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Keywords:

  • genetics;
  • cystic fibrosis;
  • social history

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Classic CF emerges
  6. The sweat test reshapes classic CF
  7. Milder forms
  8. CF as a genetic disease
  9. CF as a collection of related disorders
  10. Enter molecular genetics
  11. Discussion and conclusion
  12. Acknowledgements
  13. References

In this article I present a socio-historical analysis of the definition and diagnosis of one particular genetic disease – cystic fibrosis (CF) – in an effort the better to understand its social context both before and after the advent of molecular genetics. I begin my analysis with some background on the history of CF, before moving on to consider the emergence of the notion of classic CF, the development of the sweat test, early approaches to mild or variant forms of CF, the concept of CF as a genetic disease, the concept of CF as a collection of related disorders, and developments in the understanding and diagnosis of CF which came about in the wake of molecular genetics. I highlight a range of technological, professional and patient developments and how these stimulated new research, typologies and clinical tools. I also consider how different notions of CF were mobilised, either to support or undermine a particular approach to diagnosis or treatment, and consider how the dynamic and contextual characteristics of CF were accounted for by scientists and clinicians with an interest in CF. I end by discussing the implications of my analysis for the contemporary sociology of genetics, and related studies in the sociology of medicine more generally.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Classic CF emerges
  6. The sweat test reshapes classic CF
  7. Milder forms
  8. CF as a genetic disease
  9. CF as a collection of related disorders
  10. Enter molecular genetics
  11. Discussion and conclusion
  12. Acknowledgements
  13. References

The socio-historical analysis of disease has developed considerably in the last decades, as a range of historians, cultural anthropologists, sociologists and even medics, have unpacked the cultural, political and technical antecedents of a variety of modern ills, from the contested to the mundane (Aronowitz 1998, Wailoo 1997, Rosenberg and Golden 1997, Mol 2002, Keating and Cambrosio 2004, Fujimura 1996). This work demonstrates very clearly that disease is far from the pure ontological entity which is often invoked in medical texts, but is the product of socio-material relations, where interpretation and meaning must be continually negotiated by a range of actors, including doctors, scientists and patients, as well as technologies, bodies and institutions. A historical perspective is particularly useful for tracking the dynamics of disease definition and diagnosis, and understanding the ways in which new technological and social developments shape prevailing interpretations of disease and its consequences. This work demonstrates that far from the dramatic paradigm shifts and revolutionary discoveries of popular accounts of medical progress, disease concepts and their treatments evolve in a more piecemeal fashion, as new techniques and social mores are incorporated within existing epistemological and technological frames (Wailoo 1997).

It is curious, then, that much of the work concerning the technologies and theories of the new genetics concentrates upon their transformative properties, both in terms of laboratory and clinical practice, and in the wider sphere of familial and social relations (Rheinberger 2000, McKenzie 2004, Novas and Rose 2000). Some of this has echoes of the professional and public media where genetics is hyped on the basis of its future potential to cure a range of biomedical and social ills. Even those with a more critical agenda tend to invest considerable transformative powers in the new genetics writ large when they raise the spectre of designer babies or genetic ID cards (and I include myself in that category – see Kerr and Shakespeare 2002). Others highlight the rise of new forms of biopolitics, where support groups and activists have begun actively to influence research and service provision, as well as the micro-management of their own condition (Novas and Rose 2000, Robertson 2001). Social theorists are also orientated towards the new when they mobilise molecular genetics in the context of theories where a new modernity is invoked, particularly in the context of the risk management practices of new ‘entrepreneurial subjects’ who will use new genetic technologies to tailor their lifestyle with the aim of improving their health (e.g.Giddens 1990, Rabinow 1996). For example, Rheinberger writes:

. . . the prospect of ‘molecularizing’ diseases and their possible cure will have a profound impact on what patients expect from medical help and a new generation of doctors’ perceptions of disease (2000: 20).

Novas and Rose echo these sentiments when they argue:

As the body becomes the subject of a molecular gaze, life is recast as a series of processes that can be accounted for and potentially re-engineered at the molecular level (2000: 487).

It seems that scholars orientated towards the future are proposing a somewhat different interpretation of genetics from those orientated towards the past. Yet, we know little of the specific histories and imagined futures around particular disease entities. Although Wailoo (1997) has written about sickle cell in a socio-historical vein (up to the 1970s), and others have discussed some aspects of the histories of diseases with a genetic component, such as diabetes (Hedgecoe 2002), most work in this area takes a more macro-level approach, focusing upon broad histories of the genetic code (Kay 2000) or the genetics of cancer (Fujimura 1996).

In this article, I therefore present a socio-historical analysis of the definition and diagnosis of one particular genetic disease – cystic fibrosis (CF) – both before and after the advent of molecular genetics. CF is now thought to be one of the most common genetic conditions, affecting approximately 1:2,500 newborns. Typically, it is characterised by chronic obstruction and infection of the lungs and defective function of the pancreas, which causes digestive problems. The clinical diversity of CF, however, means that the time of onset and severity of pancreatic and the pulmonary disorders that it involves vary. An autosomal recessive mode of inheritance for the condition was first suggested in 1946 and confirmed in 1949 (Lowe et al. 1949). This means CF is inherited from two unaffected ‘carrier’ parents (the frequency of the carrier rate in the population is typically estimated as 1:25). The life expectancy of people with CF has risen to around 35 over the course of the 20th century, and people with CF are now involved in a range of adult associations with various links to CF charities. Following advances in recombinant DNA and sequencing technologies, and the development of new techniques like chromosome walking and jumping, the gene for CF was identified in 1989 (Rommens et al. 1989). Since then over 1,300 different ways this gene can mutate have been identified, but the most common one – delta F508 – is thought to account for over 80 per cent of CF cases in what is described as the Caucasian population (see the Cystic Fibrosis Genetic Analysis Consortium webpage: http://www.genet.sickkids.on.ca/cftr/). Antenatal diagnostic tests have been developed, based upon these findings, and are available as a screening test in some countries, for example, the USA.

