] there was an explosion of interest and enthusiasm in the subject of blood lipids and dietary fat and coronary heart disease. This was described, under the title of Cholesterophobia, as ‘Seldom can so much have been written by so many and read by so few.’ (Oliver 1987: 424).

Here Oliver invoked ignorance explicitly. The field had relied on epidemiological comparisons, but clinicians and researchers should acknowledge the ‘many uncertainties and unknowns’ remaining in a situation where there had been few large trials of dietary change, and where trials that had been carried out had found increased non-cardiovascular mortality, leading to no effect on total mortality. In addition to further clinical studies, more basic research was required ‘into the effects of individual dietary fatty acids on the mechanisms leading to coronary heart disease,’ (426). Another editorial, published in the Canadian Medical Association Journal in 1992, returned to such fears saying that doctors ‘should be careful that, in our enthusiasm to reduce atherosclerotic risk, we do not needlessly precipitate anxiety (stress) by counselling about minor lipid disturbances with inappropriate vigour,’ (Edwards 1992: 456). The overall message was that in a situation of uncertainty, doctors should both err on the side of caution and acknowledge their own ignorance.

In discussions of coronary angioplasty and cholesterol reduction narratives suggesting that enthusiasm was temporally distributed were used to dampen present hopes as predicted in the sociology of expectations. Yet enthusiasm here differed from hope and hype in important ways. Firstly, the term was used almost exclusively to talk about doctors’ attitudes to innovation. Where references to ‘enthusiasts’ in common language may signal a distinction from professionals, enthusiasm was not shared with scientists, patients and broader publics in the way that hope might be (e.g. Kitzinger and Williams 2005). Secondly, the dangers of being motivated by enthusiasm were not only associated with the effects of disappointment on a field, but were very concretely linked to the risk to patients attendant on premature intervention. In each case the solution was further research, both on human subjects and in the laboratory.


Trials as a resolution?

Though the use of enthusiasm in narratives of disappointment served to highlight the danger that credulous doctors might pose to patients, other accounts acknowledged the pressures on clinicians to try new treatments quickly. Here trials allowed some resolution, producing knowledge to balance belief, but also harnessing positive aspects of medical activism.

One example came in a piece by a prominent cardiologist and researcher in the US. Writing in the specialist journal, Circulation, Topol (1991) entered a lively debate on the deployment of metal stents during PTCA, as a way of keeping the artery open after the procedure. Invoking both their ‘promises’ and ‘pitfalls’ he suggested that enthusiasm was linked to marketing by manufacturers and to ‘operator exuberance,’ in turn associated with the ‘charm’ of innovative techniques, competition with other cardiologists and attempts to attract patients (691). This complex political and economic context meant that doctors should be careful while waiting for trial results.

Very similar concerns were evident for lipid modification in a generalist review published in 1993 in the BMJ. This returned to excess non-coronary mortality found in early trials as the author professed ‘doubts about the costs and benefits of lowering cholesterol concentration,’ (Dunnigan 1993: 1356). He blamed pharmaceutical companies for the intense promotion of new drugs ‘that either have not been the subject of randomised controlled trials or, as in the case of the statins, are currently being studied in randomised controlled trials whose results are unknown,’ (ibid.).

As in other situations in which certainty is illusory, [doctors’ attitudes vary] from evangelical enthusiasm for lowering lipid concentrations to therapeutic nihilism. Most doctors pursue a somewhat uncertain middle way. (ibid).

Once again, ‘better’ trials were presented as a solution to scientific uncertainty and to clinical credulity, in terms that recall the religious roots of this vocabulary. However, individual enthusiasm could also be presented as a driver for innovation, as in this popular methodological textbook.

Most clinical trials are undertaken because the trial organisers are enthusiastic about the prospect of making a therapeutic advance. The proper conduct and reporting of a trial is meant to control such enthusiasm so that the truth (whether positive or negative) is revealed… [otherwise] one is left in a vacuum of uncertainty where the most enthusiastically supported positions, which may nevertheless be misguided, are likely to be adopted. (Pocock 1983).

