Vololona Rabeharisoa

Michel Callon

Angela Marques Filipe

João Arriscado Nunes

Florence Paterson

Frédéric Vergnaud

The dynamics of causes and conditions. The rareness of diseases in French and Portuguese patients' organizations' engagement in research

Keywords: Patients' organizations, rare diseases, France, Portugal, hybrid collective model, delegation model, singularization-generalization

Many actors in the field of rare diseases point to the role played by the notion of 'rareness' in the emergence and development of what we refer to as the 'hybrid collective model' (HCM) of collaboration between patients and experts. The HCM features two main characteristics: (i) the constitution of communities which bring together families and researchers as actors in the 'war on disease'; and (ii) organized cooperation between experts and patients' organizations in the production of knowledge on diseases. This article seeks to highlight the reflexive work carried out by French and Portuguese patients' organizations on the notion of rareness and its relation with the HCM. A systematic survey and fieldwork conducted in both countries have shown that such relation is neither systematic nor univocal.

Some patients' organizations point to the limits or the lack of relevance of rareness as a category for grounding their action. These criticisms have led us to envisage a more general dynamic: the choice of the HCM as a mode of involvement in a politics of singularizationgeneralization of causes and conditions. We suggest some possible consequences of this singularization-generalization dynamic in the conclusion.

Introduction

Several studies on patients' organizations have documented the emergence of new forms of intervention in biological and therapeutic research by patients and their families [START_REF] Barbot | Les malades en mouvements[END_REF][START_REF] Brown | Embodied health movements: new approaches to social movements in health[END_REF][START_REF] Dodier | Leçons politiques de l'épidémie de sida[END_REF][START_REF] Dumit | Illnesses you have to fight to get: facts as forces in uncertain, emergent illnesses[END_REF][START_REF] Epstein | Impure Science: AIDS, Activism, and the Politics of Knowledge[END_REF]Novas 2005;[START_REF] Rabeharisoa | Le Pouvoir des malades[END_REF][START_REF] Rapp | Genealogical dis-ease: where hereditary abnormality, biomedical explanation, and family responsibility meet[END_REF][START_REF] Silverman | Understanding Autism: Parents, Doctors, and the History of a Disorder[END_REF]. These new forms of intervention, in which patients collaborate closely with researchers, clinicians and industries, have two main characteristics: (i) the constitution of communities bringing together families and researchers as actors in the 'war on disease '; and (ii) organized cooperation between experts and patients' organizations in the production of knowledge on the diseases concerning them, which in some cases, can engender patients' active participation in research work. Based on our own work on these new forms of patients' organizations' engagement in research [START_REF] Rabeharisoa | The struggle against neuromuscular diseases in France and the emergence of the 'partnership model' of patient organisation[END_REF][START_REF] Rabeharisoa | Patients and scientists in French muscular dystrophy research[END_REF], we coin the term 'Hybrid Collective Model' (HCM), in contrast with the 'Delegation Model' (DM) in which patients take care of the emotional and social aspects of diseases and delegate what they consider to be strictly medical problems to experts.

The mechanisms that lead certain patients' organizations to adopt the HCM remain largely unexplored. The marginalization of certain diseases is one of the mechanisms most frequently identified. This process, which sometimes goes as far as exclusion, is said to be largely due to the characteristics of the pathologies concerned. Rareness is a characteristic frequently referred to both by patients' organizations and by social scientists who study these organizations [START_REF] Boon | The role of patient advocacy organisations in neuromuscular disease R&D -The case of the Dutch neuromuscular disease association VSN[END_REF][START_REF] Crompton | Rett Syndrome, rare diseases and UK research[END_REF][START_REF] Panofsky | Generating sociability to drive science: patient advocacy organizations and genetics research[END_REF][START_REF] Gizycki | Cooperation Between Medical Researchers and a Self-Help Movement: The Case of the German Retinitis Pigmentosa Society[END_REF]. The aim of this article is to discuss the validity of this explanation and to further our understanding of the role of rareness.

We begin by drawing on the existing literature to examine the relationships that have developed, at particular times and in particular countries, between rareness and the emergence of the HCM (section 1). We then show that patients' organizations themselves have emphasized the ambiguous nature of these relations. Our findings from systematic surveys that we have undertaken on French (section 2) and Portuguese (section 3) patients' organizations, complemented by field observations and interviews with members of these organizations, with researchers and with clinicians in both countries, show that certain nonrare disease patients' organizations appropriate the HCM. But, and more significantly, our investigations show that certain rare disease patients' organizations privilege other forms of engagement in research than the HCM, and/or introduce other criteria than rareness to characterize their conditions. This reflexive analysis undertaken by patients' organizations on the notion of rareness, which manifests itself not only in their discourses but also in their practices, highlights the existence of a tension, at the heart of their action, between a logic of singularization (aimed at defining what makes the specificity of a condition and of the problems encountered by patients), and a logic of generalization (aimed at demonstrating how a singular condition has much in common with many others) (section 4). The existence and management of this tension enable us to suggest why rareness has played a crucial role in the emergence of the HCM in certain cases, whereas it has not in others.

Exploring rareness and shaping a new model of engagement in research: the role of patients' organizations

1.1. From orphan drugs to rareness and to the invention of the HCM The social science literature reviewed above shows that the organizations of patients and their families concerned with rare diseases have played a relevant part in the invention and development of the HCM, and that they frequently refer to the rareness of their conditions in order to justify such a model. The movement started in the 1980s in the USA, when Abbey Meyers, the mother of a child with a rare disease, discovered that there was no indicated medicine for her child who had Tourette syndrome. Apart from purely economic considerations, as rare diseases often correspond to markets which are too small to be profitable, the absence of medication was a consequence of the system regulating clinical trials. This system prohibited the testing of molecules on populations considered to be vulnerable (children, pregnant women, people with dementia), or too limited in size (people with 'rare diseases') for the 'gold standard' of clinical trials to be applied to them [START_REF] Marks | The Progress of Experiment: Science and Therapeutic Reforms in the United States 1900-1990[END_REF]). This regulation prevented not only the development of therapeutic research on innovative molecules, but also a possible extension of indications of existing medicines to 'under-served populations' [START_REF] Epstein | Inclusion. The Politics of Difference in Medical Research[END_REF]. The pharmaceutical industry coined the term 'orphan drugs' (No authors 1968;[START_REF] Lyle | Letter: more on 'orphan' drugs[END_REF] for such products that were unable to attain viability and an economic existence. In order to raise awareness of the large numbers of people who were being deprived of medicines, Abbey Meyers undertook action to unite the 'rare diseases' patients' organizations in the USA, which coalesced as National Organization for Rare Disorders (NORD). The organization's main objective was to secure an amendment of the American legislation on clinical trials. This led to negotiations on the prevalence threshold below which diseases would be considered rare and industry would benefit from special arrangements for clinical trials, along with economic incentives to develop medicines.

In 1983, the threshold, set by the American Orphan Drug Act, defined as rare a disease affecting less than one person in 2,000 in a particular area or country. Thus defined, rareness became a compound concept that US patients' organizations helped to shape in direct relation to industry and the legislator. By becoming synonymous with situations of potential exclusion, rareness appeared as the cause of discrimination against patients, and thereby became a political issue. It was in the name of equity and social justice that actions aimed at reconfiguring relations between health and markets were undertaken.

Inspired by the North Americans, the European organization for rare diseases (EURORDIS), created in 1997 by four French 'rare diseases' organizations, including the AFM 1a pioneer in the field of rare disease patients' organizations in Franceadopted a discourse that directly linked orphan drugs to rare diseases as a means to demand a European regulation similar to that of the USA. The European regulation was promulgated in 1999, setting the same prevalence threshold as in the USA [START_REF] Crompton | Mode 2 knowledge production: evidence from orphan drug networks[END_REF][START_REF] Huyard | Quand la puissance publique fait surgir et équipe une mobilisation protestataire. L'invention des « maladies rares » aux Etats-Unis et en Europe[END_REF].

EURORDIS was also influential in structuring the collective mobilization of rare disease patients' organizations in Europe. In both France and Portugal, EURORDIS facilitated the creation of national alliances on rare diseases, grouping together patients' organizations.

These alliances mobilized to develop actions based on the principles of equity and social justice, and protested against the fact that the rareness of diseases was all too often equivalent of patients' exclusion. The strength of these alliances was based on what we call a 'politics of numbers', summed up in their slogan 'Rare diseases are rare but rare disease patients are many', a motto designed to show that these pathologies are a major problem for public health.

