reflexion-thematique-du-comite-d-ethique). The gender perspective is often neglected in biomedical research in France, as opposed to Anglo-American and other European countries. One of the objectives of this Group is to conduct ethical reflection on the influence of social and cultural factors on the differences and inequalities between the sexes in health and medical research practices.

It is important to encourage physicians to take the differences between men and women into account, not as a simple dichotomy between male and female, but as the result of intricate links between sex and gender (Fausto-Sterling 2000, 2012[START_REF] Springer | Beyond a catalogue of differences: A theoretical frame and good practice guidelines for researching sex/gender in human health[END_REF][START_REF] Krieger | Genders, sexes, and health: What are the connections-and why does it matter?[END_REF]. Such an approach can improve research practices and consequently increase knowledge about the origins of differences between women and men in health.

In the first part of this document, and in order to use concrete examples, we suggest some thoughts and recommendations for the consideration of gender in three disciplines:

-MRI neuroimaging (Catherine Vidal) -Cardiovascular diseases (Jennifer Merchant) -Assisted reproductive technologies (Mylène Botbol-Baum) [3] These thoughts constitute the beginning of the debate and have already elicited responses from the Committee that will be useful for future versions of this document which, like all Committee Memos, remains open to further development.

The second part includes a report on the Group's activities for 2014/2015, followed by its projects for 2015/2016. In the following sections, we will present some principles that may be useful when considering the relationship between sex and gender, and give examples of how this approach is likely to improve the practices of MRI brain research in both women and men. We will also propose recommendations for the design, analysis and interpretation of experiments (see Rippon 2014 for a detailed review of theoretical and practical issues in MRI research comparing female and male subjects).

The interaction between sex and gender

For more than 10 years, MRI studies on brain plasticity have accumulated to

show how experience and learning shape the brains of both children and adults [START_REF] May | Experience-dependent structural plasticity in the adult human brain[END_REF][START_REF] Vidal | Le cerveau évolue-t-il au cours de la vie ? Paris, Le Pommier Vidal C[END_REF]. The concept of brain plasticity provides a fundamental [4] neurobiological insight into the processes of social and cultural construction of gender identity. Sex and gender are not separate variables, but interact in a process of "embodiment", a term that describes the reciprocal interactions between biological sex and the physical, emotional, social, and cultural environment (Fausto-Sterling 2012ab, [START_REF] Fine | Plasticity, plasticity, plasticity…and the rigid problem of sex[END_REF]. Gender influences biology, and biology affects gender.

These interactions result in a wide range of personalities, cognitive skills and social behaviors, which reveal both differences and similarities between women and men [START_REF] Hyde | Gender similarities and differences[END_REF]). This diversity is reflected in the brain and can be detected by neuroimaging studies [START_REF] Kaiser | On sex/gender related similarities and differences in fMRI language research[END_REF][START_REF] Bluhm | New research, old problems: methodological and ethical issues in fMRI research examining sex/gender differences in emotion processing[END_REF][START_REF] Mueller | Individual Variability in Functional Connectivity Architecture of the Human Brain[END_REF]. Several principles therefore arise in MRI studies on both men and women that need to be considered.

1) There is great diversity in brain anatomy and functioning, regardless of sex.

Meta-analyses comparing the brains of both sexes show that there is no strict dimorphism that differentiates male brains from female brains (MacCarthy 2011, Joël 2011[START_REF] Giedd | Magnetic resonance imaging of male/female differences in human adolescent brain anatomy[END_REF][START_REF] Ruigrok | A meta-analysis of sex differences in human brain structure[END_REF].

The brain volume of men is indeed greater (by about 10% on average) than that of women, even after considering the difference in body size [START_REF] Cosgrove | Evolving knowledge of sex differences in brain structure, function, and chemistry[END_REF].

Women also have on average slightly more gray matter, and men slightly more white matter (Hanggi 2014). These differences, however, are related to brain size, and not sex (Hanggi 2014[START_REF] Jancke | Brain size, sex, and the aging brain[END_REF]. If we compare the brains of men and women of the same volume (around 15-20% of cases in the population), we no longer see differences in gray and white matter ratios [START_REF] Luders | Why size matters: Differences in brain volume account for apparent sex differences in callosal anatomy[END_REF]. The few studies that have shown differences after taking the size factor into account are rare, and need to be replicated [START_REF] Luders | Why sex matters: brain size independent differences in gray matter distributions between men and women[END_REF][START_REF] Raznahana | Longitudinal four-dimensional mapping of subcortical anatomy in human development[END_REF].

On a functional level, meta-analyses also indicate significant diversity in brain activity (Wallentin 2009[START_REF] Bluhm | New research, old problems: methodological and ethical issues in fMRI research examining sex/gender differences in emotion processing[END_REF][START_REF] Mueller | Individual Variability in Functional Connectivity Architecture of the Human Brain[END_REF][START_REF] Miller | The new science of cognitive sex differences[END_REF]). An overview of the studies on the language areas of the brain that were published from 1995 to 2009, which together included 2,000 subjects, shows that interindividual variability is such that no statistical difference between the sexes can be detected [START_REF] Kaiser | On sex/gender related similarities and differences in fMRI language research[END_REF].

It is important to note that there is a certain degree of bias in the interpretation and media coverage of the results of some scientific studies [START_REF] Guo | A systematic review of the reporting of sample size calculations and corresponding data components in observational functional magnetic resonance imaging studies[END_REF], Ionnidis 2014[START_REF] Kriegeskorte | Everything you never wanted to know about circular analysis, but were afraid to ask[END_REF]. When comparing the brains of women and men in studies with a [5] large number of subjects, differences that are sometimes observed on a smaller scale go largely undetected. However, it is the studies that show differences that are cited the most often! When going through recent MRI studies on cognitive function, one finds that out of the approximately 16,000 articles published from 1992 to 2008, only 2.6% reported differences between the sexes [START_REF] Kaiser | On sex/gender related similarities and differences in fMRI language research[END_REF].

In conclusion, and contrary to popular belief, the brains of women and men show no distinct differences, at least to the degree that they can be easily identified.

Meta-analyses reveal that brain diversity is so rich that there is significant overlap (size effect) in the anatomy and function of the brains of both sexes. There is just as much variety in psychological traits, cognitive skills and social behaviors, all of which reflect both similarities and differences [START_REF] Petersen | Gender differences in sexual attitudes and behaviors: a review of meta-analytic results and large datasets[END_REF][START_REF] Miller | The new science of cognitive sex differences[END_REF][START_REF] Hyde | Gender similarities and differences[END_REF].

Recommendations 1:

Statistics and data analysis

Given the diversity, differences and overlap between the anatomical and functional traits in male and female brains, the following measures are recommended in statistical analysis:

-Use a sample that is large enough to avoid false positives and negatives.

-If the samples are small, as is frequent in MRI studies, the results need to be replicated before they are considered valid. Use non-parametric statistical tests.

-Estimate size effects and conduct meta-analyses.

Illustrations

MRI results for each sex often undergo separate statistical analyses that are illustrated with distinct images. If these images are different, their qualitative comparison is insufficient. It is important to instead make a quantitative statistical comparison in which the differences between the sexes are represented by a single image.

[6]

Publications

Report the absence as well as the presence of differences between the sexes in studies.

This should make it possible to implement the consultation of databases, whose keywords currently only take the differences between the sexes into account.

2) Brain and cognitive characteristics are not fixed but evolve with time and according to the environment due to the brain's plasticity.

MRI research has amply demonstrated that learning and experiences alter both the structure (thickness of the cortex, amount of white matter, etc.) and functioning of the brain [START_REF] May | Experience-dependent structural plasticity in the adult human brain[END_REF][START_REF] Fine | Plasticity, plasticity, plasticity…and the rigid problem of sex[END_REF]. When an MRI scan shows differences between the sexes, it does not mean that these differences have been engraved in the brain since birth, or that they will persist. MRI scans only give a snapshot of the state of a person's brain at a given moment.