In the case of stents, the US Food and Drug Administration specifically requested such studies from the manufacturers, and these reported generally positive results in 1994. At the same time, lipid modification was being tested in larger and longer trials than absolutely necessary for regulatory approval in an effort to counteract professional fears. The early 1990s was a period of growing visibility for trials as a means of certifying medical knowledge and managing the introduction of new interventions (e.g. Tanenbaum 1994; Timmermans and Berg 2003). For the clinical researchers who were pushing this agenda under the banner of ‘evidence-based medicine’ (EBM) the trial offered a powerful way to channel individual activism as a means of reducing collective credulity. Furthermore, though trials may be ethically and scientifically grounded in professional uncertainty, such studies allowed individual researchers to feel that they were giving patients a chance of treatment. Here a more positive aspect of enthusiasm as activism comes into view, as the term’s critical edge is softened by reference to the sincerity and energy of those pursuing innovation. Discussions of the results of the statin trials of cholesterol modification illustrate these more contested aspects of medical motivation.

The trials of statins published in 1994 and 1995 convinced Oliver and many others that clinicians should ‘lower patients’ cholesterol now!’ Here the cautionary tale of two extremes was resolved more happily with a middle position supported by evidence:

Polarisation of views has led over the past 20 years to the emergence of enthusiasts for whom cholesterol lowering and the prevention of coronary heart disease are almost synonymous and sceptics who attribute to lipid reduction more harm than good. This lack of consensus has been widely publicised by the media, and many people believe that the case for treating raised cholesterol concentrations is flawed and can be disregarded. (Oliver, Poole-Wilson, Shepherd and Tikkanen 1995: 1280).

Now Oliver felt able to advise doctors to take action. Promotional material for the new drugs, published in the same journal, mirrored this image of enthusiasm in a new alignment with evidence. While advertisements for Merck Sharpe and Dohme’s simvastatin used images of joyful survivors, the campaign for Bristol Myers Squibb’s pravastatin appealed to the new ‘facts of life’, referring to large trials. A third campaign appeared to reach for reconciliation in the individual doctor as Pfizer’s atorvastatin depicted a prescriber who was both ‘purposeful and intelligent’ and ‘enthusiastic’ in changing their practice to promote statin therapy.
Concern for unintended consequences – the nuances of medical activism

The negative associations of enthusiasm as activism did not disappear with the appeal to evidence. The risk of unintended consequences remained, relating for example to the economic cost or harm to patients who were not typical of those in trials. Arguments about statin use continued, with questions about the balance between costs and benefits in a situation where ‘about 55 patients will require treatment for five years to avoid a death,’ (Freemantle, Barbour, Johnson, Marchment and Kennedy 1995). According to their editorial in the BMJ, trial data was not always sufficient reason to act.

Enthusiasts for cholesterol lowering drugs may adopt the priorities but unless they curtail prescribing in other areas they will soon run into financial difficulties. Given the absence of information on cost effectiveness, they may do more harm than good through making savings in more cost effective areas to pay for statins. (ibid).

A barrage of letters followed this assertion. Some agreed that statins represented a case of misplaced intervention because of their cost. Others sprang to the defence of statins and enthusiasm, demonstrating the continued negative force of the term as the same time as trying to rehabilitate the sentiment.

The phrase ‘enthusiasts for cholesterol lowering drugs’ is out of place: healthcare professionals who are not enthused by the evidence from the statin trials should consider some other career. General practitioners are not overwhelmed and doing little. Many are impressed by the quality of the evidence and already implementing it. (Wallis et al 1995:1615).

Even when doctors wait for trials, the publication of apparently positive results does not guarantee their application, as professionals try to balance wider harms and benefits than those measured in medical studies. In this situation enthusiasm emerges again as a term denoting ambivalence. A final set of historical examples shows intervention portrayed at interference with reference to PTCA as a disruption to ‘natural’ or ‘biological’ processes.

Despite the publication of two trials of stents in the early 1990s, clinical researchers continued to debate their implications. Clinicians in the UK had been slower to adopt these techniques than their colleagues in the US, and writing on this subject in 1994 remained somewhat sceptical. In another BMJ article, the authors drew attention to the dangers of restenosis - recurrent blockage of the coronary artery - which they suggested resulted from the body’s attempt to heal itself after an intervention (McEwan, Henney and Humphries 1994). Efforts to combat this were presented as efforts to treat the ‘side effects’ of the initial procedure, and the authors considered the gene therapy as one possibility. However, early research using growth factors to encourage vessel repair had ‘low efficiency’. Any successful approach ‘would have to induce the local production of substances with potent paracrine [hormonal] effects,’ (996) - working with rather than against nature.

An editorial in a more specialist journal also reflected on the risks of stents. Once again, enthusiasm was located in a temporal frame in a way that cast some doubt on their eventual value.