1 Association Française contre les Myopathies -French patients' organization against myopathies.

From the point of view of certain 'rare disease' patients' organizations and alliances, this therapeutic innovation. The HCM is both an organizational and a political response to this situation, deemed to be unacceptable by rare disease organizations.

1.2. What is rareness the cause of? From rareness to the 'rare diseases concept'

The link that was established at particular times and in particular countries by particular organizations, between the rareness of conditions on the one hand and, the invention and implementation of a model of engagement enabling patients to solve the problems that they encounter on the other, has gradually been reassessed by the patients' organizations themselves. The interviews that we conducted with members and representatives of these (vi) due to their complexity, many rare diseases raise challenging scientific questions that are still to be solved.

The new depiction of rare diseases not only lists commonalities between these conditions.

It also echoes the variety of problems that patients and their families struggle with in their daily lives, and suggests the diversity of actions that should be undertaken to overcome their problems. Particularly, EURORDIS used this 'rare disease concept' to call for a European recommendation for National Plans for Rare Diseases which articulate research, clinical medicine and social support for patients and their families. From the point of view of national alliances on rare diseases, the concept implies that their social and political advocacy mission may no longer stand without research advocacy [START_REF] Dresser | When Science Offers Salvation: Patient Advocacy and Research Ethics[END_REF]. This is what the French alliance reports on its website: "The Alliance has worked with the AFM on the creation of the Institute for Rare Diseases whose mission is to promote, develop and coordinate research on these rare diseases"4 . On Rare Disease Day 2011, co-organized by EURORDIS and the national alliances, the FEDRA (Federaçao de Doenças Raras de Portugal) announced that:

"Promoting investigation, creation of databanks and solid political intervention will allow a better future for these patients, so many times forgotten and marginalized"5 . However, the variety of situations experienced by patients, captured by the 'rare diseases concept', suggests that the articulation between research advocacy and social-political advocacy should be tailored to the specificity of the condition at stake. In particular, the 'rare diseases concept' helps patients' organizations to clarify the causes for which their action should, or should not be geared towards the adoption of the HCM. This manifests itself not only in organizations'

pronouncements, but also in their practices, as we will now demonstrate. paragraphs we outline the main findings of this research, to show how the organizations have adopted and adapted the HCM in different ways.

French patients

7

Our results show, first, the diversity of the organizations' modes of engagement in research.

Some go as far as to establish tight research cooperation with academic teams, while others are content with circulating scientific and medical information to make it available to patients and their families, or else to supply the specialists with questions and data, without ever organizing a full-blown collaboration between patients and professionals. In the former case one can talk of a form of involvement that is very close to the spirit of the HCM; in the latter, we witness instead the implementation of a model of delegation. Our results also show that this diversity of modes of engagement concerns both 'rare disease' and 'non-rare disease' organizations, even though the proportion of organizations that adopt the HCM is higher in the case of 'rare disease' than in that of 'non-rare disease' (however, the gap between them narrowed between 2006 and 2009). There is therefore not necessarily a relation between the rareness of conditions and the HCM.

This finding does not exclude the fact that rareness may have served as an incentive for certain 'rare disease' patients' organizations to implement the HCM, if only because of the structuring nature of the AFM' s form of activism, which many organizations see as a reference point. What these results suggest is that the 'rare diseases concept', because it fully acknowledges the difficulties experienced by patients suffering from very different conditions, is probably more relevant than the epidemiological notion of rareness in accounting for the diversity of patients' organizations' modes of engagement in research. The interviews that we conducted with members of certain organizations enabled us to show this with more clarity.

The 'rare diseases concept' and the variety of patients' organizations' profiles

Between 2009 and 2011, we conducted interviews and carried out ethnographic observations 8 in eleven 'rare disease' organizations (cf. Appendix 1).

We selected these organizations according to three criteria. Firstly, we chose organizations concerned with pathologies that differ with regard to both their prevalence and their characteristics. Two of them are actually concerned with diseases of which only certain forms are rare (the Association Lupus Francethe Association on Lupus, and the Association des personnes de petite taillethe Little People Association), and one of them is concerned with diseases that are similar and of which some are rare and others not (the Federation de recherche sur le cerveauthe Federation for Brain Research). Secondly, we focused on organizations that were created at the time of the structuring of the French associative milieu on rare diseases in the late 1990s and early 2000s, and excluded large pioneering organizations like the AFM. Thirdly, we used the findings of our surveys to sort contrasting organizations with regard their modes of engagement in research and the types of knowledge they target.

Our interviews and observations enabled us to distinguish four different engagement profiles, and in each case, to identify the reasons why the organizations concerned adopted 8 Participation to meetings and conferences organized with or by patient organizations, written material analysis (newsletters, information leaflets, minutes, websites, reports, etc.) them. They correspond to forms of intervention that the organizations considered relevant at some point in their struggle against their diseases, and are therefore not mutually exclusive.

• The first form of intervention aims at cognitively equipping patients so that they can deal with the problems they encounter. Teaching patients to be experts of their own diseases [START_REF] Epstein | The construction of lay expertise: AIDS activism and the forging of credibility in the reform of clinical trials[END_REF], capable of talking to doctors on an equal footing, of judging the validity of a therapy, and of anticipating the evolution of their pathologies or the side-effects of treatments, is an objective frequently mentioned by these patients' organizations. This form of intervention corresponds to the scarcity and dispersion of knowledge and information available on rare diseases. More significantly, patients' organizations that develop this mode of engagement said to be preoccupied with the low numbers of clinicians who can accurately diagnose their diseases and offer care to patients.

• The second form of intervention consists of financial or logistical support for research teams. The patients' organizations do not intervene directly in defining the project orientations or in running the operations, but neither do they simply transfer money without any concern for the content of research. Their financial support is the result of a process of identification and enrolment of research teams, involving multiple interactions with a view to aligning interests. Moreover, to avoid being dispossessed of their ability to make decisions and monitor the researchers' use of the resources they allocate to them, these organizations set up monitoring procedures that cause them to take an interest in the research subjects [START_REF] Rabeharisoa | The struggle against neuromuscular diseases in France and the emergence of the 'partnership model' of patient organisation[END_REF]. This is what the vice-chairman of the HPN France -Aplasie Médullaire (the French organization on paroxysmal nocturnal hemoglobinuria and bone marrow depression) was referring to when he stated that: "The patients are attached to their doctors [at Saint-Louis hospital in Paris] and to their molecules".

This mode of engagement stems from three observations: (i) the complexity of rare diseases and the need for longstanding investments in research; (ii) the existence of academic teams ready to investigate the conditions with which the patients' organizations are concerned; (iii) the need for ensuring that supported teams explore the biological pathways and entities that the patients' organizations deem important for a better understanding of their pathologies.

• The 'rare disease' patients' organizations' third form of engagement consists of bringing to the fore questions on which no research has as yet been undertaken. Often these are topics relating to the day-to-day preoccupations and experiences of patients, and which are situated on the periphery of biomedicine. The formulation of these questions is partly enabled by the efforts that have been devoted to clinical and therapeutic research. The results obtained have had the effect not of healing patients (cure remains rare), but of gradually adjusting the care they receive. The natural history of rare diseases has thus been altered. Some of them became chronic illnesses that generated unexpected problems.

That is why SolHand Solidarité Handicap -Autour des Maladies Rares (Association on disabilities induced by rare diseases), created in 2007, has chosen to distance itself from biomedicine and to focus rather on issues that its chairwoman qualifies as medico-social, ranging from assistive technologies to rare diseases patients' inclusion in the job market. In the conferences that she organizes, she privileges speakers who are rehabilitation therapists and researchers in human and social sciences.

This form of engagement aims at mobilizing researchers and professionals in the production of knowledge focused on solutions to problems that patients encounter in their daily lives, notably medico-social problems related to multidimensional impairments and disabilities induced by rare diseases.

• The fourth form of intervention concerns patients' organizations' participation in the production of scientific and medical knowledge. The organizations contribute to therapeutic research and are involved in the definition and evaluation of clinical practices.

Some organizations undertake studies on their members to collect data on their experiences and to compare it to scientific knowledge. That is for example the case of an organization created in 2008 for Tarlov's Syndrome (whose main manifestations are cysts on the sacrum), which launched a survey in 2009 on 173 patients identified via the French Alliance for Rare Diseases. At the time of our interview, its objective was to transmit the results of this survey to a researcher-clinician that it had contacted via the French Alliance, so that this 'anecdotal evidence' [START_REF] Moore | Experts and Anecdotes. The Role of 'Anecdotal' Evidence in Public Scientific Controversies[END_REF]) could be studied more closely.