Differences between the sexes in cognitive abilities are not immutable. For example, spatial orientation test scores, which often reflect better performances from boys, become the same when the girls being tested are first trained to play video games, or do not fall victim to "stereotype threats" [START_REF] Spencer | Stereotype threat and women's math performance[END_REF][START_REF] Spelke | Sex differences in intrinsic aptitudes for mathematics and science ? A critical review[END_REF], Wraga 2006[START_REF] Feng | Playing an action video game reduces gender differences in spatial cognition[END_REF]. Epidemiological surveys show that differences in performance between the sexes in math and languages vary by country and socioeconomic status [START_REF] Guiso | Culture, gender, and maths[END_REF][START_REF] Hyde | Gender, culture, and mathematics performance[END_REF][START_REF] Nm | Cross-national patterns of gender differences in mathematics: a meta-analysis[END_REF].

In conclusion, the differences between the sexes in education, socialization and life experience are reflected in the functional structure of the brain and in behavior.

These gender differences are not fixed, and can be modified, neutralized or even reversed depending on personal experience and sociocultural, economic and political environment.

Recommendations 2:

Image interpretation

-Acknowledge the immediate nature of MRI images, and keep in mind the brain's capacity for plasticity when analyzing MRI scans.

[7]

-Question the possible origins of the presence or absence of differences between the sexes.

Take variables other than biological sex into account when comparing the brains of women and men

-Collect bibliographical information other than sex, such as age, education, hobbies and interests (such as sports or games), occupation, ethnicity, family history, social status, and economic status.

-Incorporate these different variables when selecting subject groups, in order to form groups that could be more relevant than those which are simply classified by sex.

Writing articles

Use the terms sex/gender rather than just sex to acknowledge the complex relationships between the two.

General conclusion

Categorization by sex is a general practice that implies that biological sex is a significant factor when studying the neurobiological bases of cognitive function in women and men.

Neuroimaging studies often interpret brain-related differences between the sexes as the result of genetic and/or hormonal determinism (Jordan-Young 2010, Bluhm 2013).

When a region of the brain appears to be different between the sexes, it is often seen as reflecting a difference in cognitive skills or social behavioran interpretation which is often heavily influenced by gender stereotypes.

It is clear that despite current knowledge on brain plasticity, essentialist conceptions of the origins of gender differences persist in scientific publications.

Reflection on the ethical issues has to be undertaken in order to create the intellectual and methodological conditions needed to encourage researchers to integrate gender into neuroimaging research practices [START_REF] Illes | ELSI priorities for brain imaging[END_REF], Dussauge 2012[START_REF] Vidal | Le cerveau évolue-t-il au cours de la vie ? Paris, Le Pommier Vidal C[END_REF]. It is important to question the normal and the pathological through the lens of gender, and thus move past the simple dichotomy between the sexes. This approach will allow us to develop new models that articulate the biological and social mechanisms that may [8] explain the differences and inequalities between women and men in the field of health.

Taking gender into account in neuroscience also has a social impact when transmitting scientific research to a large public. Explaining that societal roles assigned to women and men are not determined by a biological law hardwired into their brains will help fight against conservative prejudices and sexist stereotypes.

[11]

Wallentin M, 2009. Putative sex differences in verbal abilities and language cortex: a critical review. Brain Lang.108:175-83. Wraga M, Helt M, Jacobs E et al., 2006. "Neural basis of stereotype-induced shifts in women's mental rotation performance", SCAN, 2 : 12-19.

Recommendations for integrating sex and gender in research on cardiovascular diseases (Jennifer Merchant)

The link between sex, gender and cardiovascular diseases 1

Cardiovascular diseases are the leading cause of death for women in Europe.

While one in 26 European women dies of breast cancer, one in three dies of cardiovascular disease. Women develop cardiovascular disease on average ten years later in their lives than menthe most commonly cited reason is the notion that menopause can lead to hypertension, diabetes, hyperlipidemia, obesity and other metabolic disorders. This hypothesis reinforces stereotypical views among doctors and researchers regarding the differences between men and women. Yet there is no conclusive research evidence to support this hypothesis. In other words, we have been too quick to decide on the dominant role of hormones as a protective factor, followed by the lack thereof as a factor explaining cardiovascular diseases in women.

This observation invites us to reconsider research protocols. Indeed:

• Women are underrepresented in research on cardiovascular diseases, whether in clinical trials, intervention studies or biomedical research on female animals.

• Out of all of the research protocols, approximately 33.5% of participants are women.

• This underrepresentation is particularly noticeable in research on how to reduce cholesterol, the risk of ischemia and heart attacks.

1. http://www.fondation-recherche-cardio-vasculaire.org/

[12]

• Because cardiovascular diseases are perceived as only affecting men, women tend less than men to consider the risk factors and participate in screening programs.

• Yet women suffering from diabetes have a greater risk of developing coronary heart disease or experiencing a stroke. Their prognosis is less encouraging than that of men following myocardial infarction and they are at greater risk of death from cardiovascular disease.

These considerations encourage both sex and gender to be taken into account in cardiovascular disease research. Doing so will enable researchers to formulate new questions, analyze symptoms differently, and as a consequence improve diagnosis and envisage new prevention and treatment strategies for the various cardiovascular diseases.

These measures have already been taken in other countries, notably by the National Institutes for Health in the USA and have consequently led to an increase in the representation of women in clinical trials, as well as increased knowledge about the influence of sex and gender on cardiovascular diseases. Another notable result of this initiative has been the launching of new public health campaigns that target women and men differently in an effort to provide more accurate information about risk factors and preventive measures.

Taking inspiration from the programs already underway not only in the USA, but in other countries as well (particularly in northern Europe), we make the following recommendations:

Recommendation 1: Consider the various cardiovascular diseases according to sex and gender for better adaptation of the diagnostic tools 2

It had long been believed that women suffered from the same cardiovascular diseases as men, namely coronary heart disease. However, recent research in the USA has found that ischemic heart disease is particularly prevalent among women [START_REF] Shaw | Women and Ischemic Heart Disease: Evolving Knowledge[END_REF]. Angiography, the most common technique used in the examination of patients complaining of chest pain, usually results in a diagnosis of coronary heart 2. https://genderedinnovations.stanford.edu/case-studies/heart.html#heart_ischemia_patho [13] disease in men but is not as effective at detecting the disease in women. Many women complaining of chest pain have "normal" angiograms, and are therefore left untreated.

Many of these women have a heart attack or a stroke shortly thereafter [START_REF] Robinson | Cardiovascular Risk in Women with Non-Specific Chest Pain (from the Women's Health Initiative Hormone Trials)[END_REF].

It is therefore important to use different tools and diagnostic techniques for women, such as coronary reactivity testing (Von Mering et al., 2004;[START_REF] Pepine | Coronary Microvascular Reactivity to Adenosine Predicts Adverse Outcome in Women Evaluated for Suspected Ischemia: Results from the National Heart, Lung, and Blood Institute (NHLBI) Women's Ischemia Syndrome Evaluation (WISE) Study[END_REF], intravascular ultrasound [START_REF] Khuddus | An Intravascular Ultrasound Analysis in Women Experiencing Chest Pain in the Absence of Obstructive Coronary Artery Disease: A Substudy from the National Heart, Lung and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE)[END_REF], cardiac MRI, cardiac spectroscopy [START_REF] Ishimori | Myocardial Ischemia in the Absence of Obstructive Coronary Artery Disease in Systemic Lupus Erythematosus[END_REF], myocardial scintigraphy, positron emission tomography (PET) [START_REF] Johnson | Positron Emission Tomography[END_REF], and stress echocardiography (Kaul, 2011).

Recommendation 2: Take sex and gender into account in the expression of symptoms

An international study of 26,755 patients with cardiovascular disease (only 29%

of whom were women) demonstrated that the most common symptom in men (94%)

and women (92%) is chest pain [START_REF] Dey | Sex-Related Differences in the Presentation, Treatment, and Outcomes among Patients with Acute Coronary Syndromes: The Global Registry of Acute Coronary Events[END_REF]. However, significant differences between the sexes are observed for more "atypical" symptoms [START_REF] Chen | Gender Differences in Symptoms Associated with Acute Myocardial Infarction: A Review of the Research. Heart and Lung[END_REF].

Women more frequently complain of intense fatigue, nausea and jaw painthree symptoms that are closely linked to cardiovascular diseases, but do not necessarily raise red flags for cardiologists.