Here I explore the definition and diagnosis of CF from the 1940s to the present, in an effort to establish the ways in which different techniques, ideas and relationships shaped the conception of CF. This involves particular diagnostic technologies, and new theories of the underlying defect in CF, but also increasing professional specialisation, and the changing profile of CF patients, from childhood into adulthood. This raises a further question about the extent to which new genetic technologies have either clarified or confounded notions of the disease range and aetiology, and how this has impacted upon diagnoses of the condition. I am also particularly interested in the notions and approaches to identifying ‘mild’ or ‘variant’ forms of CF and their place in understanding the aetiology of CF, and establishing new forms of diagnosis.

To answer these questions, I draw upon a qualitative analysis of journal articles, conference precedings and scientific or medical books about CF, taken from a Reference Manager database on CF which I have drawn from a combined bibliographic and Medline search over the period 1930–2002. These data were collected as part of a Wellcome Trust-funded project on the history of CF, grant number 050491.The database was compiled between 1998 and 2003, and currently has nearly 8,500 entries. Of these, approximately 800 articles are on file. I collected articles and other related material which covered important changes in the definitional and diagnostic criteria for CF. I focused upon key developments, such as the introduction of the sweat test, newborn screening and antenatal screening as well as articles which reflected upon changing understanding of the aetiology of CF, changing approaches to diagnosis, and changing prognosis. I was especially interested in discussions which related to professional sovereignty over the condition, so I collected a range of articles about the relationship between genetics and CF, both pre- and post-molecular genetics. I also collected articles where patients’ experiences or attitudes were considered, and the wider political economy of CF research, and where service provision was discussed. This included material on the international race to identify the CF gene, discussion of commercial interests in CF screening, and discussion concerning the various support groups with an interest in CF.

For this article, I searched the key words and titles of the articles on file around the following broad themes: adults with CF, antenatal screening, heterozygosity, clinical forms of CF, diagnosis and misdiagnosis. I also identified a number of review articles and books on CF where general discussion of these issues was apparent. This led me to identify several topics for further analysis: the notion of classic CF, discussion of mild or variant symptoms, disagreement over diagnosis, screening and aetiology, the impact of the sweat test and molecular genetics. I reviewed a range of experimental articles, reports, letters, comments, editorials and reviews, drawn from a wide range of journals, including general medicine, medical and clinical genetics, paediatrics, respiratory medicine, physiology, pathology and chemistry journals, as well as conference proceedings and books. These were all in the English language, and most of them were for an international audience. The authors were from a variety of countries (USA, UK, France, Australia, Canada, Switzerland, Belgium, Germany, Spain and Israel) and a variety of academic and clinical departments.

This analysis was then supplemented with material from 25 interviews with some of the leading CF clinicians and scientists in the UK, USA and Canada, which took place between 1999 and 2001. These included people involved in the early study and treatment of CF in the UK, as well as current specialists in paediatrics, thoracic medicine, molecular genetics and antenatal screening. I interviewed some of the people involved in the identification of the CF gene in the UK, USA and Canada, as well as people with links to the CF Trust in the UK, the CFF in the US and the American College of Obstetrics and Gynaecology, who have been involved in antenatal screening policy and monitoring. To prepare for the interviews I read the interviewee's work on CF, and tailored my initial questions to their interests. I asked a range of general and more specific questions about their experiences of working on CF, their professional identities and relationships with other CF specialists, physicians and scientists with an interest in the disease, their links with CF organisations and patients, their views on the impact of molecular genetics, and their attitudes to antenatal screening. Interviews were tape recorded and transcribed then coded and analysed according to the themes outlined above. Interviewees will not be named in this paper.

I begin my analysis with some background on the history of CF, before moving on to consider the emergence of the notion of classic CF, the development of the sweat test, early approaches to mild or variant forms of CF, the concept of CF as a genetic disease, the concept of CF as a collection of related disorders, and developments in the understanding and diagnosis of CF which came about in the wake of molecular genetics. I highlight a range of technological, professional and patient developments and how these stimulated new research, typologies and clinical tools. I also consider how different notions of CF were mobilised, either to support or undermine a particular approach to diagnosis or treatment, and consider how the dynamic and contextual characteristics of CF were accounted for by scientists and clinicians with an interest in CF. I end by discussing the implications of my analysis for the contemporary sociology of genetics, and related studies in the sociology of medicine more generally.

Background

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Classic CF emerges
  6. The sweat test reshapes classic CF
  7. Milder forms
  8. CF as a genetic disease
  9. CF as a collection of related disorders
  10. Enter molecular genetics
  11. Discussion and conclusion
  12. Acknowledgements
  13. References

When we track the changing definitions and explanations of what ultimately came to be called cystic fibrosis (although the term muscovidosis is still used in France) there is no straightforward path towards enlightenment. However, there are certain key steps in understanding, such as the move towards conceptualising CF as a multi-systemic disorder (Farber, 1943), the development of the sweat test as a means of diagnosis (Gibson and Cooke 1959) and the identification of the gene (Rommens et al. 1989). Professional and wider political and social contexts have shaped these processes of historical movement, from the growth of the discipline of clinical biochemistry in the 1950s and the 1960s to the huge financial and political investments in the new genetics of the 1980s. But beyond this fairly flimsy historical framework, there are many variations on the conceptualisation of cystic fibrosis, variations that seem, to a large extent, to coexist without generating huge amounts of controversy. This is in part a product of the degree of difference and variation in notions of the condition. These differences are often a matter of detail rather than the general picture of disease. Historically, CF has always been difficult to pin down, so ambiguity about its boundaries is ‘normal’. This does not mean that these variations are trivial, nor is it a reason to dismiss a social investigation of the phenomena. The extent and types of variability bear closer examination, as do the different professional and social contexts that seem to influence particular readings of the disease. It is sometimes the case that quite specific professional contexts shape the local understanding of the disease and its consequences (when one laboratory is promoting their new diagnostic test, for example). This can be found in interview transcripts, where CF is cast as a ‘dreadful disease’ when neonatal screening is being justified, but a complex disease, with a large and important spectrum of mild phenotypes, when the benefits of further research are being promoted or antenatal screening is being problematised. It is also true, however, that clear-cut professional interests cannot simply be tied to particular conceptualisations of disease. The picture is more complex, as differences abound between and amongst professional, institutional and international groupings of people with an interest in CF.