If we look at the therapies, we note that certain organizations, even small and with limited financial means, actively involve themselves in designing clinical trials, liaise with the regulatory authorities, and recruit patients. That is for instance the case of the Association San Filippo that gathers families concerned with this serious and debilitating lysosomal syndrome, which entails a dramatically reduced life expectancy. It eventually imposed itself as a de facto co-promoter of one clinical trial.

Clinical practices are also activities in which certain 'rare disease' patients' organizations are proactive. For example, Generation 22, concerned with the 22q11 deletion syndrome, a complex syndrome involving heterogeneous disorders with multiple manifestations, participated in setting up the PNDS 9 . It monitored the implementation of this plan by organizing visits to the centres of reference for diagnosis and care on rare diseases 10 , during which the families related their experiences and concerns, mainly with regard to paramedical care (speech therapy, psychological help).

The patients' organizations that adopt this fourth mode of engagement enter the black box of complex biological pathways that are still unknown and remain to be explored. They thus contribute to a collective exploration close to the HCM that may result in the requalification and reclassification of their diseases. concept' for justifying their choices. The criteria underlying their actions are indeed those put to the fore by this concept: complexity of diseases and of their consequences, scarcity of expertise on diagnosis and care, lack of knowledge, etc. In the same movement, additional criteria such as the chronic nature of conditions and disability also emerge. Thus, depending on their conditions and according to their priorities at a certain moment, patients' organizations privilege certain forms of engagement over others.

In the following section, we continue to document this reflexive analysis undertaken by patients' organizations, by shifting our focus to the Portuguese case. This will enable us to further clarify the mechanisms that relate the issue of rareness to the implementation of the HCM.

Rareness put to the test by Portuguese patients' organizations

In We undertook a quantitative survey and a qualitative fieldwork in Portugal concurrently with the French survey, and using the same approach. Given the small number of patients' organizations formally active in Portugal 11 (113), all of them, whether they showed an interest in research or not, were included in the survey12 . Of the 34 answers received, 10 were from organizations that belonged to one of the two Portuguese alliances of rare diseases and/or said they were concerned with rare diseases [START_REF] Nunes | Patient Organizations as Emerging Actors in the Health Arena: The Case of Portugal[END_REF].

The majority of Portuguese organizations of patients and their families are support groups (25 out of the 34 respondents), whose main aim is to provide psychological support and practical assistance to patients. A significant number of them nevertheless show an interest in research13 : most of these organizations are concerned with rare diseases, although the nature and intensity of their engagement in research does not differ from those of 'non rare disease' organizations. The survey yielded two significant findings. First, those Portuguese organizations that explicitly refer to rareness often choose forms of engagement half way between the HCM and the DM. Second, those that develop the HCM have an approach aimed 11 In Portugal, contrary to the French case, there is no mandatory legal registry for patients' organizations. They are usually public utility organizations, private social solidarity institutions, or other kinds of associations and foundations.

at mainstreaming rare diseases, and at including them in more general categories of conditions and problems.

Portuguese 'rare disease' patients' organizations: between the DM and the HCM

Interviews with members of the ten 'rare disease' organizations in Portugal (cf. Appendix

2) revealed that they were often formed by doctors who had patients with these diseases.

These organizations were created as therapeutic groups before being transformed into selfhelp/mutual aid groups supported by the medical teams that had contributed to their creation.

This associative profile has had particular effects on the content, form and scope of the knowledge-related activities in which Portuguese 'rare disease' organizations engage. These activities have two distinct forms.

• All Portuguese 'rare disease' patients' organizations give high priority to the collection and dissemination of knowledge on diseases. These are the main means for raising awareness of the existence and seriousness of their pathologies, not only among medical and health professionals but also the general public. To this end, conventional tools are used: brochures sent to specialists, training activities for health professionals, participation in conferences, and dissemination of information in schools.

The experts involved in the Committee for the National Rare Diseases Plan we brought together in a focus group considered that 'stating the fact of rare diseases' is an important dimension of political advocacywhich, in their opinion, is one of the patients' organizations' main missions. Patients' organizations, on the other hand, value the help and the scientific authority offered by the experts from whom they seek advice in drafting their scientific and medical documents. This distribution of tasks and competencies is apparent in the status attributed to the patients' experiences. The specialists and professionals regard patient's experience as a form of knowledge that is different and complementary to scientific and medical knowledge. It helps them to understand the psychological and social impacts of diseases on the lives of the patients whom they see in consultations. Patients' organizations' point of view is not very different: most of them consider that the patient's experience is always singular and enables doctors to provide personalized care. Yet, even though testimonies circulate between patients and their families, no organization has, on its own initiative, undertaken a survey on its members with a view to producing and publicizing what is known as 'experiential knowledge' [START_REF] Borkman | Experiential knowledge: a new concept for the analysis of self-help groups[END_REF]).

• A second type of knowledge-related activity of Portuguese 'rare disease' organizations is their participation in projects or surveys launched by research institutions, and in clinical trials promoted by industry. In all cases, the organizations are more reactive than proactive. They respond to appeals made to them without intervening directly in the design and running of operations. The APPDH (Associação Portuguesa de Pais e Doentes com Hemoglobinopatias -Portuguese association of parents of patients with hemoglobinopathies), for example, participates in a project on patients' compliance with treatments and the control of pain in blood-related pathologies, in the framework of a programme launched and supported by the Portuguese national institute for health, involving various large hospitals in the country.

To sum up, one could say that the Portuguese 'rare disease' patients' organizations, along with the specialists who collaborate with them, constitute communities in which a strict division of roles and missions is observed. The social and political advocacy is handled by the former, while the research activities fall within the province of the latter. Thus, it is neither a pure DM, which excludes the idea of community, nor a pure HCM, which includes the constitution of a community but one with hybridization of competencies and prerogatives.

The choice of this middle way shows that, in the case of Portugal where rareness as an issue arrived with EURORDIS, the notion of rareness is not necessarily linked to the HCM. More interestingly, we are going to see that when certain Portuguese organizations adopt this model, they clearly reject rareness as a criterion justifying their choice.

Adopting the HCM and moving beyond the reference to rareness

The Portuguese case illuminates a debate, which is not as explicit in France, on the role that the notion of rareness ought to play in shaping the action of patients' organizations. This debate is triggered by the intervention of EURODIS in Portugal. It is expressed in two different situations: (i) first, on the occasion of the constitution of the two rare disease alliances, and with regard to the types of activity that ought to be promoted; and (ii) second, at the point at which certain rare disease organizations have to decide whether to join these alliances or not.

• In Portugal, the notion of rareness first appeared in the public sphere in 2006, when an organization called Rarissimas started to informally bring together the patients and families concerned with rare diseases. Its aim was to reveal the difficulties these people experienced in daily life, so that they could secure access to appropriate care. The arrival of EURORDIS in the country, in 2007, contributed to the formalization of this associative mobilization that very quickly split into two branches. Rarissimas and a few other organizations grouped together in FEDRA, while others formed a second alliance, APADR. The personal conflicts that led to this schism stemmed from disagreement over the meaning of associative action on rare diseases. FEDRA, which was mainly concerned with the management of life with a rare disease, invested in building a home for patients and their families who needed specific help and care. APADR, on the other hand, wanted to put the EURORDIS programme into action, concerning the structuring of research, the creation of centres of reference for diagnosis and care, the establishment of patient registries, and more generally the implementation of the Plan for Rare Diseases, the principle of which had been endorsed by the Portuguese government in 2008.

FEDRA's approach clearly indicates that rareness does not automatically imply a proactive engagement in research, notably the choice of the HCM. The case of organizations that join APADR and that subscribe to EURORDIS' politics favouring the HCM, is even more telling on the compounded relation between this model and the rareness of diseases.

• Certain member organizations of APADR do not (exclusively) deal with rare diseases, but they apply the 'rare diseases concept' to non-rare conditions in order to enable the latter to benefit from the innovative structures and forms of coordination that this concept promotes (such as the centres of reference for diagnosis and care and multidisciplinary consultations).

This is illustrated by the case of the APH (Associação Portuguesa de Pessoas com Hemofilia e outras Coagulopatias), the Portuguese organization for haemophilia and other congenital coagulopathies. As a founding member of APADR, this powerful organization, created in 1976, was clearly inspired by the European guidelines to strengthen its support for therapeutic research in a framework of collaboration with a pharmaceutical company, Baxter and Bayer, and to propose the creation of patient registries and of multidisciplinary consultations, not only for rare diseases but also for non-rare blood-related diseases. To justify its action, APH

explained that what matters is the complexity and the chronic nature of these pathologies. We thus see emerging causes that help to understand why non-rare disease organizations adopt the HCM.