Practitioners must be informed of these issues in order to improve diagnosis and determine the right treatment [START_REF] Zbierajewski-Eischeid | Myocardial Infarction in Women: Promoting Symptom Recognition, Early Diagnosis, and Risk Assessment[END_REF], and researchers need to focus more on explaining these differentiated expressions in the symptoms.

Recommendation 3: Challenge hypotheses regarding the role of hormones, particularly estrogen

As mentioned in the introduction, the decrease in estrogen levels has long been regarded as a causative factor for cardiovascular disease in women. As a result, hormone replacement therapy has often been recommended for female patients [START_REF] Khan | Nuclear Cardiology in Women[END_REF]. However, large-scale studies have shown the opposite, namely a correlation between hormone replacement therapy and an increased risk of infarction in women [START_REF] Wilson | Postmenopausal Estrogen Use, Cigarette Smoking, and Cardiovascular Morbidity in Women over 50-The Framingham Study[END_REF][START_REF] Hulley | Randomized Trial of Estrogen plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women[END_REF]. Further research is required in order to precisely analyze the potential influence of hormones on cardiovascular disease in women.

[14]

Recommendation 4: Take gender into account in order to better prevent and reduce the risk of developing cardiovascular disease

The risk factors for cardiovascular diseases are the same for men and women: age, hypertension, hyperlipidemia, diabetes, smoking, obesity, sedentary lifestyles, high-fat diets, and so on. However, the prevalence and impact of these factors differ according to sex [START_REF] Mosca | Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women 2011 Update: A Guideline from the American Heart Association[END_REF].

For example, smoking is historically more common among men than women (WHO, 2010). However, in certain countries such as Sweden and Iceland, women now smoke more than men (Shafey et al., 2009). Smoking rates among women are continuing to fall in the USA, Western Europe and other industrialized countries, but this is not the case in Central, Southern or Eastern Europe, nor in many emerging countries (Shafey et al., 2009). These geographical differences must be considered in research protocols. A recent study conducted on 3,587 people in five European countries has shown that smoking increases the risk of atherosclerosis in women as well as men. However, the adverse effects are twice as prevalent in women as in men [START_REF] Tremoli | The Association of Tobacco Smoke with Subclinical Atherosclerosis and Atherosclerosis Progression is Stronger in Women than in Men[END_REF].

These studies on smoking have shown that societal gender roles have an impact on the behavior of men and women who smoke or decide to start smoking.

Factors related to biological sex also contribute to the differences between men and women in the susceptibility to and expression of the symptoms related to cardiovascular diseases. In other words, anti-smoking programs must incorporate both sex and gender factors.

[15]

General conclusion

For the last twenty years in North America, the introduction of the factors of While these initiatives are encouraging, there is still much work to be done, and Inserm researchers will have a key role to play here.

Integrating the factors of "sex" and "gender" in their cardiovascular disease research protocols can only enrich the knowledge of these diseases and benefit the health of both women and men.

Introduction

No other issues are said to affect women's health more than reproductive health, procreation, contraception, IVF, etc. … and their consequences. How can we reduce gender prejudice and bias in assisted reproduction, which many studies 3 have shown to impact health and contribute to the growing inequalities in access to research and healthcare? While the Inserm has produced many in-depth reports on "fertility disorders", the impact in terms of sex and gender on the inextricable link between sex and reproduction for womendespite the advent of the pillare barely touched on by these texts, as if the societal and gendered consequences of the research go beyond its scientific dimension and become minimized. But does such minimization of the social effects of research not help to reinforce gender bias in a research field in which the links between sex, reproduction and female/male infertility, generate inevitable ethical questions on gender relations 4,5 ?

It is therefore important to update how these gender relations biases are presented in the research hypotheses, even when the latter aim to be objective, in order to question the conditions and effects of this aim and its communication in the social sphere, and to take into account the gender-dimension of this research without challenging women's equality under the law to make individual decisions on their choices of procreation 6 .

Gender studies began to critically challenge reproductive research in the 1990s.

Such heterogeneous studies lead to dialog and debate that rarely permeate the scientific world but raise ethical issues regarding the reproductive rights of women and [20]

the quality of biomedical research.

They require researchers in human reproduction to confront the subjective aspect of reproductive rights, as set out in the Cairo Declaration 7 and since implemented in international regulations, insisting on the autonomy of women in controlling their sexual and reproductive lives, as well as the anthropological representations that they help to alter through the reproductive techniques themselves.

Techniques which, paradoxically, open up new possibilities for women but restrict their freedom of choice through regulations that make procreation a biopolitical issue that weakens their acquired reproductive rights: techniques where a critical dialogue between the human sciences and biotechnologies is established.

Gender studies generally reject the idea of scientific neutrality when it comes to research on women's bodies and question the lack of consideration given to the gender dimension of medical research participants in terms of the consequences of the risks and benefits of research.

While feminist studies agree on the fact that reproductive techniques increase

the procreation options open to women, they also question the proportion of risk assumed by women in the development of these techniques.

This concerns the medical procedures themselves, embryo transfers, and the invasive techniques involved: donation of gametes, cryopreservation, preimplantation genetic diagnosis. The risks of these techniques, which for women involve multiple pregnancies and their associated pathologies, had rarely been considered prior to their research in order to minimize risks and increase benefits for women.

While the issues raised by assisted reproductive technologies have been the subject of many national and international bioethics committee opinions, they have above all become a means of acclimatizing the public to these technologies without reaching a sharable consensus on what makes or does not make them legitimate.

Gender studies have refused to submit to a social signification of these technologies to the biological facts of reproduction and have produced an impressive body of critical literature on these technologies, all too often ignored by researchers in the field.

I will therefore concentrate here on the ethical and scientific reasons for taking seriously gender bias and the confusion between sex and gender in this debate, so as to improve the perception and quality of the research on present and future reproductive techniques which would include a gendered perspective of these techniques. We might ask ourselves why the numerous feminist studies on the subject have not seriously impacted the methodological a prioris of reproductive research. We might naively suggest that the hierarchy between the sexes has difficulty being challenged by disciplines, or that menwho are in the majorityhave difficulty negotiating their privileges around a social egalitarianism they consider to challenge the coherence of the neutrality of their epistemological model by introducing anthropological and social data that go beyond the realms of their expertise and seem too empirical to be verifiable.

To consider, for ethical reasons, that the integration of these two epistemological discourses implies an alternative and more egalitarian biopolitical model, driven by the research institutions and the researchers in a context in which the institutional hierarchy often confirms existing gender privileges, privileges which must be undone, which research ethics requires us to challenge. It is therefore about questioningin reproductive medicine and in generalthe myth of the axiological neutrality of the natural sciences.

For that we will need to challenge the resistance to the gender perspective in science and propose recommendations for the improvement of scientific excellence through the introduction of a gender perspective, hitherto perceived as incompatible with the hypothetico-deductive approach because, we are told: [23] constitutional factors among the causes of impaired reproductive health, but above all the behavioral aspect of delayed procreation for women and smoking. The servitude concerns the biological markers of male and female fertility. It is about "controlling fertility" and it is added in the introduction that social choices must be justified in order to harmonize the advances in knowledge in fundamental research, population research and surveillance. Nevertheless, the part devoted to societal challenges appears only in a few pages of the third section of the document which reports the evolution in knowledge on human reproduction, but only mentions the question of "individual aspirations", while noting that faced with a wide variety of demands, the legislator is led to make difficult choices and observes that faced with the restrictive regulation of assisted reproductive technologies, the reasons for which are not analyzed, increasing numbers of men and women go abroad to benefit from methods that are forbidden in France, without addressing the societal or gender issues, even the democratic dimension of the respect for "individual aspirations" beyond biological and gendered determinations 9 .

The domain of reproductive technologies is also paradoxically that in which gender biases have been displaced by the opening up of new reproductive possibilities, circumventing the biological determinations of individuals, to be better confirmed by genetic sex, bringing us back to an idea of the generalized plasticity of the living which minimizes the dimension of individual and social choice of the subjects of norms, which is not without raising fundamental ethical issues regarding the legitimacy of medical or political decisions that affect the private body.