Is the coronary stent here to stay? Have interventionalists crossed the Rubicon? Or after the initial hype will the stent follow the course of many earlier intracoronary devices: with initial enthusiasm leading to increased use, followed by appreciation and then by familiarity, which will lead inevitably to contempt, disillusionment and decline in use? (De Feyter 1996: 109).

Despite this introduction the author ultimately offered a fairly optimistic account of the new technology, grounded in clinical ‘knowledge of the appealing simplicity and attractive immediate post-procedural result of stenting, which has been generally propagated through the perseverance of pioneering believers’ (ibid) - but problems remained. ‘As a solution to an engineering problem intracoronary stents seem a natural development but the biological consequences are obviously challenging,’ (110). The piece ended with reference to the limits of trials: ‘overenthusiastic interventionalists should keep in mind that [the results] were obtained in highly selected patients with predominately stable angina’ and should not be extrapolated to other groups (ibid).

Another specialist article on the promise of gene therapy to manage this problem again drew on the idea of working with the body. Writing in Circulation Research, De Young and Dichek (1998) argued that this was attractive precisely because it offered ‘a biological solution to an essentially biological problem: regrowth of intimal mass or artery wall,’ (306).

In this final set of reviews, the vocabulary of enthusiasm signals not only the dangers of credulity, but the wider risks attendant on medical activism. These risks are not easily resolved through the knowledge generated in clinical trials, as the complexity of society and of the body resist easy understanding, leading to calls for further basic research. In my last section I return to all of these themes in considering contemporary debates about research on stem cells for cardiac repair.


Stem cells for cardiac repair – the timing of trials

This section draws on comparisons of papers with or without the vocabulary of enthusiasm, exploring the wider content of a discussion on the appropriate timing of clinical trials. Here a search was carried out for review articles on the subject of stem cells AND cardiovascular disorders. From approximately 750 results, again a smaller set was identified by selecting those published in the journals used in the previous section or ones very similar to them (i.e. including both specialist cardiology and generalist sources but not more ‘scientific’ publications).


Comparison of articles analysed in part 1 and 2 of the paper

Older cardiovascular innovations

Stem cells for cardiac repair

Silverton (1985) BMJ

Kuehnle (2002) BMJ

Oliver (1987) and (1995) BMJ

Braude, Minger and Warwick (2005) BMJ

Durringan (1993) BMJ




Freemantle et al (1995) BMJ

Mathur and Martin (2004) Lancet

McEwan et al (1994) BMJ




Edwards (1992) Canadian Medical Association Journal

Rubart & Field (2006) Annals of the New York Academy of Science

Topol (1991) Circulation

Forrester et al (2003) Circulation




Welt and Losardo (2006) Circulation

De Young and Dichek (1998) Circulation Research

Kinnaird et al (2003) Circulation Research

Odemuyiwa & Hall (1986) British Heart Journal

Weissberg and Qasim (2005) Heart

De Feyter (1996) Heart (formerly British Heart Journal)

Taylor and Zenovich (2008) Diabetes, Obesity and Metabolism

Diethrich et al (1989) Texas Heart Institute Journal

Angelini and Markwald (2005) Texas Heart Institute Journal

Skolkin & Toombs (1989) Texas Heart Institute Journal

Sabti (2007) Journal of Cardiothoracic Surgery

The field of stem cell therapy in cardiac disease is often dated from animal experiments published in 2001, where scientists claimed to identify differentiation by bone marrow cells transplanted into the hearts of mice. These results stimulated a series of small human trials to see if cell transplantation might repair damaged hearts, but the pace, progress and direction of this research has been controversial. Here enthusiasm appeared again in the context of past hopes now modulated by disappointing outcomes, for example in trials of growth factors to stimulate mobilisation of the patient’s own cells in situ (Kinnaird, Stabile, Burnett and Epstein 2004), or by a lack of evidence for the process of transdifferentiation (Rubart and Field 2006). Though this narrative form was clearly evident in the editorial with which this paper opened (Welt and Losardo 2006) it was not only used with reference to the publication of new trial data. Readers were repeatedly asked to expect disappointment and prepare for problems with stem cell therapy. Thus Forrester, Price and Makkar (2003) cautioned against hopes of an easy move from animal to human studies because of the differences in scale: following a similar format to Topol’s (1991) piece on stents by enumerating sets of ‘potential’ benefits followed by possible side effects. Though ‘neovascularisation and blood flow improved [in animals]... the theoretical malignancy potential of altering progenitor cells with growth factors will need to be investigated,’ (Forrester et al 2003: 1141), while transplanting muscle cells appeared to carry a risk of arrhythmias.