• A second form of rare disease mainstreaming is defended by patients' organizations that consider the HCM to be relevant but openly challenge rareness as a criterion to justify it. This is for example the position of the Associação dos Doentes com Lupus, the Portuguese organization concerned with lupus. The organization stands as one exception in the Portuguese patient organization landscape by its adopting the HCM. A number of reasons are put forward by the organization for its choice: firstly, the uncertainty of knowledge about lupus, including its prevalence as an autoimmune disease, some forms of which are considered to be rare; secondly, the complexity of the disease; thirdly, difficulties of the diagnostic work; and finally, the fledgling nature of the treatment. The organization's chairwoman voiced the fact that it is not rareness that organizes patients' experiences, but certain characteristics that diseases conventionally defined as rare share with other pathologies considered as non-rare 14 . The organization goes further than this, explicitly excluding rareness as a criterion for grouping patients and as a relevant characteristic for action. From its point of view, the most important things are the chronic nature and the complexity of the condition and its consequencesmedical, emotional, social and professionalfor patients. The organization includes rare diseases in the broader category of chronic illnesses and wants them to be treated as such. Although defending the HCM in all its actions, it forms alliances with organizations or federations of patients' organizations concerned with chronic diseases, but keeps its distance vis-à-vis APADR, and refuses to join EURORDIS.

To sum up, the Portuguese experience confirms that rare disease patients' organizations are not necessarily oriented towards the HCM, and that this model does attract interest from nonrare disease organizations. Moreover, the case of the Portuguese organization on lupus shows that the choice of the HCM may come with a critique of the notion of rareness. Although this notion triggers a collective awareness of the existence of rare diseases in Portugal and of the 14 Huyard (2009) came up with similar findings on rare disease patients' experience in France.

importance of research to obtain better knowledge on complex pathologies, whether rare or not, it neither explains the reasons why certain patients' organizations engage in research, nor does it justify the modes of engagement they choose.

Rareness and the dynamics of singularization-generalization

The analysis of the French and Portuguese patients' organizations highlights the role they play in the definition of the conditions that they deal with. It also shows their ability to develop and implement certain forms of engagement in research, and to explain why their conditions justify certain modes of intervention. Emphasizing the problems that patients experience in their daily life (getting a diagnosis, identifying specialists etc.), some of them have put the focus on notions such as complexity, uncertainty, or the chronic nature of conditions rather than on their rareness. The (observable) relations that particular organizations develop between particular conditions and particular forms of engagement in research should thus be interpreted as the outcome of reflexive work carried out by these organizations (in relation to other actors such as public authorities, research institutions and industry). To understand the dynamics of these reconfigurations of causes and conditions, we consider, from a perspective similar to that of [START_REF] Dewey | Logic: The theory of inquiry[END_REF], this reflexive work of patients' organizations as an inquiry aimed at problematizing their conditions, while developing forms of action that provide (provisional) solutions to their problems.

To study this dynamic of problematization, we introduce the two notions of singularization and generalization and explore their essential tension. Singularization corresponds to a set of discourses and practices deployed by actors to investigate the more or less specific character of their problems, and whose definition cannot be separated from their own history (Moreira in press). Generalization denotes the reverse process, by which, to build collective causes, actors explore proximities between their singular situations. As we will see, this process of singularization-generalization illuminates patients' organizations' rationale for adopting and adapting the HCM, whether they are concerned with rare diseases or not. For the sake of demonstration, we will focus on a few French and Portuguese organizations that have explicitly embraced this process either in their pronouncements or in their actions.

Singularization

To illustrate the singularization undertaken by patients' organizations, the case of HPN France -Aplasie médullaire provides a notable example; its creation in 2003 was the outcome of reflection on the necessary singularization of two rare blood diseasesparoxysmal nocturnal hemoglobinopathy and bone marrow depression -, as compared to more common diseases. The organization split off from an older association that provided financial help and psychological support to families of patients hospitalized in the haematology ward at Saint-Louis hospital in Paris for a bone marrow transplant or a plasmapheresis. These treatments have been applied for many years to rare and non-rare blood diseases, especially leukaemia. HPN France -Aplasie médullaire had been founded by three adults with these two rare blood diseases, with the aim of finding less invasive treatments, better adapted to the specificities of their pathologies. During our interview, the organization's vice-chairman clearly described this singularization strategy underlying its action.

Defining the organization's field of competencies, he noted that the organization was meant for "young adults suffering from acquired rare blood diseases for which there exist therapeutics". It was precisely in order to single out these diseases that the organization actively contributed to the constitution of a French registry of patients concerned with these pathologies. The organization deliberately excluded patients suffering from related diseases (for instance leukaemia, myelodysplasia, or Fanconi's disease) that did not correspond to the criteria that it had defined. It was this same singularization strategy that led the HPN France -Aplasie médullaire to maintain exclusive relations with the ward at Saint-Louis hospital, which in turn contributed to an increasingly sound understanding of these diseases and facilitated therapeutic research. When an American firm contacted the ward a few years ago to test a new class of immunosuppressants called .imab, on PNH, the organization readily agreed. The head of the ward noted that, owing to this collaboration, "It took only five years between the screening of molecules, the proof of concept, the phase 3 clinical trials and the launching of the drug on the market". Interestingly, the rareness of these diseases 15 , a characteristic that distinguishes them from common blood diseases and which the organization brought to light, is now tending to become an inherent feature of their singularity.

The organization has therefore taken the decision not to join any 'rare disease' coalition, whether French or European (EURORDIS), to avoid being 'drowning by numbers', as its vice-chairman put it.

We also found this stubborn willingness to capture singularities and to draw boundaries in some of the other organizations in our surveys. This singularization process does not concern rare disease patients' organizations only, far from it. APH, the Portuguese organization for haemophilia and other congenital coagulopathies, is a telling example. APH was initially formed around haemophilia. Thanks to the emergence of the issue of rareness in Portugal, APH progressively opened its doors to patients suffering from certain rare blood diseases. As stated earlier, this extension however came with collaborations with specialists and industry that the organization was not used to in the past, with an aim at delineating the specificities of the conditions that today constitute its portfolio. Still another phenomenon illustrates this 15 500 people have been diagnosed with PNH in France, and the prevalence of bone marrow depression is 1/500,000 in Europe.

process of singularization: over the past few years, organizations have been created around singular or atypical forms of common pathologies, like certain child cancers or early-onset Alzheimer's disease among young adults. Close to 6% of our French population surveyed in 2006, and 11% in 2009, are organizations of this nature.

The process of singularization, the logic of which is to produce relevant differences, has obvious links with the notion of rareness, since it tends almost inevitably towards the constitution of strictly delimited populations. But whereas rareness implies a stabilization of the definition of the pathologyif only for it to be measuredsingularization, as a process of investigation intended to define pathologies and conditions better, suggests a dynamic of constant movement. At the heart of this process, collaborative research plays an essential part, notably when diseases are complex and evolving. Patients indeed not only formulate the problems they encounter; they also test solutions to their problems, thus contributing to the transformation of their conditions and their re-specification thereof, as manifested by the 'chronicization' of certain rare diseases that we mentioned above.

Generalization

The logic of investigation, which as we have just seen, lies at the heart of the process of singularization, simultaneously induces mechanisms of generalization, two main forms of which our fieldwork highlighted. These two mechanisms are very different from the 'politics of numbers'that is the addition of diseases and patients -, in so far as they are based, precisely, on the question of commonalities between the entities and the individuals that are to be aggregated.

• One form of generalization, which we could qualify as epistemic, has progressively transformed researchers' and firms' approach to so-called rare diseases. At a public hearing organized in 2011 by the French Parliamentary Office for Scientific and Technological

Choices on monogenic rare diseases, two researcher-clinicians vehemently argued that, because they display extremely specific phenomena, these diseases enable them to explore fundamental elements of normal functioning and dysfunctioning of certain biological pathways. They could also serve as 'disease-tests', even 'disease-models', for the study of these pathways. This form of generalization, which takes a strong interest in particular cases as they afford access to realities that traditional nosological classifications tend to hide and to mix up, is made easier with the patients' close collaboration and the constitution of hybrid collectives in which the patients are both the objects and the subjects of research. The patients' organizations see this status of patients transformed into 'models for experimentation' as a matter that needs to be treated with caution, as the chairman of the Association Ostéogénèse Imparfaite pointed out: "You can't deny the fact that our patients are guinea pigs"albeit voluntary ones who participate in their own investigation (as the case of HPN France -Aplasie médullaire shows) and therefore have a high scientific value. Because it carries the ferment of a possible generalization based on the ubiquity of certain biological mechanismsubiquity that researchers would like to prove -, singularization is also becoming attractive from an economic point of view with the upsurge of new regimes of innovation [START_REF] Callon | An essay on the growing contribution of economic markets to the prolifération of the social[END_REF]. Pharmaceutical firms, which for a long time gambled on the development of blockbusters, are increasingly focusing on markets that are differentiated yet based on shared technologies and knowledge [START_REF] Crompton | Mode 2 knowledge production: evidence from orphan drug networks[END_REF]).