The question being: how do the scientific and/or social norms that define human reproduction and filiation reconstitute and question the limits of subjects in what has become their reproductive choice? There again, the limit of legitimacy will depend on the political and institutional context of the subject, which questions the conditions of the universalization of scientific data. But also the normative capacity of States faced with reproductive tourism in a world of free movement of information and in a Europe of free movement of people.

Assisted reproductive technologies challenging the ability of biological determinism to infer social roles

9. Idem conclusion page 106.

[24]

Assisted reproduction was indeed the first biomedical technique to challenge gender roles, while practically displacing the monopoly of the heterosexual model and opening up the possibility of homosexual reproduction using surrogates, even fantasies of an artificial uterus erasing all biological determinism 10 . Although these questions are regulated by law, the latter is always late when it comes to the normativity inherent to the practice of research and to its developments in healthcare.

Indeed, reproductive biotechnologies, which have displaced the embryo from its "natural" setting to the petri dish, have as a consequence modified the social representations of filiation and gender roles, and have had an unsuspected social impact, altering the anthropological representations of the gendered role of men and women since the dawn of humanity, there again confusing male and female, social roles of men and women.

The science of reproductive technologies has become an actor of social modifications and therefore cannot claim neutral epistemology on the definition of the supposed natural character of reproductive roles. It highlights the limit of the natural character and as a consequence the contingency of reproductive roles as inferring immutable social roles. Paradoxically, the refusal of procreation also became an option for women and not a failure of their social role predetermined by an androcentric society which had medicalized sterility. Motherhood could still be chosen despite biological sterility. Science therefore brought complexity to anthropology and opened up to the interpretation of these new possibilities. Reproductive medicine became empowering (giving additional capacities) or alienating for women, depending on the place it gave the right of people to express their subjective choice, to accept or refuse the application of certain research to their person.

The specificity of gender studies involves not submitting social signification to biological facts.

However, the purpose of assisted reproductive technologies is to compensate for the failure of natural human reproduction processes. French bioethics laws, for example, define assisted reproductive technologies (artificial insemination, IVF and embryo transfer) as having two purposes:

10. Atlan, Henri, L'utérus artificiel, Seuil, Paris, 2005.

[25]

 to remedy medically diagnosed sterility in the man or woman or  to avoid transmitting a particularly severe disease to the child.

The social conditions of assisted reproductive technologies are more or less strict depending on the national culture and the representation of the family, and often exclusively concern married couples or couples which can supply proof of at least two years of living together.

We see that the social regulation of assisted reproductive technologies unconsciously reproduces the traditional social patterns which are here regulated by politics and medicine and withdrawn from the judgment of women by technical mediation.

It is therefore important to analyze the ethics of reproductive technologies, from a gendered, non-naturalist viewpoint, which defines the difference in sexual roles as social construction; this does not mean that the woman does not exist as a social reality, but precisely that she is determined by social structures that she should be able to help modify, but which often she can only confirm.

It would be useful to challenge the idea by which the technosciences are neutral and necessarily beneficent, when referring to this major biotechnological and biopolitical challenge which medicalized reproduction has become.

The critical view of assisted reproductive technologies by feminist sociologists

The epistemological and political problems related to this issue have been concealed and masked by the vague term of human reproduction, as if the issue of gender equality was already resolved. We wish to show that power issues between the sexes are fundamental around this technique whose protagonists are insidiously not the man and the woman but "the couple" and "the embryo", two new and particularly unclear legal entities 11 .

The questions asked by gender literature are: for which women are the assisted reproductive technologies intended? Why is the woman transformed into a "uterine supply system", serving the embryo and scientific research? 12 How does medical and 11. See here the French Bioethics Laws of 1994. 12. Duden, Barbara, Disembodying Women. Perspectives on Pregnancy and the Unborn, Harvard University Press, 1993.

[26] political expertise in procreation as quality production become a justified extension of the familial and private decision?

The debate is all the more complex in that it brings back into play the dichotomies between vitalism and materialism, public and private, corporatist rights of the mothers and the right of women to control their bodies, etc., and raises major power issues.

Faced with these phenomena, the need to rethink the bioethical concept of women's reproductive rights and responsibilities in the face of men re-emerges, but essentially feminist movements, too much in a minority to have political representativity, or women isolated in the face of the disappointments and suffering that these techniques often cause, even though they address a biologically determined and socially constructed desire to fulfill their womanhood through maternity. Because reproduction has become "assisted", the concepts of freedom and reproductive rights have been weakened and are perceived by some women as the price to pay for their sexual liberation. To this "personal tragedy" of infertility said to concern only five percent of women, contemporary biomedicine responded with a succession of IVF techniques. While their initially doubtful efficacy has continued to increase, they have helped to radically change our social perceptions of filiation, of the person, of the concept of birth and even the natural character of conceptionthe representations of which have gone from reproduction to production, even if common parlance refers to assisted reproduction. This concept of assisted reproduction is problematic from the gender viewpoint, because it hides from everyone that biotechnology in human reproduction takes the reductive and essentialist place hitherto held by the concept of natural reproduction, from the point that it comes an obligatory step and reimbursed by French state health insurance.

We can see, from the emergence of these new issues, that the "flip side" of this efficacy, from the viewpoint of our largely-patriarchal-remaining societies, is the intrusion or disruption of the symbolic representations in relation to the nature of reproduction 13 .

We read an underlying conflict between the social order of the biotechnologies 13. Chesler, Phyllis, Sacred Bond. The Legacy of 'Baby M' (publ. Crown, 1st ed. 1988) opposes a surrogate mother to her adoptive parents. The book reiterates the old belief that maternal filiation is more biological than paternal filiation, and this in a moment when legislators are trying to establish either biologically or genetically the role of the father (Vandelac 1990).

[27]

and the natural order. It is all as if the social order was disrupting the natural order.

Scientific realism is no longer content with describing what is real. It modifies it, thereby becoming an anthropological player, which requires ethical reflection on the legitimacy of these modifications, which affect couples seeking medical help for infertility, but do not mention the fact that the treatment is much more invasive for the woman, even when it is the man who is infertile. The complex links between scientific possibilities and the need to re-evaluate our social choices, as to the limits of the field of expertise to give to these sciences, once sociocultural issues are involved, oblige the sciences to assume a major biopolitical role: communicate and dialog in order to undo representations founded on partial knowledge or vectors of ideologies.

These issues, which seem remote from the research itself, have a major impact in terms of ethics or legitimacy of some studies, particularly on embryos and the place of the representations of the role played by women in technical decisions: implantation of a specific number of embryos, selection of the embryo under the microscope, etc.

which erases the dimension of chance. The responsibility caused by such embryo displacement has granted power and responsibility to research, which has often been criticized by women, and has given rise to the creation in Europe of national bioethics committees, meant to arbitrate these power struggles based on both scientific and ethical criteria, but again without the sex/gender perspective being incorporated in the majority of the European regulations. It gives women, particularly with the famous Perruche case in France, the impression of being dispossessed of the control over their bodies because the decision gave less space to sex-gendered representations than to "scientific" criteria.

Challenging the harmful effects for reproductive medicine of the hierarchization between the social and biological sciences

The concept of gender must be introduced into science reflectively in order to avoid supporting or reinforcing, through genetic jargon, social prejudices relating to reproductive roles and their biological determination.

It can be seen in the scientific literature that the terms sex and gender are often used interchangeably and still do not modify research practices to a sufficient extent.

It is important to promote the awareness of biomedical science researchers within the context of their respective fields, as requested by the European Commission [28] since 2010. The plasticity of the living already renders researchers particularly sensitive to these social and contextual dimensions, but tools of non-discrimination must be developed in order to transform this sensitivity into a capacity to resignify the impact of these techniques in relation to existing social norms and the hierarchization between men and women, which prevail over the topics and the priorities of research issues. Introducing the concept of gender into research must involve critical training on its relevance and on the knowledge of research regulations that the international bodies produce.

Does sexual division remain a relevant normative marker?

The status of the gender concept in the biological sciences was not the feat of the biological sciences themselves, even though they have helped challenge the social biases of gender through the reproductive possibilities that they have opened up. It was done by social sciences without always being able to establish a genuine dialog with biomedical research and assisted reproductive technologies. Nevertheless, the methodological decision to reduce sexual difference to masculine and feminine is a bias whose effects are both social and scientific. Among the scientists themselves, biological sex is inferred by simple observation, and the majority of scientific publications consider these categories as evident. The role of ethical reflection is precisely to question these unshakeable inferences by firmly showing the harmful effects they induce on the mental and physical health of those who do not recognize themselves in these a priori categories.

