Thinking about sex and gender would help scientists improve their research, a new article published today argues.
Writing in a special 150th anniversary edition of Nature, five experts say these factors are too often ignored.
They say incorporating sex (the biological attribute distinguishing females, males or intersex/hermaphrodite individuals) and gender (psychological, social and cultural factors affecting how an individual identifies in society) could improve experiments, reduce bias and create opportunities for discovery and innovation.
The article highlights a host of examples in which including sex and gender has led to advanced understanding or insight – from male and female shellfish responding differently to climate change, to gendered social robots and to computer vision improvements prompted by evidence that facial recognition systems misclassify the sex of darker-skinned women more often than lighter-skinned men.
“It’s striking to what degree sex and gender are overlooked in science,” said co-author Dr Robert Ellis, of the University of Exeter.
“We need to include this at every level of research and in everything we do, or provide robust scientific justification as to why sex or gender are unimportant, based on experimental evidence.
“Things are certainly improving. For example, the original crash test dummies were based on a male physique, however a study found that as a result US female drivers were 47% more likely than males to suffer severe injuries in a comparable crash.
Such insight undoubtedly helps engineers design more sophisticated test platforms that will ultimately prevent major injury or save lives.
“Sex and gender are increasingly seen as important in research, but misconceptions and under-consideration still persist.
We know, for example, that researchers’ sex can affect how they interpret their observations, so this should be considered during the research process.”
The paper focusses on four key areas – marine science, biomedicine, robotics and artificial intelligence – but the authors say the lessons apply across scientific disciplines.
They highlight scientific successes achieved due to consideration of sex and/or gender.
Dr Tannenbaum from the Canadian Institutes of Health Research points to our deeper understanding of the genetic basis for sex differences in immunity.
“We now know immune cells function differently depending on whether they have XX or XY chromosomal complement or are exposed to different concentrations of sex hormones in the body.
There are exciting implications for antibody treatments and new cancer immunotherapies.
Who knows? One day men and women may be treated completely differently for the same health condition. Patients should ask their healthcare provider if the treatment being recommended works equally well for individuals with their same sex and gender. ”
A study in mice showed, surprisingly, that pain levels the animals exhibited changed depending on whether a male researcher was in the room.
Researchers concluded that the animals responded to a scent associated with men. What’s more, whilst both female and male animals showed this response, female mice were more sensitive.
Marine biologist Dr Ellis said: “Within the oceans there are many examples highlighting the importance of considering sex differences within species.
In marine turtles, incubation temperature determines the sex of hatchlings, so climate change could poses a major threat to this group and could lead to the total feminisation of some turtle populations.
“Marine biology also reminds us of the need to challenge the assumption that sex is binary and fixed. Clownfish, for example, are ‘protandrous hermaphrodites’ (they mature as male; some change to female).
Living in a strict social hierarchy each family contains a single dominant female that mates with a single large male in the social group.
“All remaining individuals remain juveniles. Removal of the alpha female results in the alpha male changing sex to female, with all subordinates moving up a rung in the social hierarchy. This natural phenomenon certainly adds a fascinating plot twist to the Finding Nemo story, but it also highlights a key area of biology that requires further study in relation to things like climate change.”
The paper says the goal is to “increase transparency, promote inclusion and reset the research default to carefully consider sex and gender, where appropriate”. For instance, one would hardly assume that social robots are attributed a male or female gender.
However, as social psychologist and social roboticist Dr Friederike Eyssel from Bielefeld University emphasizes: “People use mental shortcuts to evaluate nonhuman entities and through the process of anthropomorphising social robots, humans even ascribe gender to robots.
Empirical and experimental research has shown that this impacts the perception of such novel technologies.
The article highlights a host of examples in which including sex and gender has led to advanced understanding or insight – from male and female shellfish responding differently to climate change, to gendered social robots and to computer vision improvements prompted by evidence that facial recognition systems misclassify the sex of darker-skinned women more often than lighter-skinned men.
“Moreover, gendering robots has strong social and ethical implications that need to be taken into account by developers of social robots and by stakeholders who aim to deploy robots in various domains of use in people’s everyday lives.
At the same time, clearly, further research is called for to explore the effects of gendered technologies in field settings.
The existing literature marks a relevant first step to our understanding of the role of sex and gender in the design and uptake of novel technologies.”
The Nature “Perspective” sets out a “roadmap” and calls on researchers, funding agencies, journals and universities to coordinate efforts to implement robust methods of sex and gender analysis.