Classic CF emerges

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Classic CF emerges
  6. The sweat test reshapes classic CF
  7. Milder forms
  8. CF as a genetic disease
  9. CF as a collection of related disorders
  10. Enter molecular genetics
  11. Discussion and conclusion
  12. Acknowledgements
  13. References

The initial move to define CF as a distinct disease entity was not a unique event, as historical accounts commonly have it, but was accomplished by a series of steps by different researchers. The Swiss paediatrician Guido Fanconi wrote on the familial nature of what was known at this stage as congenital intestinal obstruction during the 1920s, following in the footsteps of others with an interest in congenital steatorrheoa (fat malabsorption in the gut), including Archibald Garrod (Garrod and Hurley 1912) who went on to write Inborn Errors of Metabolism (1923). In 1936 Fanconi distinguished CF from celiac disease (a digestive disorder caused by toxic reaction to gluten) (Fanconi et al. 1936). However, the early study and treatment of cystic fibrosis was dominated by a small group of dedicated professionals, largely based in the USA.The local conditions of these workers as well as the wider state of medicine shaped their approach to the disease. Dorothy Andersen of the Babies Hospital, New York demonstrated in 1938 that the condition which she called cystic fibrosis of the pancreas was not a rare disease. Andersen, a paediatric pathologist, focused upon the distinction between CF and coeliac disease (a digestive disorder caused by a toxic reaction to gluten) because of clinical priorities – some of her patients were not responding to treatment (see Andersen and Hodge 1946). Her approach to this task was determined by her own specialist knowledge in morbid anatomy, which meant that she privileged defects in the pancreas when explaining the aetiology of the disease, a point reflected in the name which she gave it – cystic fibrosis of the pancreas. Her focus on vitamin deficiencies in treatments of other similar diseases, such as coeliac disease, also meant that she expressed discontent with a straightforward genetic explanation of the disease, thinking that vitamin A deficiency might also play a role.

Dorothy Andersen's group at the Babies Hospital, New York and Harry Shwachman's Boston group became the largest centres for CF research and treatment in the US. Paul di Sant’Agnese at the NIH Bethesda also developed a specialist interest in the condition. These groups took responsibility for considerable numbers of cases of children with CF, and this enabled them to study the disease in detail, and gather specialist knowledge about therapies and prognosis. Shwachman's group was especially interested in the range of CF, particularly what came to be known as the pancreatic sufficient form of the disease (see later). He also developed what are still considered to be the foundations of medical management of CF, and together with Kulczycki published a clinical scoring system in 1958. Di Sant’Agnese and Andersen also pioneered the use of antibiotic treatments for CF.

In the UK it was paediatricians who initially developed an interest in CF. Winifred Young at the Queen Elizabeth Hospital, London, was one of the first. She was also a personal friend of Dorothy Andersen. The emphasis on generalism as opposed to specialism in the UK nevertheless meant that there was some resistance to special CF clinics being established. Even clinicians prominent in the CF field, such as Charlotte Anderson, who moved from Melbourne, Australia to set up a Gastroenterology and CF Unit at the Birmingham Children's Hospital around this time, were reputedly opposed to specialist CF clinics, and argued against this course of action in the early days of the CF Research Trust. In the 1950s and 1960s geneticists with a clinical interest in CF were also few and far between, although at Great Ormond Street Cedric Carter worked with Martin Bodian, pathologist, and Archie Norman, paediatrician, to produce a book about cystic fibrosis, entitled Fibrocystic Disease of the Pancreas: a Congenital Disorder of Mucus Production – Mucosis in 1952.

These institutional dynamics formed the backdrop to the emerging discourse of ‘classic CF’, which followed a range of studies which sought to distinguish typical and atypical cases of CF. CF in this period was usually presented as a fatal illness of childhood, characterised by chronic lung infections and digestive abnormalities. In the early days it applied to babies, whose failure to thrive, bronchial or pulmonary disorders and large, foul smelling stools formed the main hallmarks of the disease. Newborns with meconium ileus (intestinal obstruction) were also often diagnosed with CF on post-mortem. These diagnoses involved technologies as well as interpretation of patient history and symptoms. For example, in a study of CF cases seen at the Hospital for Sick Children in London from 1942 to 1950, Bodian and colleagues (1952) defined ‘clinical recognition’ of CF as dependent upon ‘the presence of both the characteristic alimentary and respiratory symptoms together with the absence or gross diminution of tryptic activity in duodinal secretions’ (1952: 17). The measurement of trypsin (a digestive enzyme that acts to degrade protein) in duodinal secretions (in the small intestine) was one of the main diagnostic tools in the field at this time, used to determine pancreatic function. It was, however, difficult to perform, because it required intubation of young patients. An alternative test which measured proteolytic enzymes (protein-splitting digestive enzymes) in the stools was subsequently developed, but this test was also difficult to perform, and unpopular with technicians (1952: 9). ‘Occasional mild or atypical cases’ (1952: 47) were recognised, but not privileged, as the ‘unity of the disorder’, manifest in abnormal mucous and lesions in the intestine, pancreas, salivary glands and respiratory system, was more important to the contemporary understanding of this relatively new disease category.

The sweat test reshapes classic CF

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Classic CF emerges
  6. The sweat test reshapes classic CF
  7. Milder forms
  8. CF as a genetic disease
  9. CF as a collection of related disorders
  10. Enter molecular genetics
  11. Discussion and conclusion
  12. Acknowledgements
  13. References

After a report that seven out of 12 infants experiencing heat prostration in the New York summer of 1951 had CF (Kessler and Andersen 1951), a group of CF workers, including the respected CF clinician, Paul di Sant’Agnese, investigated the reasons for the salt loss underlying their condition (Darling et al. 1953). Quinton (1999) notes that di Sant’Agnese presented his findings to the American Paediatrics Society in 1953, to a very small audience, but, ‘within five years, it was established that the uniqueness of this particular abnormal physiological function afforded a method for accurate, accessible diagnosis’ (1999: s4). This refers to the development of the sweat test, in particular the standard method of sweat collection by pilocarpine iontophoresis by Gibson and Cooke in 1958. In this method sweating is induced by pilocarpine which is delivered into the skin by an electric current and the sweat produced is collected and analysed for sodium and/or chloride content.