It is the ability to challenge the criterion of sexual difference in biomedical research which, out of prejudice, continues to attribute some diseases to women rather than men.

This gender perspective is a critical perspective, which challenges the biological difference of the sexes and the legitimacy of inferring normative knowledge on others from an observation. If this challenge is not effective in the upstream stages of research, new biotechnologies will only contribute to reproducing social biases in the name of a hypothetico-deductive approach.

[29]

Recommendations for the inclusion of gender in assisted human reproduction  Train researchers in the issues of the social consequences of scientific research.

 Take seriously the polysemy of the biological sex concept from the gender viewpoint, and do not be afraid to embrace uncertainty.

 Face the challenge of the normativity criteria to be adopted for the incorporation of new reproductive technologies.

 Consider women rather than couples as decision-making agents in reproductive medicine.

It is therefore not just about promoting research policies in terms of gender equality, because research increases rather than eliminates differentiation.

By incorporating the complexity of the gender dimension in research, in the very name of research excellence, our aim must be to shed light on the gray areas and biases in research provoked by unconceived presuppositions upstream of the research protocol, which involves:

 assuming social equality between men and women in research institutions,  assuming biological differences between men and women without challenging the equality of opportunity and decision in terms of gendered reproduction,  avoiding invalid inferences by using critical thinking to update implicit gender bias in research practices 14 ,  paying upstream attention to gender bias in disease research and classification by raising researcher awareness of gendered variables,

 not presenting opposing methodologies between science and gender but promoting complementary epistemological models for the sciences that have a social effect.

  for neuroimaging research (Catherine Vidal) Principles and implications for the design, analysis and interpretation of experiments In neuroimaging research on brain functions and cognitive skills, studies that interrogate the impact of education and sociocultural environment on gender differences in men and women are still rare (Rippon 2014). Neuroscientists are still relatively unfamiliar with the concept of gender. Yet taking it into account can only enrich research on cognitive and behavioral disorders whose prevalence varies according to sex and environment (Dussauge 2012, Fausto-Sterling 2012 a-b, Fine 2014).

  gender and sex into research on cardiovascular disease has undeniably improved knowledge surrounding diagnosis and treatment. Prevention campaigns that take sex and gender into account have also helped to more accurately target at-risk populations and encourage them to adopt preventive behaviors.In 2005, the European Society of Cardiology (http://www.escardio.org/) launched the "Women at Heart" initiative, which aims to improve awareness and understanding of cardiovascular diseases in women, among both doctors and the general public. The European Medicines Agency has also made recommendations to include more women in clinical trials, and to collect data on gender in order to better assess the effectiveness of treatments for women and men(European Medicines Agency, 2006).The medical research community in France is gradually becoming aware of the importance of including the factors of sex and gender in research on cardiovascular diseases. The Foundation for Cardiovascular Research, for example, has recently launched the "At the Heart of Women" campaign, http://www.fondation-recherchecardio-vasculaire.org/coeur-de-femmes/la-recherche-pour-le-coeur-desfemmes/lancement-programmes-de-recherche-coeur-de-femmes/.

3.

  See Mikkola, Mary, Feminist Perspectives on Sex and Gender, Standford Encyclopedia of philosophy, May 2011. 4. Les troubles de la fertilité, état des connaissances et pistes pour la recherche, 2012. The report focuses on the biological causes of infertility and only addresses the social issues in the final pages, without mentioning the sex-differentiated issue of research consequences. 5. In the wake of the World Conference on Women held in Beijing in 1995, the French daily Le Monde pointed out that over forty Catholic and Muslim states had expressed reservations on the passages of the declaration recognizing for the first time the right of women to control and freely decide their sexuality. How does this right of women to control what happens to their bodies apply in the face of "fertility disorders", if decisions are made as a couple? 6. Novaes Bateman, Simone, Biomédecine et devenirde la personne, Collection Esprit, 1992.



  either neutrality towards gender would deny male/female biological determinism,  or positive discrimination skews the objective data from research on biological determinism through a belief in unalterable universals, or in an irrational relativism of the cultural values.Biotechnologies: redefining the reproduction playersRecent developments in assisted reproductive technologies have led women to question the purpose of the reproductive technologies in the redistribution of the roles of the procreation players.The field of reproductive research as laboratory for changing gender categories and power strugglesThe field of reproductive research is one of the most illustrative of this methodological bias and of the power struggles involved from a heterosexual research perspective, as the work of many sociologists and feminist biologists (Haraway, Fausto-Sterling) has shown.Indeed, men for a long time remained the principal players and women the subjects of research, without implementation of ethical rules of research, until the bioethics law in France in 2004. Reproductive technologies straddle multiple disciplines in the domain of therapeutic innovation, faced with women made vulnerable by sterility that deprives them of their traditional social role and for which they demand therapeutic solutions which did not require very clear informed consent protocols as they were the ones calling for those solutionsa situation which has evolved thanks to recent bioethics opinions and work. Feminist studies first criticized the seizing of power over women's bodies, in an area that was the only recognized social role of women. Science was going to make children with and for women. The situation in France, as the 2011 report by the French Biomedicine Agency shows 8 , is more nuanced. It states that sustained research efforts will be needed to improve infertility treatments, particularly assisted reproductive technologies, and highlights genetic or 8. Les troubles de la fertilité, état des connaissances et pistes pour la recherche. Rapport remis au parlement le 18 décembre 2012.

More generally

 In medical research, take into consideration both the differences between males and females and the social norms concerning men and women, which do not obey the same epistemological models.

 Fight the effects of sexism in the teaching of biomedical research.

 Associate social science researchers with innovative medical research.

 Take gender aspects into account in sex-specific medicine. They are not contrary to the equality of rights of access to research and healthcare. 15  Incorporate gender issues in the internal and external evaluations of research institutions.

 Implement at institutional level a strategy to promote gender equality and not positive discrimination, which would call into question people's real abilities.

 Continuously train researchers, by addressing the new technologies and their social impact, by involving human science researchers in the laboratories.

 Improve communication on biotechnological innovations, incorporating the gender perspective into the social consequences of research.

 Do not oppose social egalitarianism and gender-specific medicine.

General conclusion

The aim of these recommendations is to promote a culture that is more inclusive of gender issues, which can only improve the quality of and public receptivity to therapeutic innovations, rendering researchers more accountable for the social implications of their research in terms of the gender and sex aspects.

While assisted reproductive technologies have considerably modified the possibilities for women and men suffering from sterility, they have also modified our [31] anthropological perception of procreation and filiation. It is crucial that new biotechnological advances affecting procreation do not remain closed to research concerning conflicts of social perception of these technologies.

This also implies devising a more integrative and interdisciplinary epistemology and reducing opacity in decisions and in the choices of biomedical research subjects.

"GENDER AND HEALTH RESEARCH" GROUP 2014-2015 ACTIVITY REPORT

International Gender and Health Colloquium, held by the Emilie du Châtelet

Institute in partnership with the Inserm, June 8-9, 2015, Amphithéâtre Buffon, Paris

Diderot University

The objective of this multidisciplinary colloquium is to analyze how societal gender roles tend to influence how women and men (i) are exposed differently to health problems, (ii) perceive their health problems, (iii) use or do not use the healthcare system, and (iv) how healthcare professionals respond differently depending on the sex of their patients.

The colloquium looks at the links between gender and health in various For clinical research, a document summarizing the recommendations of this Memo will be sent to the project leaders for consideration regarding the links between sex and gender in the design, analysis and interpretation of experiments.