Despite this cautious language, all three papers introduced above supported clinical studies, as long as they were properly randomised, in contrast to the Welt and Losardo (2006) piece, which called for a halt to trials. These authors enumerated a number of questions which they felt needed answering before further clinical studies began.

Which disease should we be treating? At what point in the disease process should we treat? Which cells should be injected? How should these cells be delivered? What are the mechanisms by which transplanted cells exert influence, if they do? (ibid. 1272).

Such questions recall discussions of both stents and cholesterol reduction where mechanistic understanding was suggested as a means of avoiding unintended harms to patients as well as defending the field. However, clinical researchers had already marshalled a number of reasons that such uncertainties should not delay human trials.

One approach was to argue simply that as long as transplantation was ‘feasible’ and ‘safe’ in the short term, the existence of ‘unanswered questions’ did not prevent the randomised controlled clinical trial acting as the best and ‘final arbiter of the effectiveness of stem cell therapy’ (Forrester et al 2003: 1144). This review featured a striking diagram depicting a total of four ‘potential beneficial mechanisms’ of cell transplantation (1141) without suggesting that the inability to identify a single mechanism should put a brake on research. A similarly relaxed position was proposed one year later in the Lancet by a team involved in clinical and laboratory research. They suggested that ‘the exact mechanism of potential benefit [from stem cells] might never be discovered,’ (Mathur and Martin 2004:186).

Most of the pharmacological agents used in the management of cardiac patients were tested in man without a full understanding of their mechanism of action. Our understanding of the beneficial effects of drugs is always provisional. Indeed, without compromising safety, it would be unreasonable to have withheld some of the major breakthroughs in the management of cardiovascular disease until a full understanding of their mechanism of action had been established. (ibid. 188).

These arguments might be understood as gestures of ‘epistemic modesty’ grounded in experience with earlier innovations.

Such strategies did not command general agreement, even when clinicians were involved in writing reviews. In 2005, a clinician and a researcher team used doubts about transdifferentiation to frame a more cautious narrative about the way forward in the Texas Heart Institute Journal. Suggesting that researchers might actually be seeing ‘fusion’ of cells, they expressed concerns about the potential of elderly cells, about the environment of the heart in acute disease, and damage to tissues in chronic disease. This led up to a call for a moratorium on clinical studies, motivated by ‘prudence and patience’ (Angelini and Markwald 2005: 485). ‘Once it has been proved that stem cells from different sources can develop into myocytes, biologists will need to teach clinicians how to optimise this process in order to achieve significant myocardial heart muscle] regeneration,’ (ibid). This version of epistemic modesty presented it less as a collective predicament than a problem for the individual clinician.

Participants in these debates were well aware that if epistemic modesty failed as an argument for clinical research, gestures of ‘therapeutic modesty’ could also be used. It remains common for reviews to begin with the human and financial burden of heart trouble and the limitations of current treatments. Thus one more recent paper informed readers that ‘in the next 25 years, up to 15% of the population over the age of 65 in the USA is projected to have heart failure,’ (Taylor and Zenovich 2008: 5). Conventional management is not suitable for all patients (Sabti 2007), and is expensive. ‘Extrapolation of US data … indicates that in Europe the direct cost of cardiovascular disease is €473 billion and the indirect cost is €15392 billion per year,’ (Mathur and Martin 2004: 183). The experience of hopelessness in the face of this disease could also be contrasted powerfully with the potential of stem cells.

Ischaemic myocardial damage is an increasing cause of heart failure in the western world and has long been considered irreversible because adult cardiomyocytes [heart cells] are terminally differentiated and do not proliferate... Over recent years attention has turned to the potential of stem cells to repair damaged hearts because of their ability to differentiate in vitro. (Weissberg and Qasim 2005: 696).

These expressions of hope in the face of clinical failure were not particularly identified with generalist rather than specialist, or clinical rather than scientifically oriented publications. A multi-disciplinary team, writing in the BMJ in 2005, enumerated previous cases where patients had been infected through blood transfusions to argue that incautious use of embryonic stem cells might ‘put patients at risk of viral or prion disease’ (Braude, Minger and Warwick 2005: 1159) and specifically opposed the idea that clinical failures should drive early trials.