• The second form of translation of the specific into the general that can be observed has Complexity, multiplicity and heterogeneity are the keywords of this strategy that leads Génération 22 today to join collectives of researchers and patients' organizations working on chromosomal syndromes with psychiatric symptoms. From its point of view, these alliances could lead to a revision of the prevalence of this syndrome, currently estimated at between 1/4,000 and 1/3,000. In particular, the organization believes that adults suffering from schizophrenia, a co-morbidity of the syndrome, could carry the 22q11 micro-deletion, which would have the effect of making the syndrome a borderline case in respect of rareness This 'politics of recombinant science' and the process of generalization that it induces however are not exclusively arranged around bio-entities. The Portuguese organization on lupus for instance, points to what its chairwoman considers as critical social issues like depression that patients, who are mostly women, undergo over many years and that leads them to be stigmatized as "lazy" and "self-victimized" individuals. ALF, the French association on lupus, voices similar concerns. In 2009, it participated in a conference with other rare autoimmune patients' organizations, and raised questions they share, including depression and pregnancy, for which it called for cooperation between biomedical researchers and scientists in human and social sciences. This preoccupation is also to be found in SolHand, which focuses on the emotional, psychological and social impacts of rare diseases.

To sum up, we can reasonably argue that the process of singularization-generalization is driven by a form of collective inquiry seeking differences and similarities, and requiring close collaboration between patients and specialists, in the spirit of the HCM. This explains why such as Huntington's disease or multi-systematized amyotrophy, around the exploration of the brain.

rareness, which designates a sort of frozen moment in this process, has been able to be (and still is) associated with the HCM, and at the same time why this association between the two may well vanish in the long run for certain conditions.

Conclusion

Our article sought to test a hypothesis, made by a number of patients' organizations, as well as by certain social scientists who study them, which posits that the rareness of diseases has led patients' organizations to become proactively involved in research. Based on the interand intra-national disparities we observed in France and Portugal, we considered the diversity of ways in which patients' organizations take part in research, and the role of the notion of rareness in their choice of a given mode of involvement over another. Before synthesizing the results of our analysis, we would like to revisit the methodology underpinning our surveys.

The aim of these surveys was not to compare national situations in order to see how contrasting contexts could explain different modes of involvement. The objective was more fundamentally to capture the intense reflexive work that patients' organizations carried out on the notion of rareness and on the links between this notion and the modes of action they chose to follow. This reflexive work led these organizations to think about the problems posed by their diseases, in other words to specify their conditions and the causes they wished to defend.

It is this dynamic of causes and conditions, which our surveys highlighted as crucial to patients' organizations' activism, that we described and analyzed.

The first set of results from our surveys concerned the ubiquity of the notion of rareness and, as such, its 'evidential' status in the choices made by patients' organizations regarding given forms of involvement in research. We have shown that many rare disease patients' organizations opted for other forms of involvement in research than the HCM, which supposedly prevails because of the rareness of their diseases. We also highlighted the fact that, conversely, some non-rare disease patients' organizations did adopt the HCM, thereby calling into question the relevance of the link between the rareness of diseases and the proactive involvement of patients in research. Finally, we gave examples of patients' organizations which, although they chose the HCM, explicitly denied rareness any role in their choice.

The second point that emerged from the surveys is that patients' organizations do not simply put the explanatory power of the notion of rareness into perspective; they also, and more significantly, elaborate new ways of characterizing diseases. The chronic and evolving nature of diseases, the complexity of clinical manifestations, areas of ignorance that they struggle to overcome, the search for diagnoses, and specialists' lack of competence, are raised by patients' organizations to justify their chosen modes of intervention in research. The abstract and formal notion of rareness is thus called into question by patients' reflection on the problems they encounter in their daily lives.

To account for both the historical role of the notion of rareness in the emergence of the HCM and the gradual shift, within certain organizations, towards other justifications for choosing this model, we examined the tension between singularization and generalization. We argued that these two notions emerge as the rationale underpinning the enactment of the HCM by some organizations, albeit not in a consciously expressed form. As we have suggested, the collective investigation organized and structured by the HCM seeks to identify diseases and the associated issues more and more specifically and precisely, while also facilitating and stimulating the connexions with other diseases, thereby giving the questions raised a more general reach. Rareness can beand often isassociated with the tension between singularization and generalization, of which it is a product rather than a starting point. The distinction is no longer between non-rare and rare diseases, but between organizations that choose to undertake this process of singularization-generalization and those which, for good reasons, prefer to think of the diseases they deal with as stabilized frameworks, and to develop their action without changing these frameworks.

In proposing that the singularization-generalization of causes and conditions is core to patients' activism, we must then identify the drivers of this dynamic, as well as its consequences. As we have shown, rareness is one of those drivers, which owes its strength to its capacity to make patients major political actors (of what we have called the 'politics of numbers') and scientific actors in their own right (of what we have called the 'politics of recombinant science'). The dynamic of singularization-generalization takes this in a direction that is likely to echo a more general movement, which simultaneously affects political and economic life. Singularization, a process very different from individualization [START_REF] Rosanvallon | La République des égaux[END_REF], can be viable and sustainable only if it simultaneously contributes to the construction of common causes. The same dynamic is witnessed in economic markets and innovation regimes they promote [START_REF] Callon | An essay on the growing contribution of economic markets to the prolifération of the social[END_REF]. By granting particular attention to this dialectic of singularization-generalization, patients' organizations would be in a position to participate in (and to benefit from) a more general trend affecting political and economic activities.

  public health problem was largely a result of the lack of both academic and industrial investment in research, what[START_REF] Hess | Alternative Pathways in Science and Industry: Activism, Innovation, and the Environment in an Era of Globalization[END_REF] and[START_REF] Frickel | Undone science: charting social movement and civil society challenges to research agenda setting[END_REF] have since called areas of 'undone science'. It was with an aim to fill this knowledge gap that they advocated patients' active engagement in research, as well as the creation of communities of patients and researchers united around a single objective: war on disease. The convergence between the notion of rareness and the HCM was promoted by certain influential actors, which made it a key element in their strategy 2 . This model is now considered by certain leaders of patients' organizations, researchers and clinicians that we met as a form of relevant action to fight against rare diseases.The history briefly outlined above shows that rareness has been explored, defined, andmobilizedby certain patients' organizations to highlight and explain the situation of exclusion in which people with rare diseases find themselves. It has served to legitimize political demands, in the name of equity and social justice. Instituted in the form of a threshold, rareness took on new meaning related to the absence of investments in research and 2 In France, for example, the AFM, created in 1958, was actively involved in research to put an end to what it called "the vicious circle of ignorance and indifference" (Paterson & Barral 1994; Rabeharisoa & Callon 1999; Rabeharisoa & Callon 2004). It was instrumental in the invention of the HCM, which it consolidated throughout the 1980s and 1990s, and in the creation of the French Alliance Maladies Rares and of EURORDIS. It contributed to developing strong ties, both in France and in other European countries, between the cause of rare diseases and the establishment of the HCM.

7

  The full results of these two surveys are available upon request to our team (MAPO Report -Mapping and Analyzing Patients' organization Movements on Rare Diseases, and EPOKS Report -European Patients' organizations in Knowledge Society, Centre de sociologie de l'innovation, Mines-ParisTech).