It concludes: “Eyes have been opened, and by integrating sex and gender analysis into their work, researchers can enhance excellence and social responsibility in science and engineering.”
The study was led by Professor Londa Schiebinger (Stanford University, USA), and co-authored by Dr Ellis, Dr Cara Tannenbaum (University of Montreal, Canada and the Canadian Institutes of Health Research), Professor Friederike Eyssel (University of Bielefeld, Germany) and Dr James Zou (Stanford).
Dr Ellis, Dr Tannenbaum and Dr Schiebinger are part of an expert panel which will report to the European Commission, helping to inform the integration of sex and gender in funding decisions in the next major round of EU research projects.
Even though we know that males and females are not the same, experiments have sometimes been carried out without considering sex in scientific research. Scientists have often used only one sex (generally male) for experiments and applied the findings to both sexes, without solid grounds. These kinds of inadvertent extrapolations might cause unintentionally harmful results to the neglected sex and economic loss.
During the time period from 1997 to 2000, ten prescription drugs were withdrawn from the market by the US Food and Drug Administration (FDA). Eight of the withdrawn drugs caused greater health risks in women (1).
Looking in detail, four of the drugs caused more adverse events in women because they were prescribed more often to women than to men. However, the other four drugs had more detrimental effects in women, even though they were equally prescribed to both women and men, suggesting that physiological differences between males and females predispose women to some adverse drug-related health risks (1).
Deleterious effects of these drugs on females only became evident as a result of post-marketing reports, mainly because preclinical studies were undertaken using mainly male subjects (2) and, even during clinical studies, females were under-represented (Fig. 1).
Schematic drawing shows male-biased preclinical and clinical research can leave detrimental side effects for women undetected till marketing.
In 1992, the FDA released a report on the practices for approving prescription drugs (3). The report showed that women were generally under-represented in drug trials and, even when women were included in large numbers, data were not analyzed to determine sex-related differences in drug responses. After decades of clinical research, mostly excluding women, researchers began to realize that men and women have large differences beyond their reproductive systems (4). As a result, the FDA cleared restraint for the inclusion of women with childbearing potential in clinical trials and established guidelines regarding the analysis of data by sex. The US Congress codified this amendment to NIH policies into public law, through a section within the 1993 National Institutes of Health (NIH) Revitalization Act (available at https://orwh.od.nih.gov/resources/pdf/NIH-Revitalization-Act-1993.pdf). Under this law, NIH made certain that women and minorities are included in all clinical research, and Phase III clinical trials include women and minorities in sufficient numbers to enable valid analyses of differences among groups.
In 1999, the Institute of Medicine (IOM) of the National Academy of Sciences formed the ‘Committee on Understanding the Biology of Sex and Gender Differences.’ The committee, consisting of experts from a wide range of disciplines, evaluated and considered a contemporary understanding of sex differences and determinants at the biological level. As a result, IOM published a report in 2001 (5), concluding that “Sex matters” and “Being male or female is an important basic human variable that should be considered when designing and analyzing studies in all areas and at all levels of … health-related research.”
Based on human biology research over the past decade, it is now widely accepted that normal physiological functions and many pathological functions are influenced by sex-based differences (5, 6). Thanks to all these efforts, women are now better represented in clinical trials.
Much of our understanding of disease processes and treatment measures are based on the results obtained from basic and preclinical studies that use nonhuman animals and cell cultures. Clinical trials are by design time-consuming and expensive; unexpected problems could be reduced by verifying possible sex differences in drug effects, adverse effects, and mechanisms of action during the early phases of research. Thus, it is very important to integrate sex as a biological variable for preclinical research. However, the realization that sex influences biology and pathology has been slow in coming for preclinical studies (7, 8). Furthermore, instructions or guidance to consider the effect of sex on basic and preclinical research were rare, until recent years.
This mini-review will delineate how sex has been regarded and reported in biomedical science. Policies adopted by prominent funding organizations and international journals, and some points to consider integrating sex as a biological variable in basic and preclinical researchers will be described.