[34]

"GENDER AND HEALTH RESEARCH" GROUP PROPOSED ACTIONS


John R Dolan
email: dolan@obs-vlfr.fr

Ernst Haeckel's Radiolarians and Medusa: The influence of his visits to Villefranche on his science and his art

Keywords: History of science, plankton, scientific and artistic voyages, microscopy

ABTRACT:

Early in his long career, Ernst Haeckel (1834Haeckel ( -1919) ) twice visited Villefranche-sur-Mer. First, as a student, in 1856 during a sampling trip to Nice, and again in 1864 when sent to Nice by his parents for a change of scenery following the untimely death of his first wife. The two visits appear to have been key events in the development of Haeckel's science and art as they are the beginnings of his studies, first on radiolarians, and then on medusa. During the 1856 visit he observed for the first time living radiolarians, the group of microscopic planktonic protists, the subject of his first monographic work in 1862 that brought him fame at a young age. During the 1864 visit he resided in Villefranche-sur-Mer. There, for the first time, he made detailed observations on the development and morphology of medusa. He subsequently produced monumental monographs on both radiolaria and medusa, e.g., the Challenger Reports, which remain today his major scientific contributions. Haeckel's artistic fame is largely from his Kunstformen der Natur. The book relies heavily on illustrations of both radiolarians and medusa, more so than other groups of organisms, and contains iconic images of medusa and radiolarians, suggesting a major importance in Haeckel's art for the two groups linked closely with Haeckel's visits to Villefranche-sur-Mer.

Les radiolaires et les méduses d'Ernst Haeckel : influence de ses visites à

Villefranche-sur-mer sur sa science et son art. RESUME: Au début de sa longue carrière, Ernst Haeckel (1834Haeckel ( -1919) ) s'est rendu deux fois à Villefranche-sur-mer. D'abord en tant qu'étudiant, en 1856, lors d'un voyage d'échantillonnage à Nice, puis de nouveau en 1864, lorsque ses parents l'envoyèrent à Nice pour un dépaysement total à la suite du décès prématuré de sa première femme. Les deux visites semblent avoir été des événements clés dans le développement de la science et de l'art de Haeckel au début de ses études, d'abord sur les radiolaires, puis sur les méduses. Lors de sa visite en 1856, il observa pour la première fois des radiolaires vivants, groupe de protistes planctoniques microscopiques, sujet de son premier travail monographique en 1862 qui le rendit célèbre à un jeune âge. Pendant la visite de 1864, il résida à Villefranche-sur-mer. Il y fit pour la première fois des observations détaillées sur le développement et la morphologie des méduses. Il a par la suite produit des monographies monumentales sur les radiolaires et les méduses, par exemple les rapports Challenger, qui demeurent aujourd'hui ses principales contributions scientifiques. La renommée artistique de Haeckel provient en grande partie de son livre "Kunstformen der Natur". Le livre s'appuie beaucoup sur des illustrations de radiolaires et de méduses, plus que d'autres groupes d'organismes, et contient des images emblématiques de méduses et de radiolaires, suggérant une influence majeure dans l'art de Haeckel pour ces deux groupes, étroitement liée aux visites de Haeckel à Villefranche-surmer.

mots-clés : histoire des sciences; plancton; voyages scientifiques et artistiques, microscopie

Backstory/Introduction

This article grew out of a recent serendipitous discovery. I was searching for an obscure species description by Ernst Haeckel, an important personality in the history of biology. He was a contemporary and staunch advocate of Charles Darwin and is one of the best known and most read zoologists [START_REF] Egerton | History of ecological sciences, part 47: Ernst Haeckel's ecology[END_REF]. I came across another obscure species description by him, one that surprised me. It was a description of a meduse (a jellyfish), and he called it "Carmarina", the Niçois word for sea meat, a term used by the fisherman of the Nice region for gelatinous plankton caught in their nets.

Haeckel's use of the word suggested a certain familiarity with both the medusa and the fishermen of the region. Given the date, his striking illustration appeared to be his first published drawing of any medusa. His illustrations of medusa are famous, even iconic. In fact, Haeckel is well known for his detailed studies and magnificent illustrations, primarily of two groups of organisms: radiolarians, microscopic creatures with fabulously intricate skeletons or shells, and the medusa (fig. 1). I was familiar with the fact that he first saw living radiolarians when he visited the Bay of Villefranche in 1856 as a young medical student (fig. 2), the veritable start of his studies radiolarians. However, the medusa description suggested his other major obsession, medusa, may have also begun in the Bay of Villefranche with his 1864 stay. The stories presented here, of two relatively short visits, aim to convince you dear reader, that his visits to southern France were key events in the development of Haeckel's science and his art. I hope to convince you that his major scientific and artistic legacies, both of which are considerable, are intimately linked to Villefranche.

Fig. 2. Ernst Haeckel and his microscopes, ca. 1856, when he was a medical student. His parents bought him his first microscope, a Schiek barrel microscope (on the table at the left), in 1853 and he quickly became very fond of it, calling it "my darling" and "my divine microscope"; he developed the unusual ability to look through the eyepiece with one eye and with the other draw what he saw in the microscope [START_REF] Otis | Müller's Lab[END_REF]. Photo courtesy of SLUB Dresden/Deutsch Fotothek.

Haeckel's 1856 Visit

Ernst Haeckel saw the Bay of Villefranche for the first time during a sampling trip to Nice in the autumn of 1856, at age 22. He had been invited to participate in the expedition by his teacher, Albert Kölliker. Based in Nice, they spent 4 weeks in the region. Many years later, Haeckel stated: "In company with Heinrich Müller and K. Kupffer, we investigated especially the rich pelagic animal life of the beautiful bay of Villafranca. There, for the first time I met those wonderful forms of the pelagic fauna which belong to the classes of the siphonophores, pteropods, and heteropods. I also there first saw living polycyttariia, acanthrometra, and polycystina, those phantasmic forms of radiolaria, in the study of which I spent so many later years". [START_REF] Haeckel | Plankton studies: a comparative investigation of the importance and constitution of the pelagic fauna and flora (translated by G.W. Field)[END_REF]. According to a letter sent to his parents at the time [START_REF] Haeckel | Ernst Haeckel an Charlotte und Carl Gottlob Haeckel[END_REF], during their stay they met repeatedly with the Berlin Professor Johannes Müller who was himself sampling along the French Mediterranean coast, in Villefranche, Nice, St. Tropez and Cette (now Sete) for his study of Mediterranean radiolarians published posthumously in 1858 (Müller 1858). Johannes Müller is credited by Haeckel as the one who initiated him to the study of planktonic organisms, earlier, in 1854 during a trip to Helgoland. [START_REF] Haeckel | Plankton studies: a comparative investigation of the importance and constitution of the pelagic fauna and flora (translated by G.W. Field)[END_REF] states " When at Helgoland, investigating the wonders of the plankton with the microscope, Johannes Müller, pleased with the care and patience with which his zealous students tried to study the charming forms of medusa and ctenophores, spoke to me the ever-memorable words, "There you can do much; and as soon as you have entered into this pelagic wonderland you will see that you cannot leave it." According to [START_REF] Haeckel | Plankton studies: a comparative investigation of the importance and constitution of the pelagic fauna and flora (translated by G.W. Field)[END_REF], in Nice in 1856, Müller stressed to him the particular interest of studying radiolaria as he ".... called my attention to the many and important questions which the natural history of these enigmatical microscopical organisms present.".

Haeckel mentions, in that same letter to his parents [START_REF] Haeckel | Ernst Haeckel an Charlotte und Carl Gottlob Haeckel[END_REF], that towards the end of their stay, they used "Müller's fine nets" to collect organisms in the Bay of Villefranche noting that among the catch were the most remarkable Thalassicolla (a group of radiolarians). It was perhaps this outing from Nice that provided the sample containing the radiolarian Haeckel described in his 1862 monograph, Sphaerozoium italicum (Fig. 3), as from his stay in Nice in 1856. It appears to be the first new species of radiolarian he collected. In recent years, the species was collected again from the Bay of Villefranche and molecular data from it used to refine the phylogeny of radiolaria [START_REF] Bass | Polyubiquitin insertions and the phylogeny of Cercozoa and Rhizaria[END_REF]. The 1862 'Die Radiolarien' was Haeckel's first monographic publication (excluding his thesis and habilitation volumes) and he dedicated it to Johannes Müller. The study was largely the result of a long stay in Messina devoted mostly to collecting and examining radiolarians. Haeckel credited Müller's suggestion, made in Nice in 1856, as the motivation for his "spending an entire year in pelagic fishing" [START_REF] Haeckel | Plankton studies: a comparative investigation of the importance and constitution of the pelagic fauna and flora (translated by G.W. Field)[END_REF]. The massive two-volume work earned Haeckel a promotion to "Extraordinary Professor" and the Cothenius medal of the Leopold-Caroline Academy of German Naturalists in 1863. Haeckel sent a copy to Darwin and it is said to have astonished him [START_REF] Richards | The Tragic Sense of Life: Ernst Haeckel and the Struggle over Evolutionary Thought[END_REF].

