by Kate Allen for Toronto Star:Gillian Einstein, a distant cousin of Albert Einstein, is exploring why brain disorders like Alzheimer’s disproportionately affect women. Her research raises a difficult question - Do cultural practices and health anomalies reflect differences between the sexes, or do they create them?
Soon after opening her lab at the University of Toronto in 2006, Gillian Einstein began investigating the effects of female genital cutting. For a cognitive neuroscientist, this might seem like an unusual part of the body to study.“So much of the focus of these women has been on their genitalia and reproductive lives,” Einstein says. “Of course I care about that if that’s important to them. But I actually started out by telling the women, I’m not interested in your genitalia. I’m interested in your brain.”Einstein began sifting through research on what is sometimes called the sensory “homunculus,” the pictographic map of the brain showing where sensation in each body part is processed. This map, one of the most famous illustrations in neuroscience, looks like a bit like a ghoulish Spartan helmet: a curved hemisphere of cortex with drawings of limbs, digits and organs sprouting from every inch.Einstein knew that the brain region where sensation from the genitalia is processed sits right beside the spot for sensation from the feet and lower limbs. She wondered, among other questions, if cutting these women’s genitals affected their gait. But as she and her team rummaged through 65-plus years of literature, every illustration of the sensory homunculus depicted a man.Nobody had mapped a woman’s body. The “hermunculus,” as Einstein later termed it, is mostly blank apart from the breasts and vagina.
Aside from the potent symbolism, this ignorance has real consequences.The sex and gender bias in clinical health research is long established. Published studies on erectile dysfunction outnumber studies of premenstrual syndrome five to one, though a fraction as many men suffer from ED as women suffer from PMS. Because women were under-represented in clinical trials for decades, the efficacy and safety of therapies are less certain for them; of the 10 prescription drugs withdrawn from the U.S. market between 1997 and 2001, eight were more dangerous for women. Policies to address the clinical trial sex gap have existed since the 1990s.The imbalance in basic cellular biology is less obvious to non-scientists, and even to some scientists. Researchers often rely on male mice and cells in basic experiments, and assume their findings will hold up in female mice or cells, too: male biology is assumed to be universal. Neuroscience is the discipline in which this bias is most pronounced. One survey found 5.5 times as many neuroscience studies that only used male animal models compared with those that used only females.n recent years, a chorus of scientists has argued that this assumption is dangerous, and risks occluding sex differences that could help us understand disease in both women and men.Einstein has staked her career in the middle of this bald desert of ignorance.She runs the rare lab that focuses almost exclusively on the basic biology of women’s brains. But her research is also bolstered by an even less common concept, at least in neuroscience: that to understand the brain we need to examine not only sex differences like hormones and genetics but also the cultural context of gender, and how social and cultural life experiences are absorbed into our biology. “The world writes on the body,” Einstein often says.In December, Einstein was awarded the inaugural Wilfred and Joyce Posluns Chair in Women’s Brain Health and Aging, which comes with $1 million over five years to investigate why women are more affected by brain disorders like depression, stroke and dementia. Along with her work on sex differences, the grant specifically supports her research on the cultural and social factors that might be tilting this disease burden onto women.“This idea that gender is only social, and doesn’t get under the skin,” Einstein says, “is no longer true.”
Her famous surname is not a coincidence: Einstein is a distant cousin of Albert Einstein on her father’s side, a blood tie that the theoretical physicist confirmed in a letter to a relative who had inquired about the connection, Gillian Einstein says.But it was her mother, a lover of science, who installed a telescope on the family’s front lawn in Texas when Einstein was a child. Her father was in the U.S. air force, and the family moved from New York City to Texas to Massachusetts before Einstein’s first year of high school.Einstein studied art history as an undergraduate at Harvard. But after a class on the richly coloured, exquisitely detailed Indian paintings of the Mughal and Rajput eras, she felt an urge to understand vision on a different level.“I started wondering, how is it that people actually see the colour and the composition? What’s the mechanism by which we perceive this?”Einstein was sitting on the steps of the museum where the class was taught, talking to a friend. “Isn’t there a way that we could know about how people actually view, literally see, these paintings?” Einstein remembers saying. “She said, ‘Yes, there is a field, and it’s called neurobiology.’”This was not an obvious response — the discipline was barely hatched. Harvard’s neurobiology department, the world’s first, had been established in 1966, less than a decade before that conversation on the steps.“It was almost like a fortune cookie,” Einstein says.She decided to commit herself to this nascent field, gaining admission to the University of Pennsylvania, where she studied the visual system and earned a PhD. By 1989, she was an assistant professor at Duke University in Durham, N.C.Duke offered two important resources: a pioneering, multidisciplinary group devoted to the study of Alzheimer’s, and “very fresh brains,” Einstein says. The Alzheimer’s group had set up a program to receive the brains of patients soon after they died. Einstein had realized that some of the brain areas affected by Alzheimer’s were the same as those she studied in her vision research, and often found herself looking at brains riddled with the plaques and tangles of the disease.