DEFINITION OF ‘SEX’ AND ‘GENDER’
Sex and gender are occasionally used in an interchangeable manner. Both sex and gender affect research results, but they have different meanings. Thus, it is important to know the correct meanings of them and to avoid interchangeable use. According to the US Institute of Medicine (IOM) (5), sex is “the classification of living things, generally as male or female, according to their reproductive organs and functions assigned by chromosomal complement”, while gender is “a person’s self-representation as male or female or how that person is responded to by social institutions on the basis of the individual’s gender presentation. Gender is shaped by environment and experience.” Thus, sex is related to reproductive organs, sex hormone, gene expression, anatomy, and physiology. Gender refers to socio-culturally constructed roles, norms, identities, and power relations (9) that, together, shape ‘feminine’ and ‘masculine’ behaviors (10). Sex can be used for both human and animals as whole organisms or materials derived from them such as cells and tissues, while gender is in general used only for humans. Importantly, sex and gender affect each other, as gender is rooted in biology and can influence biological outcomes.
NEGLECTED AND BIASED SEX IN BASIC AND PRECLINICAL STUDIES
Animal experiments
A literature review was conducted to grasp the sex bias in experiments (11). Among articles that reported non-human animal studies in the Journal of Pharmacology and Experimental Therapeutics and the Journal of Physiology in 1909, 79% failed to report the sex of the animal. The percentage of articles with an unspecified animal sex decreased steadily from 79% to 50% through 1969. There was a sudden drop in those values, reaching 20% in 1979, and then stabilized to around 20–30% during the period from 1979 to 2009. The ratios of papers reporting male-animal-only reports were around 5–20% between 1909 and 1969. It jumped up to 70% in 1979 and then stabilized at around 50% up until 2009. Studies that enrolled both female and male animals remained low, reaching only 15% during 1909–2009. To make matters worse, among the studies using both sexes, only 34% analyzed data separately by sex.
Journal articles published in 2009 across 10 major biological disciplines (pharmacology, endocrinology, behavior, behavioral physiology, neuroscience, general biology, zoology, physiology, reproduction, and immunology) were then analyzed to compare sex bias status among research fields (11). The articles were classified according to species studied and the sex of the subjects. Survey results showed that over 50% of articles in general biology and immunology fields did not specify the sex of the animals used in the study. For the articles that defined the sex of the animal, a male bias was observed in 8 of the 10 fields. A male skew was especially conspicuous in neuroscience (5.5: 1), pharmacology (5: 1), and physiology (3.7: 1) fields. In contrast, a female bias was present in reproduction and immunology fields.
The ‘Thomson Reuters Web of Science’ database for 2009 was also examined to investigate the use of female animals in studies for particular diseases such as anxiety, depression, epilepsy, thyroiditis, hypertension & stroke, multiple sclerosis, obesity, and pain (12). The results showed that the percentages of females in rat and mouse models of the diseases under investigation were not in proportion, but that female animals were severely under-represented, given the prevalence of corresponding diseases in women worldwide. For example, women are twice as likely to be diagnosed with anxiety and depression than men, but fewer than 45% of animal studies used females to investigate these disorders (12). Regrettably, the situation has not improved much until recent times (13, 14).
Cell experiments
Cells do have sex and the sex of cells influences experimental results by affecting cellular behaviors such as proliferation, differentiation, response to stress, and apoptosis (15–17). However, most scientists do not give any thought to the sex of the cell and the effect of sex at the cellular level. Consequently, sex of cell is not properly reported in articles. Only 45 (23.6%) out of 191 articles published in top cardiovascular journals reported cell sex in 2010 (18). Among these 45 studies, most (68.9%) used only male cells and none exclusively used female cells. Omitting the sex of cells is not limited to any specific research field. Shah et al. (19) reported that the sex of cells was described in only 25 of 100 randomly selected articles from the American Journal of Physiology-Cell Physiology published in 2013.
The sex of cells is also ignored by commercial cell vendors. Approximately 15.5% of human cell lines were sold without sex identification as of the year 2014, by three prominent cell providers: American Type Culture Collection, European Collection of Cell Cultures, and Japanese Collection of Research Bioresources (20). Sex identification was even scarce for animal cell lines compared to human cell lines. In addition, the majority of primary cells and stem cells were sold without defined sex (20).
SEX/GENDER ANALYSIS POLICIES OF MAJOR GRANTING ORGANIZATIONS
Recently, funding organizations including the European Commission (EC), Canadian Institutes of Health Research (CIHR), and the US National Institutes of Health (NIH) put efforts into influencing researchers to integrate sex and gender in the whole study processes from hypothesis to publication.