Despite inadequate preliminary data on clinical safety or from animal experiments, trials using cells derived from autologous bone marrow samples are already being conducts on patients with heart disease, with urgency and therapeutic need being cited as the reasons for immediate implementation. However, urgency is not an excuse for bad science. Animal experiments should be conducts to understand further the host destination and integration of transplanted cells, and the risks of neoplasia arising in cells implanted into new environments. (ibid. 1160).

Such arguments help make sense of a final set of narrative strategies used by those who supported the continuation of clinical research.

Once again the Lancet piece stands out as a strong statement of this argument: reflecting on the apparent biological basis of the stem cell approach in contrast to other therapeutic modalities. This review began with verbal and visual examples of what the authors called ‘natural repair’ in the other human organs such as fingers and in animals such as newts (Mathur and Martin 2004:184). In the same year Kinnaird et al started a more technical review in Circulation Research with the observation that renewal of coronary vessels went on throughout adult life (2004: 354) and went on to consider the different mechanisms by which this process might be clinically ‘enhanced’ (358). Elsewhere the idea of ‘ongoing repair’ was complicated by the body’s other inflammatory responses.

The concept of exogenous cell therapy is based on the assumption that supplying appropriate cells can overcome this pre-existing failure of repair, reduce inflammation and restore tissue integrity and tip the balance between injury and repair towards repair. (Taylor and Zenovich 2008: 2).

In this article ‘enthusiasm’ was linked to the idea that bone marrow cells might simply ‘accelerate’ existing repair processes (4). Cells further offered the hope of less heroic intervention such as surgery or angioplasty, which might be dangerous for fragile patients (7). Mechanism could be explored gradually through investigation of blood collected in clinical trials, but these ‘biological’ solutions should be tested quickly in response to unmet need.

Though these papers clearly contrasted with the argument in Mathur and Martin (2004) that the mechanism might never be understood, they created a more positive atmosphere with reference to ‘encouraging’ or ‘exciting findings’ (Taylor and Zenovich 2008: 5; Weissberg and Qasim 2005: 699) and ‘the prospect of an exiting and powerful treatment’ (Mathur and Martin 2004: 183). Even one of the articles proposing that the pace of clinical research should be slowed acknowledged the power of this argument in driving scientific work, for if ‘the theory that the adult heart has an intrinsic regenerative capacity has not yet been fully proved... it has stimulated the imagination of many investigators,’ (Angelini and Markwald 2005: 481). The use of this final strategy may therefore be linked to its ability to cross the divide between science and the clinic erected in some of these debates. Though clinical researchers say they are comfortable with acknowledging the limits of their knowledge and therapeutic ability, scientists are more likely to join them when these limits are contrasted with the wonders of nature.


Discussion

Analysed as part of the vocabulary of the medical review article, ‘enthusiasm’ first appeared interesting precisely because it retained a negative flavour absent from other contemporary uses of the term. Yet closer examination of the ways in which this term was used to convey approval or disapproval of medical motivation (drawing on Mills, 1940) revealed ambiguity around the word with reference to its invocation of both credulity and activism among doctors. Enthusiasm without clinical trials might be seen as an example of naïve belief in new therapies, especially those promoted by commercial interests, but researchers had complex positions on the appropriate relationship between ‘knowledge’ and ‘action’ in medical innovation. References to excitement and enthusiasm in the professional literature acknowledged the role of ‘hope’ in driving therapeutic discovery and made space for more positive accounts of active intervention. However, such motivations needed to be carefully managed or modulated to avoid unrealistic expectations among publics (hype) and undue risks to patients. In older medical sociology, the tension between these positions, experienced by clinical researchers such as the authors of these reviews, has been discussed as a conflict between different professional identities. In Fox’s (1959) ethnography of hospital-based research, hopefulness was associated with scientific curiosity while clinical responsibility was expressed through decisions not to pursue a particular experiment with individual patients, and the combination defused through black humour. Merton (1976) presented a more pessimistic account of the problems of ‘role strain’ for this group, which he used as an example of what he termed ‘sociological ambivalence’. Yet recent discussions of ambivalence surrounding medical innovation have tended to focus on mixed or divided public responses echoing the wider literature on expectations (Kitzinger and Williams 2005; Kerr, Cunningham-Burley and Tutton 2006; Tutton 2007).