The sensory "homunculus," the pictographic map showing where in the brain sensation in each body part is processed — at least for men, in this iteration. (SYSTEM)
As her interest in Alzheimer’s, aging and cognition grew, she became an advisory board member — the “token scientist” — for Duke’s women’s studies program. She wanted to develop a course that could be offered in both biology and the women’s studies department, and she wanted to teach substantive biology.Einstein started reading about sex differences and particularly hormones. The course ended up informing her own research agenda, too.Scientists have spent the last century uncovering the pathways that push a featureless embryo to differentiate into a male or female. The picture they have established describes a cascade: in males, genes on the Y chromosome switch on a surge of hormonal interactions that give rise to male features. Females, with XX chromosomes, develop in the absence of this powerful cascade.Researchers also wanted to know whether sex hormones “organize” neural tissues, creating male and female brains as well as male and female bodies. If they did, could this influence behaviour? Early experiments tinkered with animals’ exposure to hormones in the womb, and found that it did affect sex-typical mating behaviours, like how often males mounted females. These discoveries in guinea pigs and rats set off a hunt to identify equivalent differences in human brains, and to understand how male-female brain organization affects human behaviour — even behaviour as complicated as language and sexual identity.But Einstein also took pains to teach material that complicates this simplistic split pathway. Intersex individuals, whose genetic, hormonal and genital sexes do not align or are indeterminate, have long troubled our binary observations of sexual differentiation. Even in research that formed the basis of brain organization theory, animal and human behaviour didn’t always fall into two neat camps. More recent research has suggested that the mainstream theory of embryonic sex differentiation, with its powerful male cascade and passive female pathway, is too simplistic.Einstein wanted her students to understand this “beautiful” field, but also “how complicated sexual differentiation actually is” — humans, she stresses, don’t only come in two forms. Science tends to straighten the messy variability of nature into two discrete categories, overlooking when no differences exist, or when differences do exist, but don’t have an effect.When differences are discovered, particularly in the brain, they tend to be amplified — especially by the media — into a Men are from Mars, Women are from Venus narrative, says Gina Rippon, a professor of cognitive neuroimaging at Aston University in the U.K. Rippon calls this propping up of stereotypes “neurotrash,” and offers a mocking headline: “At last the truth: why women can’t read maps and men can’t cry!”Einstein wondered if sex differences really begin to matter when the body experiences disease. In the lab, she began to question whether sex differences might explain the higher prevalence of Alzheimer’s in women.At the time, in the 1990s, not much fuss was made over this statistic: age is the biggest risk factor for the disease, and women have longer average life spans than men. But Einstein knew that the loss of synapses — the connection between individual neurons — is a hallmark of Alzheimer’s. And she knew that research on female rodents showed changes in connectivity in the hippocampus, one of the first areas affected by Alzheimer’s, during the ovulation cycle.Looking at the imbalance of Alzheimer’s in women, “I wondered if it had to do with estrogen depletion and replacement,” she says. Most women with the disease are diagnosed after menopause, when estrogen sharply drops. Experiments in her lab showed that dendrite density in female rat brains, in an area affected by Alzheimer’s, changed in response to estrogen exposure differently than male rat brains did.Hormones began to be the key question for Einstein: they allow organs as disparate as the gonads and the brain to communicate, and respond to external cues from the environment.“You can’t study hormones without realizing that the entire body is connected. The mind is the body, as far as I’m concerned. The body has a mind,” she says. “Cognition isn’t necessarily something that just happens in the brain.”
Mughal art, like this example circa 1570, prompted a young Gillian Einstein to wonder about the neurobiological underpinnings of human perception. (METROPOLITAN MUSEUM OF ART)
Teaching the class sharpened other questions for Einstein. She had “always been feminist,” she says. Her literature search introduced her to feminist scholars who, rather than accepting the interpretation of scientific results as objective truth, questioned how politics and culture influence the production of knowledge.In a classic 1991 essay, anthropologist Emily Martin observed how accounts of the human reproductive process usually depict sperm swimming heroically upstream in order to forcefully penetrate a passive, waiting egg — even after research showed that’s not what happens. Adhesive molecules on the egg’s surface allow it to trap sperm, which would otherwise flail ineffectually because of weak forward thrust. The damsel-in-distress narrative survives anyway.Cultural narratives can influence how we interpret results, or stop us from asking questions that might lead to different results. Most influential to Einstein’s research was the work of Anne Fausto-Sterling, a geneticist and professor emerita at Brown University who writes about biology, gender and sexuality. Fausto-Sterling has examined bone density, a trait with sex differences: women have less dense bones, leaving them more susceptible to breakage and osteoporosis.But ultra-Orthodox Jewish teens, who are exposed to less sunlight and less physical activity, have less mineralization of their lower vertebrae than non-religious teens, Fausto-Sterling notes, while women in China who work in fields have high levels of mineralization and bone density. Are weaker bones in women a sex difference, or a gender difference, the result of how people who present as women are usually socialized?