  By and large, our interviews and observations all confirm the diversity of rare disease patients' organizations' modes of engagement in research. This diversitywhich, in various ways, combines the translation of information, the monitoring of research, the formulation of questions and the production of knowledgeincludes the HCM but leaves room for intermediate forms of involvement between this model and what we have called the DM. Moreover, patients' organizations provide evidence on the relevance of the 'rare disease 9 Plan national de diagnostic et de soins = National Plan for Diagnosis and Care. 10 These centres of reference were created in the frame of the French National Plan on Rare Diseases in the mid-2000s.

  contrast to the French context, the issue of rareness was brought to Portugal from the outside and by EURORDIS. This top-down movement was a subject of debate among Portuguese patients' organizations, which have highlighted the contingent and questionable nature of the notion of rareness. The controversy has resulted, in particular, in the creation of two rare disease umbrella organizations, FEDRA (Federação de Doenças Raras de Portugal -Portuguese rare diseases federation) and APADR (Aliança Portuguesa das Associações de Doenças Raras -Portuguese alliance of rare diseases associations), with contrasting approaches. Before examining this aspect further, we examine the choices made by Portuguese 'rare disease' and 'non-rare disease' patients' organizations with regard to their engagement in research.

  gradually altered the self-description of the patients concerned and their families. The case of Génération 22 is interesting in this respect. The organization was formed in 1998 by the mother of a then young adolescent, born in 1983, who was diagnosed in 1996 with 22q11 deletion syndrome, a syndrome characterized by multiple organic, mental and psychiatric disorders. The manifestation and severity of disorders vary from one patient to another. The syndrome was not previously unknown but was diagnosed in patients scattered between different medical consultations, based on the most visible signs. In the literature, there are at least three labels and descriptions of the syndrome: DiGeorge syndrome, VCFS (velo-cardiofacial syndrome), and Shprintzen syndrome. The former chairwoman chose to name her organization after the deletion, discovered in 1991, because the main problem for the families is the complex and multiple combinations between heterogeneous that accompany this deletion. The organization thus embraces what[START_REF] Rabinow | Artificiality and enlightenment: from sociobiology to biosociality[END_REF] Gibbon & Novas 2008) calls 'biosociality'.

' organizations' response to the issue of rareness

	collecting, disseminating and comparing knowledge and information in the biomedical field
	as well as the more general health field. In 2006 we counted 497 organizations that met these
	criteria, 281 of which were 'rare disease' organizations and 216 'non-rare disease'
	organizations. This population has grown significantly in the following years: in 2009 it
	consisted of 650 organizations, 328 of which were 'rare disease' and 322 'non-rare disease'.
	A self-administered questionnaire was sent out in 2006 and in 2009 to these organizations,
	to collect data on the following: (i) their organizational characteristics; (ii) the actions that
	they undertook in the field of research; and (iii) the relations that they maintained with one
	another and with academic teams. A total of 215 organizations responded to the 2006 survey,
	2.1. French patients' organizations' adoption and problematization of the HCM
	In what ways have French patients' organizations translated the notion of rareness and
	their reflection on it into practice, especially in their forms of engagement in research? To
	answer this question we undertook a longitudinal survey in France -in 2006 and 2009 -with
	the following objectives: (i) to draw up a typology of the modalities of French patients'
	organizations' engagement in research; and (ii) to compare the forms of intervention of 'rare
	disease' and 'non-rare disease' organizations in research.
	Considering our objectives, we limited these surveys to those organizations -both 'rare
	disease' or 'non-rare disease' -whose discourse and practices reflected an interest in
	research	6 . By 'research' we mean not only laboratory work but also any activity aimed at

143 of which were 'rare disease' and 72 'non-rare disease'. In 2009, 293 organizations responded, 187 of which were 'rare disease' and 106 'non-rare disease'. In the following lists of associations registered by the Journal Officiel, websearch, etc.). The main directory was Annuaire des associations de santé®, which was created in 1996 and regularly updated (until 2008) by B. Tricot Consultant SARL, and listed all French non-profit organizations active in the field of medicine, disability and health (approximately 7000 at the time of our 2006 survey, of which about 2,000 patients' organizations). To identify the 'rare disease' patient organizations within this population, we used data from Orphanet, a web portal on rare diseases created by INSERM (the French research institute on medicine and health) and present today throughout the world, as well as the list of organizations that are members of the French Alliance for Rare Diseases.

  like to foster relations with organizations that deal with schizophrenia, to undertake work that could result in the production of generality on the basis of scattered observations focused on singularities. Such an inquiry closely relates to the HCM. It cannot but be collective, for the production of knowledge on complex and intersecting conditions involves an increasing number bio-entities, patients and specialists from various backgrounds. Patients' organizations are key actors in the mobilization and coordination of these multiple biosocial networks that entails what we call 'politics of recombinant science'.

	16 . It
	16 This attention to certain bio-entities brings to the fore the reconfiguration of nosological
	categories (Hedgecoe 2003; Rabeharisoa & Bourret 2009) as a new basis for translating
	specific concerns into general issues. When these entities are associated with genetic material,
	the re-classification resembles what Navon (2011) proposes to call 'genetic designation'. But
	other entities may be concerned. The French Federation for Brain Research (Fédération de

Recherche sur le Cerveau), for example, brings together organizations concerned with Alzheimer's disease, strokes and epilepsy, as well as less common neurodegenerative diseases would therefore

www.alliance-maladies-rares.org/

http://www.fedra.pt/

The survey population was identified by crossing different sources (directories, membership lists of umbrella organizations, lists of participants to workgroups, conferences,

The data collected in 2006 and 2009 show no noteworthy differences, probably because Portuguese civil society organizations developed much later than in France, after the transition to democracy in 1974. We have therefore mainly used data from 2009-2010.

In our survey, 11 organizations said they had a scientific committee or the intention to create one; 6 had raised funds for research;

had participated in research programmes; 5 had participated in clinical trials; and 19 had mobilized the public authorities for the development of research on their diseases.

Acknowledgements

This article is based on a European research project called EPOKS (European Patients' Organizations in Knowledge Society), supported by the European Commission FP7. We warmly thank all patients' organizations which participated to our surveys, as well as leaders of patients' organizations, researchers and clinicians who agreed to be interviewed. We owe a lot to our partners in this project, who took an active part in the discussion of our data and analysis. We are also grateful to the members of Centre de sociologie de l'innovation of Mines-ParisTech who offered thoughtful comments on a previous version of this article.


Louis Daniault
email: louis.daniault@institutoptique.fr

Marc Hanna

Dimitris N Papadopoulos

Yoann Zaouter

Eric Mottay

Frédéric Druon

Patrick Georges

Passive coherent beam combining of two femtosecond fiber chirped-pulse amplifiers

We propose and demonstrate an architecture that achieves passive coherent combination of two fiber femtosecond chirpedpulse amplifiers. The setup consists in the use of a well-balanced amplifying Sagnac interferometer. The experiment shows that the temporal, spectral, and spatial qualities of each beam are retained, with the generation of 250 fs pulses at 35 MHz repetition rate, an uncompressed average power of 10 W, and a combining efficiency of 96%. The behavior of this architecture in the presence of high accumulated nonlinear phase is investigated.

Ytterbium-doped fiber amplifiers have great advantages to amplify ultrashort femtosecond pulses. Indeed, their geometry offers a good thermal handling compared to bulk systems, allowing the generation of high average powers at high repetition rates. For most applications, fiber chirped-pulse amplifiers (FCPA) involve two stages. Starting from a high repetition rate oscillator that generates pulses in the 10 pJ -1 nJ range, a pre-amplifier allows to obtain pulses at intermediate energies of 10 nJ -1 µJ. A second power-amplifier is required to reach energies requested by most applications ranging from 10 µJ to 1 mJ at average powers of tens to hundreds of Watt level. [1][2]. This last step is challenging because nonlinear effects appear at high peak-powers, especially self-phase modulation (SPM), which can strongly deteriorate the pulse properties. For the last years, a lot of efforts have been made on designing fiber power-amplifiers with larger core sizes, known as large mode area (LMA) fibers. These fibers exhibit lower nonlinearity, thereby increasing the maximum output peak-power achievable while maintaining good temporal pulse quality. Unfortunately, this cannot be considered as a fully scalable solution, as it is limited by the appearance of higher-order spatial modes.

Another way to scale the output power consists in coherently combine the output beams of several amplifiers that are seeded by the same source. This has been demonstrated in continuous-wave [3] and recently experimented in nanosecond [4] and femtosecond regimes [5][6]. This approach is scalable by increasing the number of combined amplifiers, but requires an active control of the relative phase between them. This necessitates the implementation of a phase detection scheme, feedback electronics, and the insertion of a phase-controlling element in each amplifying arm. Passive coherent combination techniques have been investigated, but in this case the recombination is done within an oscillator [7], which limits their potential. Ultimately, a setup that performs passive coherent beam combining of amplifiers could be a real benefit for obtaining higher peak-powers with FCPA. We demonstrate in this paper the passive coherent beam combining of two femtosecond FCPA. This system has the same complexity and efficiency as the standard two-stage scheme, but distributes the power over two channels, thereby reducing power-related issues. The relative phase between the two channels is self-matched, and no active control is required. This is achieved by using a Sagnac interferometer that allows two identical pulses to travel the exact same path in opposite directions. This setup has already been used for other purposes, such as nonlinear optical loop mirrors [8], where a dissymmetry between the two paths is exploited. In our case, the interferometer has to be as symmetrical as possible to efficiently combine the beams. We obtain output pulses of 250 fs with 10 W uncompressed average power at a repetition rate of 35 MHz and a combining efficiency of 96%. We also investigate this scheme in nonlinear regime, and show that the combining efficiency is well maintained in the presence of self-phase modulation (SPM).