In subsequent years, Haeckel turned his attention to other groups of organisms and topics. He returned to studies of radiolarians only in the 1880's as he was asked to exploit the sample gathered during Challenger Expedition. His resulting radiolarian "masterpieces" are the monographs constituting the "Report on the Radiolaria" (Haeckel 1887a,b), totaling over 1700 pages of text and 140 plates. Although Haeckel's taxonomy has been revised, and many species have been found to be synonyms, (e.g. [START_REF] Aita | Haeckel Radiolaria Collection and the HMS Challenger Plankton Collection. Joint Haeckel and Ehrenberg Project: reexamination of the Haeckel and Ehrenberg microfossil collection as a historical and scientific legacy[END_REF][START_REF] Lazarus | The legacy of early radiolarian taxonomists, with a focus on the species published by early German workers[END_REF]), the work is still regularly cited today (e.g. [START_REF] Biard | Biogeography and diversity of Collodaria (Radiolaria) in the global ocean[END_REF][START_REF] Grattepanche | Microbial diversity in the eukaryotic SAR clade: Illuminating the darkness between morphology and molecular data[END_REF][START_REF] Dolan | Past President's Address: Protists of the Mesopelagic and a Bit on the Long Path to the Deep Sea[END_REF][START_REF] Kachovich | Adding a new dimension to investigations of early radiolarian evolution[END_REF] It is speculation to propose that Haeckel may not have studied radiolarians if Kölliker had not invited Haeckel to join his sampling expedition. However, it is not speculation to state that a firm link exists, not least of all in Haeckel's mind, between his 1856 visit to Villefranche and his subsequent work on radiolarians.

Haeckel's 1864 Visit

As mentioned above, following the appearance of his monograph on radiolarians, Haeckel was named "Extraordinary Professor" in Jena. This was in June 1862. The financial stability of the new position allowed him to marry Anna Sethe (to whom he had been engaged since 1858) in August of 1862. Unfortunately, the marriage was short-lived. Anna Sethe Haeckel died suddenly in early February of 1864, perhaps of appendicitis. Haeckel was completely devastated by the loss of his wife. Apparently unable to end his grieving, his parents sent him to Nice for a six-week stay in March-April 1864 for a change of scenery [START_REF] Richards | The Tragic Sense of Life: Ernst Haeckel and the Struggle over Evolutionary Thought[END_REF].

From a long letter to his parents (Haeckel 1864a), we know that Haeckel found Nice disagreeable. He quickly moved to Villefranche, profiting from contacts made during his previous visit. He took rooms in Casa Montolivo, describing his host, Abbé Montolivo, as a "marine doctor". Abbé Montolivo, along with Jean Baptiste Vérany, were the Nice naturalists who had provided aide in sampling during Haeckel's previous visit [START_REF] Haeckel | Ernst Haeckel an Charlotte und Carl Gottlob Haeckel[END_REF]. In Villefranche, he sought to distract his grief through work (Haeckel 1864a). He apparently worked quite hard as his stay in Villefranche was remarkably productive.

Haeckel's time in Villefranche appears to have marred by bad weather, responsible for many days of poor sampling conditions in the bay (Haeckel 1864b). This, and the fact that he was residing in Villefranche, he proudly declared himself to be the first naturalists to reside in Villefranche rather than visit from Nice (Haeckel 1864a), perhaps explains why his work consisted of largely observing living specimens rather than cataloguing new forms. Haeckel did not completely ignore radiolarians, devoting some time to observing feeding behaviour (Haeckel 1865a). He also described new species (Fig. 4). Notably, his description of one as "Protogenes primordialis" appears to be the beginning of his now discredited theory of the primitive protist cell as a form without a distinct nucleus [START_REF] Haeckel | Nachträge zur Monographie der Moneren[END_REF]). However, he must have spent most of his time observing medusa, especially following their complicated developmental stages, given the large amount of data he gathered on medusa. Haeckel's first published illustration of medusa, describing a new species (Haeckel 1864c) came from his 1864 stay in Villefranche (Fig. 5). Remarkably, Haeckel named the new form in a sort of tribute to the local fisherman, using their term "carmarina" (Niçois for sea meat) for gelatinous plankton, as the name of the new genus, Carmarina. It would be featured later in his art book Kunstformen der Natur. Haeckel also named a new medusa shown in Figure 5, found while walking along the bay, for his deceased wife: Mitrocoma annae (Anna's headband) in a most poetic manner [START_REF] Richards | The Tragic Sense of Life: Ernst Haeckel and the Struggle over Evolutionary Thought[END_REF]. The small medusa would be the first of 3 species named for Anna Sethe, the second being the iconic medusa Desmonema annasethe of the Kunstformen der Natur (plate 8 below in fig. 6). The third, and last species, he named for her was a radiolarian, Dictycodon annasethe also shown in a plate in Kunstformen der Natur (plate 31 below in Fig. 8). Haeckel's publications based on his observations of medusa while in Villefranche (for less than 4 weeks!) number 4 (1864b,c; 1865b,c) with a 5th as a monograph combining 3 of the 4 papers (1865d). He continued his studies of medusa later in Jena with descriptions of fossil medusa (1865e, 1866, 1869a, 1874) and extant medusa (1869b). His medusa studies culminated with his Das System der Medusen (1879, 1880) and the deep sea medusa of the Challenger expedition (1881, 1882). In the Das System der Medusen, in the 1879 atlas of illustrations, 9 of the 154 species shown are stated to have been specimens from Villefranche, presumably collected or drawn during his 1864 visit. Through the years, much of his taxonomy has been revised but other parts have been validated using molecular methods (e.g. [START_REF] Bayha | Evolutionary relationships among scyphozoan jellyfish families based on complete taxon sampling and phylogenetic analyses of 18S and 28S ribosomal DNA[END_REF]).

Haeckel's interest in medusa, unlike the radiolarians, cannot be said to have begun in Villefranche. His first 'field trip' devoted to plankton was to Helgoland (Germany) in 1854 in the company of Johnannes Müller who introduced him to "plankton fishing" [START_REF] Florey | Highlights and sidelights of early biology on Helgoland[END_REF]. According Haeckel, it was then that he discovered "the charming forms of medusa and ctenophores" [START_REF] Haeckel | Plankton studies: a comparative investigation of the importance and constitution of the pelagic fauna and flora (translated by G.W. Field)[END_REF]. Nonetheless, Haeckel's first detailed studies of medusa were conducted in Villefranche and only after his stay in Villefranche did he begin his ultimately very large number of studies on medusa (Fig. 7).

Radiolarians and Medusa in Haeckel's Art

Haeckel's artwork is known almost exclusively from his Kunstformen der Natur, although it can be found in many of his monographic works such as the Challenger Reports [START_REF] Williams | Art Forms from the Abyss -Ernst Haeckel's Images from the HMS Challenger Expedition[END_REF]. Kunstsfomen der Natur was published in 10 installments of 10 plates each from 1899 to 1904. The 100 plates had a considerable impact on the Art Nouveau movement and continue to have an impact in the fields of art and design. Furthermore, according to some, he is remembered today, even in the scientific community, more for his artwork than for his contributions to science [START_REF] Williams | Art Forms from the Abyss -Ernst Haeckel's Images from the HMS Challenger Expedition[END_REF]. Given that Haeckel's work on radiolarians and medusa can be closely linked to his visits to Villefranche, one might ask how did radiolarians and medusa feature in his artwork? How important were they?

The relative importance of radiolarians and medusa in Haeckel's art quickly becomes apparent in surveying the 100 plates of the Kunstformen der Natur. Medusa and radiolaria feature very prominently (Fig. 8), accounting for 22 of the 100 plates. Among the 10 installments, usually both were represented. No other groups of organisms are so abundantly featured. However, a greater prominence was given to medusa to which he devoted 12 plates compared to 10 for radiolarians. One might speculate that Haeckel had a slight preference for medusa. In this regard it perhaps worth recalling that Haeckel named his house in Jena "Villa Meduse" and named two medusa, and but one radiolarian, for Anna Sethe Haeckel.