A space opens up for further discussion of professional positions when we consider that mixed identities and motivations have appeared less problematic to recent sociologists than to Fox and Merton. For example, in other work on clinical trials, Moreira and Palladino (2005) have argued that trial results simultaneously support ‘regimes of hope and truth’ around stem cell therapy for Parkinson’s disease. Different parties can use the uncertainty remaining after early studies to argue for optimism (‘we do not know the truth: there is hope’) or to close down development (‘we know the truth: there is no hope’) (67), but patients may experience both beliefs or regimes. An earlier paper by Singleton and Michael (1993) on general practitioners’ attitudes to cervical screening similarly suggests a complex interplay between positive and negative accounts of medical intervention. Here clinicians mediate between laboratory and clinic, sometimes claiming ignorance, sometimes expertise, but using the space available for this movement to reduce their responsibility for the scheme as a whole.

The accounts of motivation behind research discussed in this paper suggest another strategic distribution of clinical responsibility. Though hopefulness may be generally a positive quality, it is a risky one for doctors, who frequently remind each other of interventions that were greeted as breakthroughs and subsequently shown to be ineffective or even harmful. This temporal pattern is often narrated with reference to clinical trials, which are seen as providing evidence to balance enthusiasm. Here ‘truth’ may be set against ‘hope’ and ‘knowledge’ against ‘belief’ but as Moreira and Palladino (2005) acknowledge, trials play quite complicated roles. In the data presented in this paper for example, they appeared as a way to separate activism from credulity, channelling the positive side of hope into the production of truth. Even before reports from early trials enter controversies, these tensions may be expressed around the question of the right time to start such studies (see also Waldby 2002: 307).

In the case of stem cells, concerns about the timing of trials were answered by some researchers with reference to ignorance about, or the limitations of, existing interventions. This is not then the argument that ‘we do not know’ from Moreira and Palladino’s (2005) regime of hope but rather ‘we may never know’. In particular, though doing research allows clinicians to speak on the side of knowledge/science, the focus on outcomes means that they may not have to produce information about mechanism, relocating the controversy in a debate about the appropriate form of knowledge required to develop a field, i.e. laboratory or clinical.

In the final section of this paper these narrative strategies were identified as ‘gestures of epistemic and therapeutic modesty’ which balance the dangers of credulity and activism conveyed by the language of enthusiasm. This point recalls older debates about the ability of doctors to tolerate and acknowledge uncertainty in clinical practice (e.g. Fox 1957, 2000; Atkinson 1984), but we might also follow Singleton and Michael (1993) to suggest that deferring to ‘nature’ in both cases can appear to redistribute clinical responsibility. Furthermore this strategy may link to wider conventions in scientific writing. Here we can draw on histories by Shapin and Schaffer (1985) or Haraway (1997) who see scientific reporting as a particular form of testimony, apparently deferring to nature by making the speaker invisible. Clinicians may produce their own versions of modest witnessing by referring to the limits of current therapies, or the boundaries of knowledge about their mechanism or side effects. Such strategies were particularly attractive in the cases of gene therapy or stem cell transplantation, which can be presented as a way of enhancing or assisting biological repair. Appeals to ‘nature’ may both increase or temper professional and public expectations, but in either case seem to limit the responsibility of doctors, and deflect the parsimonious critique contained in the vocabulary of enthusiasm. ‘Modesty’ about what can be known, or what may be hoped, creates the space for clinical researchers to defend a novel approach to other professionals including laboratory scientists.


Conclusions

The sociology of expectations has several features that might not have been predicted when it started just a few years ago. Its focus on cases of very recent and unresolved innovation may be obscuring the extent to which these tensions are typical. The interest of the cases where broader publics, media and patients are involved in debates about new technologies may be distracting attention from examples where clinical researchers try to pursue a more private path, while images of them as strategic players of the expectations game means we have lost the interest of previous sociologists in the lived experience of medical research. If we abandon the attempt to locate hopefulness or realism with particular groups, we may find more to say about the ambivalence of individuals who combine clinical and research roles in pursuing innovation. In their published positions, ‘enthusiasm’ emerges as a specific vocabulary signalling professional awareness of the dangers of hope as well as hype, while broader narrative strategies invoking different types of modesty appear to answer such concerns, by creating space for more positive accounts of careful medical action.



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Notes



i PubMed Central was chosen rather than the more clinically focussed PubMed because it allows searches for terms that appear anywhere within an article, rather than only in the abstract, or as a MESH item or keyword.

ii This helped move from a total of almost 2000 to a smaller set for close reading, and allowed the author to extend previous research in these areas rather than risk misunderstanding an entirely new field.

iii ‘The degree of certainty which is ascribed to knowledge increases catastrophically as it crosses the core-set boundary,’ (Collins 1985: 144-5).




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