EC (EU)
The EC is an institution of the European Union (EU). EC has emphasized “questioning systematically whether and in what sense, sex and gender are relevant in the objectives and in the methodology of projects” since 2003 (European Commission, 2003). Likewise, gender has been supported as the main theme in Horizon 2020 which is the largest ever EU Research and Innovation program and the EC’s current funding framework. To propose new ways for integrating the gender dimension into all aspects of research and innovation contexts, Horizon 2020 Advisory Group for Gender issued a position paper in Dec. 2016 (21). The position paper argues that the gender dimension is an essential aspect of research excellence and the quality and accountability of research are negatively affected by not taking into account sex and gender. The paper also emphasizes that “Addressing the gender dimension in research and innovation entails accounting for sex and gender in the whole research process, when developing concepts and theories, formulating research questions, collecting and analyzing data, and using the analytical tools that are specific to each scientific area.”
CIHR
CIHR is the Government of Canada’s health research investment agency. CIHR is using four approaches to improve sex and gender integration in health research (22). 1) CIHR requires all research applicants to report sex and gender integration in their proposal. 2) CIHR mandates research teams to include a person showing sex and gender expertise (sex and gender champion) for the research topic under investigation. Sex and gender champions ensure that sex and gender are essential ingredients of the research principle, study design, experimental methods, data analysis, and knowledge interpretation. 3) CIHR asks a cross-cutting sex and gender platform is included within large research consortia. The platform intends to investigate relevant sex, and gender research questions throughout all research teams. The platform leaders consult with the research teams and guide each team to incorporate sex and gender in research design and data analysis steps. Fourth, CIHR ensures that all grant applicants complete sex and gender online training programs (available at http://www.cihr-irsc.gc.ca/igh-competency.html) which CIHR developed in September 2015. Grant applicants should submit proof of completion of at least one of three online training modules (22). Furthermore, the CIHR provides a detailed checklist for reviewers who evaluate biomedical and translational research proposal (available at http://www.cihr-irsc.gc.ca/e/49337.html).
NIH
Even after decades of efforts to integrate sex/gender in biomedical research, the change has been slow. To rectify this situation, NIH announced a policy aimed at integrating sex as a biological variable (SABV) into biomedical research in May 2014 (23). The policy requires that “applicants to report their plans for the balance of male and female cells and animals in preclinical studies in all future applications, unless sex-specific inclusion is unwarranted, based on rigorously defined exceptions.” NIH then declared NIH Guide Notice NOT-OD-15-102 in 2015 (available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-102.html). A document serves as a companion reference to NOT-OD-15-102 says that “In particular, sex is a biological variable (SABV) that is frequently ignored in animal study designs and analyses, leading to an incomplete understanding of potential sex-based differences in basic biological function, disease processes, and treatment response. NIH expects that sex as a biological variable will be factored into research designs, analyses, and reporting in vertebrate animal and human studies. Strong justification from the scientific literature, preliminary data or other relevant considerations must be provided for applications proposing to study only one sex.” (available at https://orwh.od.nih.gov/resources/pdf/NOT-OD-15-102_Guidance.pdf). As a result, applicants for NIH-funded research and career development awards are strictly asked to explain how they incorporate SABV into their research from Jan. 25, 2016. Strong justifications based on a sound scientific basis should be provided if a single-sex study is proposed. In addition, NIH also prepared guidelines to help grant reviewer (available at https://grants.nih.gov/grants/peer/guidelines_general/SABV_Decision_Tree_for_Reviewers.pdf).
NIH and CIHR adopted a consensus list of 13 evaluation criteria as a minimal standard for reviewers (24). Key questions peer reviewers should ask when evaluating the overall score of a grant application include: Quality and appropriateness of SABV; Justification for a single-sex study; Evidence that the research question incorporates SABV; Potential for the research to add value to the current state of knowledge on a given topic that has potential to, but has not yet fully elucidated the impact of sex on biological mechanisms, pathophysiology, or translational science; Impact of research incorporating SABV; Potential for a significant contribution to the improvement of women and men’s health, the health of boys and girls, or the health of gender-diverse persons.
Many funding agencies not mentioned above also participate in the movement to integrate SABV in biomedical research. More information can be found at the Stanford University’s Gendered Innovations home page (available at http://genderedinnovations.stanford.edu/sex-and-gender-analysis-policies-major-granting-agencies.html).
Source:
University of Exeter
Media Contacts:
Duncan Sandes – University of Exeter
Image Source:
The image is in the public domain.
Original Research: Closed access
“Sex and gender analysis improves science and engineering”. Cara Tannenbaum, Robert P. Ellis, Friederike Eyssel, James Zou & Londa Schiebinger.
Nature doi:10.1038/s41586-019-1657-6.