The setup is described in Fig. 1. The seed comes from an air-cooled Yb 3+ :KYW bulk oscillator that delivers 250 fs pulses at 35 MHz repetition rate. It is followed by a pulsepicker, and a stretcher that broadens the pulses to 150 ps. The beam is seeded into a Sagnac interferometer, whose output is directed to a compressor that exhibits an efficiency of 65%. All output powers and energies in this paper are given before compression to illustrate the important parameter which is combining efficiency. The interferometer is made of an isolator and a polarizing beam splitter (PBS) that divides the seed into two crosspolarized waves with same power. Each of them are seeded into a 1.6 m length Yb-doped double-clad 30/150 µm polarization-maintaining LMA fiber amplifier. The respective outputs are collimated and reinjected into the other fiber, in opposite direction. Half wave-plates are used throughout the setup to match the polarization of the beams to the fibers principal axes. The optical isolator allows both coherent combination and extraction of the combined beam from the seed path. The first PBS projects the two polarizations at 45° so that the beams can interfere, and its rejection corresponds to the uncombined part of the beam. The rotator and second PBS extract the combined beam out of the seed path. The combining efficiency is measured using these two outputs. At any time, each fiber amplifies two beams with different powers and propagation directions. They both work as pre-amplifier for one channel and as poweramplifier for the second one. The pumping is copropagative for the first pass, so that it is counterpropagative for the way back. This arrangement involves lower B-integrals due to SPM. The overall optical path length for one round-trip inside the Sagnac interferometer is 5 m. This implies that the setup is not sensitive to phase noise frequency below 30 MHz, whereas thermal and acoustic noises do not extend significantly beyond 10 kHz. The combination is thus very stable and robust to strong environmental perturbations. The setup has been operated first at 35 MHz repetition rate, with a total seed power of 300 mW. With 30 W total pump power, the output power is 10 W with a combining efficiency of 96%. The non-perfect efficiency is essentially due to mismatch in the beam profiles and amplified spontaneous emission (ASE). The output pulsewidth is well retained, with an obtained duration of 250 fs FWHM, as shown in Fig. 2. To investigate the dependence of the combining efficiency to SPM, the repetition rate is set to 1 MHz. At this point, the accumulated nonlinear phase becomes nonnegligible and must be the same for the two counterpropagating beams to retain a good combining efficiency. This is done in practice by adjusting the pump powers and injection conditions, as demonstrated in [9]. Considering that SPM mainly occurs near the output of the poweramplifier, each pump power controls the nonlinear phase of one of the beams, with little effect on the other one. This is observed experimentally, and the tolerance on the pump power to remain at maximum efficiency is about 100 mW. Figure 2 shows the spectrum and autocorrelation obtained at 10 W average power, corresponding to 10 µJ energy and estimated B-integral for each path of 12 rad. This high B-integral completely distorts the output pulse, but the corresponding combining efficiency is still 84%. This efficiency is plotted as a function of pulse energy in Fig. 3, at both 35 MHz and 1 MHz repetition rates. At identical output pulse energies, the difference in efficiency between the low and high repetition rate is due to the higher emitted ASE power at 1 MHz repetition rate. We observe a slow decrease of the efficiency with pulse energy, even with a careful adjustment of the pump powers. This effect essentially comes from the mutual reinjections between the two fibers, which are not perfectly symmetrical. The nonlinear propagation is strongly affected by this parameter, and the relative spectral phase between both paths features higher-order terms that cannot be tuned independently. The power spectral densities of each path also present significant differences, as the temporal shapes do, which impacts more loosely on the combining efficiency. These limitations might be partially solved by replacing the two fibers by a single one with adequate length. To illustrate the advantage of this amplifying architecture, we compare it to a standard two-stage scheme by inserting an isolator inside the interferometer. In this last case, the compressor length has to be shortened to minimize the pulse duration, which is characteristic of stronger SPM effects. The autocorrelations obtained at 2 W output power and 1 MHz repetition rate are shown in Fig. 4 both for the combined geometry and for the standard two-stage setup. The temporal distortions observed in the standard setup configuration do not appear in the combined case due to the lower B-integral, and the pulses remain Fouriertransform limited in the combined setup. Moreover, the measured power fluctuations of the combined beam are perfectly identical to the power fluctuations of each isolated channel, indicating that phase noise plays a negligible role in the output power stability.

The beam profile and the M 2 are shown in Fig. 5. The obtained beam quality is good in all cases, following a careful adjustment of the relative tilt and defocus in both arms. This alignment is crucial to obtain high combining efficiency. In conclusion, we demonstrated passive coherent beam combining of two femtosecond FCPA, with 96% combining efficiency in the linear amplification regime, and a good tolerance to nonlinear effects. The setup is equivalent to a standard two-stage scheme in terms of complexity, output power and beam profiles, but distributes the peak and average power-related issues over two amplification paths. Although this architecture can only combine two beams, other schemes are being investigated to scale the number of passively combined amplifiers.

The research described here has been supported by Triangle de la Physique contract 2009-026T.

Fig. 1 .

 1 Fig. 1. (Color online) Experimental setup. AOM : acousto-optic modulator. PBS : Polarizing Beam Splitter.

Fig. 2 .

 2 Fig. 2. (Color online) Autocorrelation power (top) and optical spectrum (bottom) of 10 W at 35 MHz (blue) and 10 W at 1 MHz (red) pulses.

Fig. 3 .

 3 Fig. 3. (Color online) Combining efficiency as a function of pulse energy at 1 MHz (red) and 35 MHz (black) repetition rates.

Fig. 4 .

 4 Fig. 4. (Color online) Autocorrelation for the standard two-stage architecture (black) and the combining architecture (blue).

Fig. 5 .

 5 Fig. 5. (Color online) Beam profiles and M 2 of one isolated channel (left), the second one (middle), and the combined beam (right).


L Daniault
email: louis.daniault@institutoptique.fr

M Hanna

L Lombard

Y Zaouter

E Mottay

D Goular

P Bourdon

F Druon

P Georges

Impact of spectral phase mismatch on femtosecond coherent beam combining systems

We experimentally investigate the impact of spectral phase mismatch on the coherent beam combining of two femtosecond fiber chirped-pulse amplifiers. By measuring the differential spectral phase, both linear and nonlinear contributions are identified. An accumulated nonlinear phase as high as 6 rad has been measured, for which a combination efficiency of 91% can be obtained by symmetrizing the pump and injection powers. This also allows us to quantitatively separate the spatial and temporal contributions of the non-perfect combining efficiency.

In ultrafast ytterbium-doped fiber amplifiers, the onset of nonlinear effects, especially self-phase modulation (SPM), implies limited pulse energies. One way to overcome this drawback is to use large mode area (LMA) fibers that are less subject to SPM effects at equivalent output powers. This core size scaling is limited by the appearance of higher-order transverse modes, thereby limiting the scalability. A solution to reach higher energies consists in coherently combining the outputs of several fiber amplifiers in free space. This approach has recently been demonstrated in femtosecond regime with two fiber amplifiers, both in active [1][2][3] and passive [4] architectures.