Around this time di Sant’Agnese posed the following question in a paper entitled ‘Fibrocystic disease of the pancreas with normal or partial pancreatic function’:

In the average patient the combination of symptoms of pancreatic insufficiency and of chronic pulmonary involvement leads to the suspicion of fibrocystic disease of the pancreas. Up to the present, definitive clinical diagnosis has rested on the demonstration of absence of pancreatic ferments in the duodenal assay. Now the question arises: Are there other patients who have the disease but do not show clinical or biochemical evidence of pancreatic involvement? (1955: 690).

Di Sant’Agnese went on to argue that ‘the generalized disease (ibid.) called “fibrocystic disease of the pancreas” may occur in patients in whom pancreatic function is normal’, paving the way towards a distinction between pancreatic sufficient and the more common pancreatic insufficient forms of the disease. Other CF workers, such as Peterson, also noted the ‘marked variability in the number of exocrine glands involved [with CF] and the degree of their involvement’ (Peterson 1959: 88) and characterised ‘the most commonly described patient’ as ‘the child with a recurrent or chronic lower respiratory infection that responds poorly to treatment and has steatorrhea’ (1959: 88) He went on to note that ‘Symptoms classically appear between 6 months and 2 years of age . . . Nearly all of these patients have chronic endobronchial disease and most have some degree of pancreatic insufficiency, but either condition may be mild or absent’ (1959: 88).

These clinicians’ efforts to highlight differences in the onset and range of the disease at this time, particularly the pancreatic sufficient form of the disease, made the case for the importance of the sweat test in diagnosing typical as well as atypical patients. It became the principal diagnostic test for CF during this period and sweat sodium and chloride content were incorporated into the clinical picture of CF, despite the fact that high salt content in sweat, for the most part, was not pathological in its own right (the exception being in situations where heat stroke is possible). The sweat test was particularly successful because it gave backing to an emerging unified hypothesis about the origins of CF; a hypothesis which took account of the variability of CF, and was to prove important in guiding further research inquiries. As Barbero and Sibinga argued, ‘As a result of the knowledge initiated by the discovery of the sweat electrolyte abnormality, the concept of cystic fibrosis of the pancreas has emerged as a familial disease with focal involvement of all the exocrine glands of the body’ (Peterson 1959: 221).

Paediatricians and biochemists worked together to develop the sweat test, focusing upon specificity, repeatability, safety and speed of diagnosis and more thorough studies of the differences in measurements between groups of patients. Problems with evaporation of samples and inadequate sweating were tackled by engineers, biochemists, manufacturers and clinicians (see NAS/NRC Report 1976). But even as late as 1976, an ‘ideal’ instrument was not established in theory or practice, with one study reporting that only 60 per cent of US CF Centres used the Gibson-Cooke method of quantitative pilocarpine iontophoresis (developed by Farrall Instruments Co. and Dr Harry Shwachman) (NAS/NRC Report 1976). Particular problems were found when the test was applied to the very young and newly emerging groups of adult patients (Anderson and Freeman 1959). The description of high concentrations of sodium and chloride eventually became CF with a sweat sodium level of over 60 meq/litre, although the use of sodium and chloride values, and sweat test performance in recognised laboratories was subject to considerable contestation and revision (1976). As the sweat test became more established, concerns were also raised by some specialists about misdiagnosis on the basis of a dubious sweat test results (Gibson et al. 1972, Shaw and Littlewood 1987). As Shaw and Littlewood commented,

The most common diagnostic error is the uncritical acceptance of an abnormal sweat test. It is important that this test is performed by a laboratory used to carrying out the investigation and that the results are interpreted correctly in the light of the patient's age, clinical findings and additional investigation. . . . It is important, therefore, to reconsider the diagnosis where typical clinical features are either not present or only mild, and to have two reliable sweat tests as well as evidence of malabsorption or pancreatic abnormality (preferably both) . . . Evaluation of problems in diagnosis is an important function of a cystic fibrosis referral centre (Shaw and Littlewood 1987: 1273).

This further emphasised the importance of standardised, specialised diagnostic services, fully integrated with treatment provision.

The application of the sweat test to prevention was also considered in its early history. Clinicians treating patients with CF had advocated marriage avoidance to reduce the incidence of CF, and advised parents with CF children not to reproduce further, but recognised that this was difficult for families to bear, so the possibility of a screening test was widely welcomed. Various reports suggesting that parents and siblings of children with CF had elevated sweat sodium and chloride levels that might be indicative of their carrier status (e.g.di Sant’Agnese et al. 1953) and adult population screening was suggested as a good preventative strategy. The extension of sweat testing to new-born or nursery screening was also explored (e.g.Kopito and Shwachman 1969). However, high costs and low detection rates, as well as the considerable overlap between the sweat test results from the so-called ‘normal’ population and the heterozygote CF population, meant that carrier screening was not pursued at this time. The main application of the sweat test was diagnosis.

Milder forms

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Classic CF emerges
  6. The sweat test reshapes classic CF
  7. Milder forms
  8. CF as a genetic disease
  9. CF as a collection of related disorders
  10. Enter molecular genetics
  11. Discussion and conclusion
  12. Acknowledgements
  13. References

During the 1960s and 1970s, CF specialists tended to describe CF in the following kind of terms:

When the classic findings are presented, the child with cystic fibrosis is unmistakeable. The failure to thrive, steatorrhea, chronic obstructive pulmonary disease and pancreatic insufficiency, accompanied by abnormally high concentrations of sodium and chloride in the sweat make the diagnosis definitive (Grand 1970: 588).

‘Mild’ or ‘variant’ forms of CF were, however, counter-posed to these classic cases, as clinical oddities, or fuel for further research, or a cause for speculation about genetic heterogeneity. The variability of CF was, in fact, recognised, from its early history. This is illustrated in the discussion of a child with CF called James R, age seven, in Bodian et al.'s 1952 book Fibrocystic Disease of the Pancreas, who is described as having ‘never really been ill’ (1952: 44). This book also contains pictures of ‘three children [with CF] who are doing well’ (1952: 46). In the text Bodian and colleagues highlight variations in the types of symptoms as well as their severity, referring to the 1949 work of May and Lowe, which they noted, ‘began by emphasizing the immense variety of symptoms that appear in fibrocystic disease of the pancreas and the variability and intensity of the symptoms both from child to child and at different ages in the same child’ (Bodian et al. 1952: 7).