Fig. 8. The plates from Kunstformen der Natur featuring radiolarians or medusa numbered 22 out of the 100 plates. The numbers in the lower right corners denote the plate number. The book was published in installments, sets of 10 plates. Thus, the first installment contained plates 1 to 10, the second 11 to 20, etc.,; it can be seen then that most of the 10 installments contained both a medusa and a radiolarian plate. Plate 8 shows Desmonema annasethe, one of the two medusa species Haeckel named for his deceased wife. Plate 26 featured the medusa Carmarina hastata described from Villefranche. Plate 31 includes Dictyocodon annasethe (bottom row center), the radiolarian he named for he named for deceased wife.

According to [START_REF] Richards | The tragic sense of Ernst Haeckel: his scientific and artistic struggles[END_REF], Haeckel's illustrations in Kuntsformen der Nature have been criticized by some as being more artistic than scientific, for example artificially adding symmetry to radiolarians. In this regard it is interesting to compare an illustration from the original description to that in the Kunstsformen plate. Figure 9 shows the illustration of Dictycocodon annasethe from the original description in the Challenger Report with that in Plate 31 of the Kunstformen. Near perfect symmetry is apparent in the Kunstformen version compared to the rather approximate symmetry shown in the Challenger Report (Haeckel 1887b). Aesthetics trumped accuracy in the Kunstformen illustrations of at least some organisms. Furthermore, Haeckel's own words concerning the use of color in the Kunstformen (from Richards 2009, a translation of text from the Forward) are telling. It would appear then the Kunstformen illustrations likely should be considered as primarily artistic works rather than scientific illustrations.

I have been convinced that colored images (even of a mediocre production) are much more valuable for a vivid intuitive awareness of nature than the photograph or the simple black-and-white illustration. Indeed, a crude color sketch (if it conveys the landscape in a vivid fashion) has a deeper and more stimulating effect than the best black-and-white illustration or photographic representation. This distinction lies not only in the effect of color itself-since different individuals are sensitive in different measures-but also because the painter, as thoughtful artist, reproduces in his subjective image the conceptually articulated character of the landscape and emphasizes its essential features. The objective image of the photograph, by contrast, reproduces equally all parts of the view, the interesting and the mundane, the essential and the inessential. Thus the colored photograph, if it should be brought to perfection, will indeed never be able to replace the individually conceived and deeply felt image of the painter. It is perhaps noteworthy that the two volume tribute to Ernst Haeckel, published the year of his death (Schmidt 1904) and filled with laudatory texts from scientific notables was illustrated not with any of his scientific illustrations but mainly with Haeckel's landscapes. Furthermore, the last image of Haeckel in the book of remembrances is of him as an artist (Fig. 10). Regardless of any scientific view, for the general public, Haeckel's illustrations are artworks. For the general public, what in Haeckel's art appears to be most popular? One manner of assessing popularity is the price of the individual plates of Kunstformen der Natur plates. Dealers in old books and prints offer for sale the individual prints. Presumably the plates were printed in about equal numbers so that price differences among the plates should reflect differences in demand more than supply. One dealer offering individual plates for many years now is Stefan Wulf of Berlin. His 2019 catalogue [START_REF] Wulf | Ernst Haeckel's Artforms in Nature: A Catalogue of all 100 plates, 33 suites and 2 fine copies[END_REF]) includes all the plates. In Wulf's catalogue, the prices of the Kunstformen plates vary considerably, from $25 to $250, with the highest price asked for the plate 8 of the medusa Desmonema annasethe. One naturally assumes that the multi-colored plates fetch a higher price than the mono-chromatic plates, regardless of subject, and indeed the average prices are $91 and $49, respectively. Still, among the multi-colored plates, the medusa plates average $91 and the radiolarian plates $61. Thus, it appears that, based on prices, the medusa plates are more popular than the radiolarian plates. Are the medusa and radiolarian plates overall more appreciated, based on price? The average price of the medusa and radiolarian plates is $71 compared to $63 for the other subjects. It appears then that is a higher demand for plates with medusa or radiolarians than for other subjects.

Conclusion: Villfranche & Haeckel

As a final note concerning the importance of Haeckel's visit to Villefranche, it does appear the subjects linked to his stays in Villefranche, the radiolarians and medusa, were to the most popular with Haeckel himself, among the many zoological topics he studied, given the number of publications he ultimately devoted to them (Fig. 5). His medusa and radiolarian artwork, compared to his other subjects, appear to be the most popular with today's general public based on the asking prices for Haeckel's artworks. Thus, his major scientific and artistic legacies, both of which are considerable, are intimately linked to Villefranche. Despite the apparent links, Haeckel did not return to Villefranche until late in his life, just a few years before his death in 1919. He visited his former student Michael Davidoff at the Russian Zoological Station in Villefranche while attending the 1910 opening of the Oceanographic Museum [START_REF] Davidoff | Was für mich Haeckel's "Natürliche Schôpfungsgeschitchte[END_REF]. One can only speculate that perhaps Villefranche was also intimately linked to his grieving for Anna Sethe.

Fig 1 .

 1 Fig 1. Examples of Haeckel's illustrations of radiolarians (left panel), plate in Haeckel 1862 and medusa (right panel), plate 3 in Haeckel 1879. In actual size, the radiolarians shown are about 1/10 mm in diameter and the medusa shown are about 3 cm long.

Fig 3 .

 3 Fig 3. Plate 33 from Haeckel's 1862 monograph Die Radiolarien, showing the radiolarian species first collected during his 1856 visit, Sphaerozoum italicum (figs. 1 & 2). The diameter of the radiolarian is about 1/3 mm.

Fig. 4 .

 4 Fig. 4. The plate from Haeckel 1865a (Über den Sarcodekörper der Rhizopoden) illustrating the radiolarians observed during his 1864 visit. Fig. 1 & 2: Protogenes primordialis 'feeding'; Fig. 3: Acanthodesmia polybrocha; Fig. 4: Actinelius purpureus; Fig. 5: Cyrtidosphaera echinoides. The actual size of all are about 1/4 mm in longest dimension.

Fig. 5 .

 5 Fig. 5. Haeckel's first published illustration of a meduse: Plate 11 from Haeckel 1864c (Die Familie der Rüsselquallen, Medusae Geryonidae) Carmarina hastata. Actual size of the meduse is about 10 cm long.

Fig. 6 .

 6 Fig. 6. One of the new medusa Haeckel found in Villefranche he named for deceased wife Anna Sethe Haeckel, Mitrocoma annae. It was the first of 3 species he named for her. The illustration is from his 1879 'System der Medusan'. The actual size of the 'bell' portion is about 4 cm

Fig. 7 .

 7 Fig. 7. Haeckel's output of publications concerning radiolarians and medusa from 1860 to 1890 based the titles given in Way's Haeckel bibliography (Way 1909).Haeckel's many publications on medusa began appearing shortly after his second visit to Villefranche. Note the apparent alternations of periods dominated by publications on one group. Haeckel's total output from 1855 to 1900 numbered 107 titles. Radiolarians and medusa accounted for 14 and 17 titles respectively, many more than any other individual groups. For example, the third most represented group was sponges with 4 titles (not shown).

Fig. 9 .

 9 Fig. 9. Dictyocodon annasethe from Kunstformen der Natur in plate 31 (left) and from the plate 71 in the Challenger Report (right). Note the near perfect symmetry in the Kunstformen version compared to the original version. The actual size is about 1/5 mm long

Fig. 10 .

 10 Fig. 10. Ernst Haeckel in 1914 from the Heinrich Schmidt's 1914 tribute to Haeckel "Was wir Ernst Haeckel Verdanken". Photo by Alfred Bischoff taken in 1914.

Acknowledgements

Encouragement was kindly provided by Robert J. Richards and Marie-Christine Maurel. The comments of David Montagnes on earlier drafts resulted in considerable improvement. However, I retain full responsibility for all errors of fact and interpretation.