In contrast with CW [5] and ns [6] regimes, the efficient combination of femtosecond pulses requires the optical phase to be matched over the whole spectrum: in addition to the zero-order phase stabilization, the shape of the spectral phase must be identical in both arms. In the linear amplification regime (negligible B-integrals) and for pulses longer than 100 fs, this essentially means that the two first orders of the spectral phase, i.e. group delay and group-delay dispersion, should be identical. Experiments showed that a static adjustment of these quantities is sufficient to obtain good combination over hours [2] and high efficiencies up to 97% have been demonstrated [1]. However, all practical high-energy femtosecond fiber systems operate at non negligible B-integrals. In these nonlinear amplification regimes, the accumulation of SPM results in a distortion of the spectral phase profile. It is therefore important to investigate the compatibility of the nonlinear regime with coherent beam combining. In this Letter, we experimentally investigate the influence of dispersion and SPM effects on the coherent beam combining of two femtosecond fiber chirped-pulse amplifiers. Although coherent combining experiments with non-negligible B-integrals have already been demonstrated [2,4], no detailed analysis on dispersion and nonlinear phase management has yet been presented. In this Letter, a way to identify and quantify the various contributions to the non-perfect combining efficiency is described. The measurement of the relative spectral phase between both arms of the combining system allows us to precisely balance the SPM effects, resulting in a combining efficiency of 91% at a B-integral of 6 rad in each amplifier. This method also allows us to determine the spectral and spatial contributions separately. The experimental setup is described in Fig. 1. A femtosecond Yb 3+ :KYW oscillator delivering 200 fs pulses at 1030 nm and 35 MHz repetition rate is followed by an acousto-optic modulator and a stretcher that broadens the pulses to 100 ps. A half-wave plate with a polarizing beam splitter is used to divide the seed into two arms with adjustable input powers. The first arm consists of a fibercoupled LiNbO3 integrated phase modulator followed by a 1.6 m Yb-doped 30/150 μm large mode area (LMA) fiber amplifier. The second arm contains a 2.4 m single-mode fiber, a free-space delay line, and another 1.6 m of the same LMA fiber. The single-mode fiber is used to match the group-velocity dispersion of both arms, and also acts as a coarse delay matching element. Both amplifiers are seeded with 50 mW average power at 35 MHz and are pumped to deliver identical powers. The outputs of the fiber amplifiers are collimated and overlap on a 50/50 beam splitter. The constructive output of the beam splitter goes to the compressor that exhibits 65% efficiency. The rejected output is followed by a photodiode that detects an error signal to be minimized. The zeroorder active phase control system is the same as described in [3], with an improved bandwidth of 10 kHz.

By changing the reference phase of the lock-in amplifier in the phase control electronics by π, we are able to switch the 50/50 beam splitter outputs, so that both the combined and rejected beams can be characterized. At the output, the spectra of channels 1 and 2, along with the combined and the rejected beams are measured. The spectrum at the output is given by the standard interference expression for each frequency component,

) ( cos ) ( ) ( 2 ) ( ) ( ) ( 2 1 2 1 I I I I I ,
allowing us to retrieve the absolute value of the relative spectral phase ∆φ(ω) between the two incident beams. As opposed to single pulse complete characterization techniques such as frequency-resolved optical gating, this method is differential and includes zeroth-and first-order contributions of the relative spectral phase. It is therefore well-suited to measuring precisely spectral phase mismatch.

For reference, the system is first operated in linear regime at 35 MHz repetition rate. A combined output power of 12.5 W is measured before compression, corresponding to 92 % combining efficiency and stable for several hours. The autocorrelation of the recombined pulse is shown in Fig. 2, and corresponds to a 230 fs pulsewidth assuming a sech-square shape, a record value for a beam combining experiment. The absolute value of the relative phase is retrieved using the method described above, and is plotted in Fig. 2 along with the combined spectrum. The curve is fitted with the absolute value of a parabola

2 2 1 0 ) (
that takes into account the zeroorder phase, delay and group-velocity dispersion discrepancies respectively. In this expression, the zero frequency is set to be the mean frequency of the pulse. The fit coefficients exhibit a zero-order term φ0 = -0.3 rad, and a delay of 20 fs between the pulses using φ1. The second-order term, which mostly contributes to the efficiency losses, allows an estimation of the pulse duration discrepancy, but cannot be solely attributed to fiber length mismatch. Indeed, the mirrors in the setup are not GVD controlled, and introduce random amounts of second-order phase. Since the phase modulator tracks the maximum efficiency, the zero-order term φ0 is not null and set to partially compensate the high-order contributions. To control the validity of these measurements, we reconstruct the recombined spectrum using the experimental spectra of the two channels and the fitted spectral phase. The result is in excellent agreement with the experiment and corresponds to a combining efficiency of 97%. This implies that 3 % of the overall combining losses are due to spectral effects, while the remaining losses are related to polarization and spatial issues, such as wavefront and beam profile discrepancies and estimated here to 5%. The combining efficiency is also calculated with φ0 varying from 0 to 2π, which simulates the phase modulator tracking. Its curve exhibits a cosine shape with a maximum at 97 % and a corresponding φ0 = -0.2 rad, in good agreement with the measured value for φ0.

To investigate the nonlinear regime, the repetition rate is set to 1 MHz. In that case, each channel experiences a priori the same SPM effects, which should not affect the combining efficiency. In practice, the accumulated nonlinear phase is different, and leads to a significant drop of the combining efficiency. The spectral phase measurement provides a way to measure and compensate for this effect. For moderate SPM effects, the nonlinear contribution in the spectral phase can be expressed as proportional to the spectral shape [7]. With a spectrum shape normalized to 1, the related coefficient is directly the B-integral of the pulse. Considering similar spectra for the incoming pulses, as it is almost the case experimentally, the nonlinear contribution to the relative spectral phase corresponds to the B-integral discrepancy between the two channels, weighted by the initial spectra.

To take into account the nonlinear contribution to the differential spectral phase, the fit expression is modified as The study in nonlinear regime is performed in two configurations. The first series of measurements is realized by adjusting the pump powers so that both arms deliver the same output power. The corresponding output power is measured to be 8.8 W and exhibits 86 % combining efficiency, illustrating the nonlinearitiesrelated efficiency drop. The autocorrelation of the two initial and the recombined pulses are shown in Fig. 3 (left). The B-integral experienced by each pulse is estimated around 6 rad. The two incoming pulses do not exhibit the same temporal shape and have experimentally different compression points, although they present similar shapes at best compression. The spectrum of the combined pulses and its associated relative spectral phase are plotted in Fig. 3 (left). The B-integral discrepancy derived from the phase fit is ΔB = 2.5 rad and the zeroorder phase is now φ0 = -2 rad. The origin of this high value of B-integral discrepancy, despite similar output powers, is not well identified. Possible reasons include differences in injection conditions and polarizations at the input and fiber parameter discrepancy. The retrieved φ2 value is unchanged from the linear case. The delay value is 60 fs, higher than the 20 fs in linear regime. This additional contribution comes from dissymmetry in the combined spectrum that introduces odd-order terms, and can be partially compensated in the setup using the fine delay. The combining efficiency calculated from the spectral data is 90 %, implying here 4 % of spatial overlap related losses. In the second configuration, the nonlinear effects are balanced by tuning the injection and pump powers [8] together with the delay, in order to minimize the rejected power. This is achieved by observing the behavior of the uncombined spectral content and minimizing it carefully. In this situation, the two amplifiers do not deliver the same power and the related efficiency losses are 0.5 %. This new configuration exhibits a combining efficiency of 91 % with 9.2 W output power, i.e. only 1 % less than in linear regime. The autocorrelations of each channel and the combined beam are shown in Fig. 3 (right). The incoming and combined pulses now share the same shape and compression point. The autocorrelation FWHM is 410 fs, yielding pulse duration of 320 fs according to simulations. The combined spectra are plotted with the relative spectral phase in Fig. 3. Noticeable differences appear between the fit and the experimental data in the middle of the spectrum. This comes from differences between the arms in power (ratio = 0.7) and central wavelength (Δλ = 1 nm) that appear due to the injection condition modifications. The recovered B-integral difference decreases to ΔB = -0.4 rad and the delay to 25 fs. The second-order term still matches the linear regime and thus introduces the same losses. The efficiency calculated from the spectral data is 96 %, showing that the spatial overlap related losses still remain around 5%. Thus, the measurement allows us to improve the system efficiency by balancing the B-integrals in both arms. This operation is gainful even in the present case where it results in slightly imbalanced output power, because the efficiency is much more impacted by phase mismatch than by intensity mismatch.

) ( ) (
In conclusion, we demonstrate the coherent beam combining of two fiber chirped-pulse amplifiers with a high-accumulated nonlinear phase of 6 rad and show that the efficiency demonstrated in linear regime can be maintained. The measurement of the relative spectral phase provides a powerful tool to analyze different contributions to the non-ideal combining efficiency This analysis and identification provide guidelines to experimentally optimize coherent combining systems, even in the case of stretcher-free highly nonlinear systems systems delivering sub 100 fs pulses.

The research described here has been supported by Triangle de la Physique contract 2009-026T, and Agence Nationale de la Recherche through the Multifemto project.

Fig. 1 (

 1 Fig.1 (Color online): Experimental setup

Fig. 2 (

 2 Fig.2 (Color online): Autocorrelation of channels 1, 2 and combined beam (left); Spectrum of the combined beam and relative spectral phase between the two initial channels (right)

  ΔB the B-integral discrepancy and IN(ω) the normalized fit of one of the two incoming spectra.

Fig. 3 (

 3 Fig.3 (Color online): Autocorrelation of channels 1, 2 and combined beam (top); Spectrum of the combined beam and relative spectral phase between the two initial channels (bottom); Left: unmatched case; Right: balanced SPM effects.