More frequent reports of people with mild or so-called ‘variant’ forms of the disease appeared in the literature from around the late 1960s: as more cases were diagnosed, better treatments were developed, and research interest in CF grew. Changes in the extent and severity of gut and lung abnormalities were also highlighted. This is in part due to medical advances, which could lessen the severity of the disease, but also delays in its identification. As Kulczycki and Macleod noted, by 1961:

the classic pattern of the disease has also changed, since many of the clinical manifestations are conditioned by modern medical care which in many instances prevents or delays the appearance of manifestations or at least ameliorates the severity of the disease (1961: 85).

Antibiotics being used to treat chest infections are an obvious example of the changing medical care referred to here. Changing diagnostic strategies, and increasing awareness of the disorder amongst paediatricians, also meant that they identified milder cases more frequently. In 1970, for example, Brusilow detailed eight adults out of 140 patients with CF in his clinic, comparing this with data from other clinics, to conclude that, ‘approximately 5 per cent of all patients with cystic fibrosis survive past the age of 17’ (1970: 99). He went on to note that, ‘the extreme variability in severity of disease seen in children is also present in adults’ (1970: 100). By 1982, Barbero concluded: ‘cystic fibrosis has become a disease of adults. More than 50 per cent of the patients now live into adulthood and more and more cases are found in their thirties and beyond’ (Barbero 1982: 915).

This changing definition of CF was linked to various arguments, about the benefits of strict treatment regimes, the need for further research into the variability of the condition, or the need for better facilities and more resources for people with CF. Interestingly, these discussions also began to shift out of a purely clinical domain. By this time, organisations such as the UK CF Research Trust had already established a network of CF branches, regions and groups, to provide education and support and to raise funds for research. In the early 1980s adults with CF formed their own groups, linked to these organisations, to lobby for better facilities and access to insurance and mortgages. Although lay members were not represented on the CF Trusts’ Research and Medical Advisory Committee until the late 1980s, some CF adults have also shaped service provision for CF, particularly policies concerning treatment protocols and clinical standards. The US CFF also played an important role in the promotion of research into CF, and sets standards for accreditation for CF Clinical Centres in the US (Stockdale 1999).

Despite their emphasis upon better research and service provision, some adults with CF have expressed opposition to the hype surrounding gene therapy and antenatal screening for CF, which developed since the late 1980s when the gene was identified (see below). As one adult with CF who is a prominent member of the CF Trust commented:

. . . what you have to say is that the termination of the pregnancy must be for a serious life threatening condition. Children born today are going to live 50 years. Is that now a serious life threatening condition? It's probably no more life threatening than diabetes or asthma, and therefore can you really then say that these kids are suffering from that kind of condition? The prognosis has improved so much, just because they need life-long treatment, doesn't mean they are going to live short lives, and that is going to keep going up.

Stockdale (1999) also highlights the ambivalence of some US-based CF adults towards fund raising by the CFF in the 1990s, especially the privileging of the search for a genetic cure and the portrayal of CF as a disease of childhood. Some CF adults have also been critical about the lack of support for people living with CF, and have stressed the need to focus upon basic service provisions, such as drug treatment and physiotherapy. By raising questions such as these, and highlighting improving prognosis, adults with CF are actively participating in the definition of CF, the development of appropriate diagnostic strategies, and the management of the disease. This has changed the priorities of both the CF Trust and the CFF to some extent, as both are now more focused upon a broad programme of research rather than the Holy Grail of genetics, and services for adults as well as children with CF.

CF as a genetic disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Classic CF emerges
  6. The sweat test reshapes classic CF
  7. Milder forms
  8. CF as a genetic disease
  9. CF as a collection of related disorders
  10. Enter molecular genetics
  11. Discussion and conclusion
  12. Acknowledgements
  13. References

The characterisation of CF as a classic Mendelian recessive disorder also occurred relatively early in the history of the disease, from the 1950s onwards. CF was often presented as the most common lethal recessive genetic disease in Caucasian populations in the 1960s, as statistical evidence of the mutation frequency accumulated. As time went on, however, CF was described as ‘one of the most common’ (as opposed to the most common) ‘life-shortening’, ‘serious’ diseases or a ‘semilethal’ (Anon 1979: 626) disease. By the 1980s and the 1990s, the emphasis seemed to move to the frequency of CF in ‘white’ populations or populations of particular countries. For example:

CF is a chronically debilitating, autosomal recessive disease that affects the respiratory, gastrointestinal, and reproductive systems. It is the most prevalent, life-shortening, hereditary disease among white children (Cono et al. 1997: 1).

These descriptions of CF changed as the life-expectancy of people with CF increased (a change which was usually attributed to improved treatments and early diagnosis), and more detailed knowledge of the mutation rates (including those of other diseases) developed. Sensitivities about ethnic labels may also have played a part in this changing discourse. Growing awareness amongst the medical profession of their tendency to focus on ‘white’ as opposed to ‘black’ diseases (e.g. sickle cell) might be a factor in this story (see Wailoo (1997) for further discussion).

The discourse of heterozygote-advantage was also apparent in the CF literature, mainly from the 1970s onwards. Some CF workers suggested that CF carriers might have higher resistance to tuberculosis (Crawfurd 1975) or influenza (Shier 1979), and that this might explain the presence of the genetic mutation in particular populations. This supported the characterisation of CF as a classic Mendelian recessive disorder, without contradicting the wider scientific discourse of selective advantage, but it remained a theoretical rather than empirical case.

As we might expect, however, heterozygosity was more often invoked in relation to the prevention of CF through antenatal screening. The development of amniocentesis for chromosomal abnormalities and the liberalisation of abortion legislation across the West meant that considerable attention was also given to antenatal testing for CF during the 1970s. Several groups tried to develop an antenatal test for CF, based on biochemical analysis, in this period. Although these tests could rarely be reproduced outside the authors’ laboratories and were associated with high rates of false positive and negative results, their promise amongst CF workers was powerful, because of the potential to prevent the suffering with which CF was associated (Dodge and Ryley 1982). Particular emphasis was placed upon recognising the psychological problems of CF patients and their families (Gayton and Friedman 1973).

CF as a collection of related disorders

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Classic CF emerges
  6. The sweat test reshapes classic CF
  7. Milder forms
  8. CF as a genetic disease
  9. CF as a collection of related disorders
  10. Enter molecular genetics
  11. Discussion and conclusion
  12. Acknowledgements
  13. References

An alternative discourse of CF as a collection of related disorders, as opposed to a single disease entity, also ran alongside these discussions of classic disease, mild variants and heterozygosity. Once again, the dilemma of whether CF is one disease or many is not new, and can be found at various points in the history of the condition, dating back to early discussions in the 1940s. As one scientist, who began working on CF in 1962, recalled in interview:

. . . I think for those of us who've worked in the disease for many years, we always realised that it wasn't all one disease. We always knew that it was more than one disease. We suspected that there would be mutations. I don't think that we quite realised the extent of the ramifications. I know I didn't.

This dilemma intensified as work on cell cultures and serum in the 1960s and 1970s was interpreted as suggesting a heterogeneous genetic effect. Danes and Bearn's (1968) work in the 1960s on cilia activity on CF fibroblasts, led them to propose a three-tier typology of CF which supported the theory of multigene involvement, and underlined the importance of their quest to develop a new diagnostic tool for CF which took these types into account. In the words of Brimblecombe and Chamberlain, ‘This may lead to the conclusion that CF may not be a single entity but rather a group of closely related disorders with similar pathological consequences’ (1973: 1428). As Gurwitz and colleagues (1979) put it: ‘some investigators have questioned whether cystic fibrosis is not just one disease but a disease of different genetic types, indicating more than one gene local’ (1979: 604). Speculation about the possibility of one or more gene can be found throughout the 1980s, as in the review article by Beaudry, where he asks: ‘Which gene or genes, can explain all of the above inconsistencies?’ (1987: 5).

Enter molecular genetics

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Classic CF emerges
  6. The sweat test reshapes classic CF
  7. Milder forms
  8. CF as a genetic disease
  9. CF as a collection of related disorders
  10. Enter molecular genetics
  11. Discussion and conclusion
  12. Acknowledgements
  13. References

In the early days of the new genetics, the identification of the CF gene was often cast as the solution to the confusion surrounding these different aspects of the disease. The problems with the ‘subjectivity’ of existing tests (Brock 1985: 93) were frequently highlighted, as was the frustration with current knowledge in the field (Anon 1985: 249). As new techniques of reverse genetics developed the older biochemical studies were described by one CF worker as ‘the scenic route’ to identifying the basic defect (Welsh and Ramsey 1998). As Kolanta (1985) also noted at the time, much emphasis was placed on the need for a fresh approach so ‘the challenge posed by the elusive cystic fibrosis gene is rapidly assuming the status of a virility test for the new genetics’ (1985: 167). This stimulated considerable interest in CF genetics, and saw the entry of a range of research groups without a prior interest in CF. Competition between molecular geneticists to identify the gene was intense.

As information about sites close to the CF gene became available in the mid-1980s it was rapidly applied to antenatal testing in the first trimester in cases where parents were known to have a one in four risk and already had a CF child. This test was also offered to close relatives of people with CF. Robert Williamson, David Brock and others have noted that CF scientists and clinicians and affected families involved in organisations such as the CF Trust in the UK had formed close relationships. They have argued that these families were keen that their DNA was used to establish linkage and develop antenatal testing. There was also considerable hype about the possibilities of more widespread heterozygote screening around this time (e.g.Beaudet 1990).

The CF gene locus was identified in 1989 and largely superceded these linkage analyses. A large array of further research which identified other CF mutations (Welsh and Ramsey 1998) and the documentation of the distribution of mutant alleles in human populations through the CF Genetic Analysis Consortium (1990) (Scriver and Fujiwara 1992) followed. Antenatal screening was, however, slow to develop, for a range of technical, institutional and political reasons. In the UK, this was partly because antenatal screening came onto the agenda at the same time as postnatal screening (although the later does not involve DNA technology). Postnatal screening has long been favoured by organisations such as the CF Trust, but evidence of its effectiveness has been patchy. Even although its cost effectiveness can be clearly demonstrated, antenatal screening did not gain a comparably large support base in the UK because many CF clinicians and, indeed, families with CF, are not enthusiastic about its widespread provision, and lobbying for postnatal screening has been more successful. Its development is, however, still on the agenda of the National Screening Committee. In the USA antenatal screening is now widely available, but its introduction has also been problematic because of difficulties with matching common mutations with particular population groups, and inconsistencies between genotype and phenotype. Recently it became apparent that some women have been given amniocentesis, and sometimes terminations, on the basis of dubious mutation analysis (Concor 2003). As one US-based CF specialist commented in a discussion where he expressed qualms about antenatal screening:

It is very important that parents understand the range of phenotypes associated with this disorder even those that carry the common mutation which causes severe – the classic form of the disease – but the classic form of the disease has a range, and I have no way today, and nor does anyone else, of telling you where your child is going to be [on that range].

In fact, CF families are often well informed about the complexities of this kind of genetic information. Living with CF involves dealing with this information in the context of their relationships and priorities. This can mean choosing to ignore or to embrace genetic knowledge. Antenatal testing is far from the simple solution to CF that some of its advocates imply (see Duster and Beeson 1997). In the USA, unresolved tensions also exist, within families and professional circles alike, about the prioritisation of antenatal and postnatal screening for CF.

Qualms about predictive screening notwithstanding, in the late 1990s the ‘classic diagnostic triad’ of CF (Davis et al. 1996: 1229) still consisted of the ‘abnormal sweat test result, pulmonary disease and pancreatic disease’ (1996: 1229). Interestingly, it does not seem that the identification of the gene ever really raised the possibility of a new definition of classic CF on the basis of genotype, rather than phenotype. This was largely because, as suggested above, genotyping did not necessarily simplify the process of CF diagnosis. As Bonnefort and colleagues argued in a 1997 paper:

Whatever the power of molecular biology, the diagnosis of CF in index cases with a classic phenotype continues to rely primarily on clinical findings and the sweat test. Whether all diagnosed CF patients should be genotyped remains a matter of debate (1997: 63).

Wallis (1997) also pointed out:

Since genotype analysis has become a major player in the diagnostic armoury for cystic fibrosis, the situation can remain as confusing and clinics are increasingly facing the question: does this patient have cystic fibrosis? (1997: 85).

The terms of classic CF nevertheless had to be renegotiated in response to these new genetic identifiers. This occurred in two main ways. First, genetic evidence for CF was incorporated into the diagnostic process at a subsidiary level to that of the ‘gold standard’ (the sweat test). For example, the Cystic Fibrosis Foundation in the US altered the diagnostic criteria for CF to incorporate the genetic mutations as one part of the evidence for CF in 1997, as represented below:

Criteria for the diagnosis of CF

One or more characteristic phenotypic features

 – or a history of CF in a sibling

 – or a positive newborn screening test result

AND an increased sweat chloride concentration by pilocarpine iontophoresis on two or more occasions

 – or identification of two CF mutations

 – or demonstration of abnormal nasal epithelial ion transport.

Second, genotyping meant that additional features of CF became more prominent in the definition of classic CF. One obvious example, which is extensively discussed in Kerr (2000), is the foregrounding of a form of male infertility as part of classic CF. For example, Wallis (1997) describes ‘classical cystic fibrosis’ as consisting of ‘bronchiectasis, pancreatic insufficiency, male infertility and hepatic cirrhosis’ (1997: 86). Note also that this version of classic CF has shifted to take account of features of CF commonly found in later life, as the life-expectancy of people with CF increases. This foregrounding of male infertility in some accounts of classic CF involved a transition from research to diagnosis; this has, however, had a mixed reception amongst clinicians in particular. Initially, researchers with a primary interest in infertility investigated the genotype of men with a form of infertility similar to that of men with CF – congenital bilateral absence of the vas deferens (CBAVD). They then went on to the identification of mutations on one or both cystic fibrosis transmembrane regulator (CFTR) genes or an incomplete mutation in a non-coding region of this gene in these CBAVD men. CBAVD had long been known to be a diagnostic indicator of CF, but when it was included in clinical criteria that form a part of the overall diagnosis of the disease, it was with some caution, because of concerns that CBAVD should not be accompanied by other signs of the disease before it became the basis for diagnosis (e.g.Rosenstein and Cutting 1998). In clinical practice CBAVD was even sometimes ignored (Sawyer et al. 1998).

Since then, some CF clinicians and scientists have pulled back further from treating CBAVD as a form of CF, as this extract from an interview with a leading CF specialist demonstrates. This is part of a discussion about the shift from understanding CBAVD (sometimes also known as Congenital Absence of the Vas Deferens or CAVD) as a mild form of CF to conceptualising it as a CF-related disorder:

We can look at CAVD as having a mild CFTR contribution but depending more on other [genetic factors]. So is it [the result of] the CFTR mutation? I mean it's a different question. But is it CF-related? Yes. The reason is that you will look at this group of patients as a whole, some of them do have CF symptoms, very mild symptoms . . . But then as I said they are affected by other genetic factors, so there's a spectrum, so many of them are normal, and not CF, if you use those terms. There's a spectrum of those people, so whether they are in or out, I think it is a clinical definition.

The large numbers of CF mutations (now in the region of 1,300) has also fuelled the discourse of CF as a clinical continuum or number of related disorders. Additional information on differences in patients with the same genotypes, from the same families, were also taken to suggest that there was, in the words of Estivill and colleagues (1995), ‘a wide spectrum of clinical differences observed in CF patients with the same CF transmembrane conductance regulator genotypes’ (1995: 331). This leads on to speculation about the influence of other genes on CFTR (e.g.Harris 1998), and research into so-called ‘modifier genes’ (e.g.Drumm 2001). This further problematises the use of genetic technologies as a form of diagnosis. However, more recent research which has highlighted an increased incidence of CFTR mutations in people with conditions such as bronchiectasis, chronic pancreatitis, allergic bronchopulmonary aspergillosis and chronic rhinosinusitis, might also be used to promote the extension of CF screening to a wider range of ‘at risk’ groups, on the basis that it might offer clues for the development of targeted drug treatments of these conditions (Super 1999).

Clinicians working closely with people with CF have a range of responses to these kinds of genetic developments. Some are closely allied with molecular genetics work, and are keen to see its development in the clinic. Others are more sanguine about its potential to help in the diagnosis and treatment of the disease. As Sawyer and colleagues (1997) commented, information on CFTR mutations associated with mild disease is ‘very interesting for the CF scientist, but particularly daunting for the CF clinician’ (1997: 7). Tensions are also evident around clinical versus research priorities where CF is concerned. For example, although one UK CF clinician with a strong track record in scientific research spoke in interview of his admiration for the ample funds for clinical scientific research in the US, he also wryly commented that there are ‘so many scientists that . . . I could see a CF patient fighting her way through them to get to the doctor’. Another adult chest physician commented in interview:

I think the money in CF research basically needs to go into two pots, one is to find a cure for the condition, which is the genetic stuff, but the rest does need to go into improving treatment, because we know that in 1938, 70 per cent died within a year of birth, the average survivor, in this country, now is 31 years. That is not due to genetics treatment or gene therapy, this is special-centre care, better techniques of physiotherapy, better antibiotics, better nutrition, probably transplantation just beginning to come in, I mean we've been doing that for 14 years now . . . so that alone isn't responsible for the improved survival. If you look at those survival curves they’re doing this and this is good routine treatment and so I think there's a large proportion of the research budget should go into that as well as into gene therapy.

Here, new developments in the treatment of lung disease, including transplantation, are cited as more important in improving the lives of people with CF than the identification of the CF gene and the promise of gene therapy. As for some CF adults who are involved with organisations such as the CF Trust, treatment and service provision remain a strong priority for many clinicians. This means that genetics might be one route to better diagnosis or improved treatment of lung disease and other disorders associated with CF, but it is far from a miracle cure.

Discussion and conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Classic CF emerges
  6. The sweat test reshapes classic CF
  7. Milder forms
  8. CF as a genetic disease
  9. CF as a collection of related disorders
  10. Enter molecular genetics
  11. Discussion and conclusion
  12. Acknowledgements
  13. References

This short review has shown that CF is a dynamic entity, whose various meanings and interpretations are shaped by a range of social and material actors, including professionals, patients, technologies and bodies. Diagnostic strategies obviously change as time goes on. This is not simply a matter of heightened complexity or truthfulness, but of layer upon layer of social and material change. Our knowledge of CF has not solidified because of the entry of a particular professional group, diagnostic test or the stabilisation of certain bodily processes. Rather, CF can be associated with two key interpretive repertoires across its lifetime, from the notion of ‘classic CF’ to a more open-ended notion of CF as a set of diseases or a range of symptoms, from mild to severe. The defining features of these versions of ‘classic CF’ or what we might call ‘heterogeneous CF’ have changed across time, but they can also be seen to have changed according to the terms of discussion and debate at a more local, contextual level. These different discourses of classical and heterogeneous disease are not mutually exclusive, nor are they inherently contradictory. Instead they exist in a necessary tension throughout the history of CF, as scientists and clinicians pursue further research, refine typologies and establish new diagnostic standards. Their place in the discourse is tied to the technological and clinical arrangements that prompt each contribution to the literature, and they can be mobilised in quite different ways to support a particular argument (e.g. for or against screening).

Professional alliances and patient experiences and priorities have clearly shaped these accounts of CF, as have the introduction of new diagnostic strategies. These are also mediated by longstanding tensions between clinical and research priorities, diagnosis and therapy, and expansion and contraction of the disease boundaries. Even today the definition of CF remains open to revision, both in meta-exercises aimed at defining consensus (as in the CFF example) and locally, when clinicians grapple with the nature of CF on a daily basis. Although some scientists and clinicians with an interest in CF are devoted to a particular version of the disease over another, it is also striking that the dynamic and contextual characteristics of the definition of CF are well-recognised, and possibly even viewed as productive, by some.

Although we can identify particular historical developments with special significance, such as the development of the sweat test and the identification of the gene, in a broad socio-historical analysis these new approaches were far from revolutionary. Instead, as Keating and Cambrosio (2004) suggest, they were, ‘articulated and aligned in complex ways with existing biomedical platforms, as they became integrated into an expanding set of clinical-biological strategies’ (2004: 19).

It is particularly important to stress this wider context of negotiation and alignment when considering the impact of molecular genetics on the understanding, diagnosis and treatment of CF. A discourse of increasing uncertainty and risk measurement for a widening population of people whose conditions can be linked to the CF gene is clearly apparent in the molecular era. However, the emphasis upon uncertainty and expansion of screening for other populations as a means of prevention pre-dates the 1980s and can be found throughout the history of the disease. Running alongside this discourse of heterogeneity there is another set of arguments where CF is more closely identified as a classic disease, and identified with routine methods of diagnosis and treatment. Clinicians and, increasingly, adults with CF sometimes mobilise this discourse to query the hype of the latest CF discovery, genetics included. Tensions around the relationships between basic research and service provision are also long standing and far from unique to the molecular era.

It is, however, also important to note that certain features of these repertoires and relationships do seem to have intensified in recent years. It is only now, with the development of molecular genetics, that widespread antenatal screening for CF has become possible. Although the hype around the expansion of CF screening has not necessarily been realised in practice, because of a range of technical and financial constraints, the emphasis upon prevention, as opposed to clinical management of CF, is nevertheless reinforced as these screening programmes are planned and slowly implemented, and the population now under surveillance for being ‘at risk’ of CF is expected to expand. The recent focus upon CFTR-related disorders and screening technologies for these related groups echoes these themes of increased surveillance and prevention of CF and related disorders in the future.

As we might expect, however, these developments are far from uncontested, particularly by adults with CF whose links to CF clinicians and organisations have given them an inroad into the hitherto largely professional circles concerned with CF research and clinical priorities. One need not invoke biological determinism to recognise that the increasing life expectancy of people with CF has meant that they are more likely to challenge the experts and institutions who define, diagnose and treat the disease. This is partly because their age enables them to criticise and question professional approaches, as does their better health, and this is due, to some extent, to improvements in treatment. However, the culture of expert patients, as well as the increasingly complex network of professionals, funding bodies and commercial companies with an interest in CF, also allows for patients’ entry into negotiations over the definition and management of their illness. Patients’ individual health-management is likely to be a feature of these activities, alongside campaigning for better access to clinical and financial services. These interests in service provision, however, pre-date the molecular era, as does the challenge to the portrayal of CF as a disease of childhood. This means that active patienthood is not implicitly based on a renewed sense of the genetics of CF and/or an especially positive outlook on molecular diagnostics and cures. Indeed, precisely the opposite is sometimes the case, as adults with CF sometimes also challenge the hype surrounding gene therapy and antenatal screening in favour of a more positive image of CF as a chronic disease of adulthood which can be effectively managed through routine treatment. CF clinicians and scientists sometimes place a similar emphasis on the classic version of CF in an effort to secure resources for more traditional forms of diagnosis and treatment instead of the imagined futures of molecular treatments and services.

This means that it would be wrong to cast the more recent genetic approaches to defining, diagnosing or screening CF as radically different from those of the past. Although the increasing life expectancy of people with CF and the development of genetic screening have introduced new elements to the negotiation over CF research and clinical service, many of the values, tensions and priorities in the world of CF genetics can also be found in the early history of the condition. Genetics has not revolutionised the diagnosis of CF, which still relies on other clinical and diagnostic criteria, such as the sweat test. Genetics does not simply clarify or confound the nature of the disease. Indeed, the very notion of CF as a genetic disease is open to multiple interpretations, now as in the past.

What does this mean for the sociology of genetics, or of medicine more generally? This paper demonstrates, once again, that an empirical focus, across a considerable time frame, is important for unpacking the complex interplay of social, material and technological aspects of disease definition, diagnosis and indeed treatment. Such an analysis mediates against some of the more breathless claims about revolutionary discoveries or forms of life politics with which molecular genetics is sometimes associated, but also clearly demonstrates that shifts do occur in people's experience of illness and the ways in which their ailments are understood and managed. Furthermore, molecular genetics, like other developments in biochemistry and pathology before it, have played an integral part in these processes. The task now is to elaborate and fuse these types of socio-historical analysis to the many overlapping areas of biomedicine that remain to be subject to such close academic scrutiny, but are in many ways more important to healthcare delivery and people's experiences of health and illness than the latest ‘new’ development, such as molecular genetics.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Classic CF emerges
  6. The sweat test reshapes classic CF
  7. Milder forms
  8. CF as a genetic disease
  9. CF as a collection of related disorders
  10. Enter molecular genetics
  11. Discussion and conclusion
  12. Acknowledgements
  13. References
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