“If ‘facts’ about biology and ‘facts’ about culture are all in a muddle, perhaps the nature/nurture dualism, a mainstay of feminist theory, is not working as it should,” Fausto-Sterling writes. “Perhaps, too, parsing medical problems into biological (or genetic or hormonal) components in opposition to cultural or lifestyle factors has outlived its usefulness.”Einstein has absorbed that philosophy in her lab.“I think there’s a lot to be learned about how gender influences Alzheimer’s disease. I think women are exposed to gendered life experiences that men aren’t, and I think that sets a stage for neurodegeneration. But I also think there are biological factors that do that as well,” she says.People who have been depressed are more likely to have dementia later in life, for example, and women experience more depression than men. How much of that depression is attributable to burdens placed on women: the stress of caregiving, the trauma of sexual violence, the straitjacket of economic inequality?“I don’t think you can imagine that experience doesn’t shape biology anymore. They’re almost inseparable … you dissociate them for purposes of an experiment, but really you can’t dissociate them.”In 2004, Einstein moved to Toronto to take up an administrative position at Women’s College Hospital’s research institute, the Centre for Research on Women’s Health, with a cross-appointment in Public Health. She always wanted to move to Canada, a country whose social values pulled her, and she credits the country with being a leader in gender and health research.Soon after Einstein came to Toronto, a research position opened in the psychology department at U of T. Einstein started building a lab again, one that would pull all these concerns under a big tent: sex, gender, aging, cognition and women’s health.Centring a research program on women’s biology can be challenging, Einstein’s colleagues say.“So little research has been done in women,” says Kathryn Sandberg, director of Georgetown University’s Center for the Study of Sex Differences in Health, Aging and Disease. “We’re starting at a much lower level. If somebody sees two grant applications and one seems far more sophisticated, that’s because they have this whole literature (behind them) — science is building blocks.”That, of course, is also what makes Einstein’s work important, Sandberg says: “She’s studying topics no one else is looking at.”One of the first studies Einstein carried out was the research on female genital cutting — a term that she prefers to either “female genital mutilation” or “female genital circumcision” because it describes what is happening to the nerves and muscle.She had begun thinking about the practice in 1995, and was surprised that no one had explored its neurobiological repercussions: studies of phantom limb syndromes are widespread. Einstein hypothesized that cutting the genitals may lead to a rewiring of the central nervous system, resulting in degeneration of nerve pathways and changes in the somatosensory cortex — the “hermunculus” — that give rise to chronic pain.Einstein reached out to a midwife and three other health care workers from Toronto’s Somali diaspora. (FGC is practiced in many countries worldwide, but Einstein wanted to focus on one cultural group so that the study participants would have similar backgrounds.) These four Somali-Canadians became the project’s community advisory board, helping the lab understand the perspectives of the 14 study participants.Einstein is still investigating the gait question. But her research did find that these women had areas, including their legs but especially their vulvas, with extremely high pain measurements. These measurements are indirect support for her theory about rewiring of the nervous system.This research is still ongoing. But Einstein believes she is beginning to prove that these women have “embodied their culture,” that they walk, carry themselves and experience the world differently as a result of this practice — that the social has become biological.The brain “isn’t CEO of the body,” she adds: it is transformed in response to the genitals, and the genitals are changed in response to culture.“It can raise awareness about our own social practices. The results of the surgery don’t just stay at the point of surgery,” she says.Myriad other projects are underway in the lab. Einstein describes a great day as a day in which she talks to a student about a new idea. When an undergraduate, Seth Watt, approached her with a hypothesis about sex-typical cognition in trans men, she brought him on board.Watt found that their cognitive patterns were highly malleable. “It is undermining the whole assumption of the fixed, static, sexed brain,” says Watt, who is trans himself and who is starting a graduate degree in evolutionary biology later this year. “We really didn’t see that at all. Everyone went through periods of male-typical or female-typical (cognition).”But the work Einstein considers especially important is the project on estrogens, cognition and aging.Research has borne out her hunch from the 1990s that the increased burden of Alzheimer’s on women is more than the result of their longer average lifespans. Nearly 25 years ago, a neurologist from the pioneering Duke University Alzheimer’s group that Einstein worked with, Allen Roses, was the first to discover the ApoE-4 gene variant. Studies that compared people with the gene variant to those without it found that carriers had a higher risk of developing late-onset Alzheimer’s. But only in the last few years, when researchers began to account for sex, was an important difference uncovered: female ApoE-4 carriers nearly doubled their risk, while male carriers’ risk only slightly increased.Einstein is looking for similar clues in hormones. She launched a study of women with mutations in the BRCA gene, who carry a significantly higher risk of breast and ovarian cancer. This group of women presents a natural case study for the effects of the loss of estrogen on cognition.Some BRCA mutation carriers undergo surgeries to remove their ovaries, a pre-emptive shot at reducing cancer risk. The removal causes a sudden drop in estrogen and sends the women, if they haven’t already reached it, into early menopause. These women can be compared to their BRCA-carrying and non-BRCA-carrying peers who haven’t had surgery, reducing the complicating brain effects of aging.The study is still recruiting participants. But so far Einstein and her team have met with approximately 50 women in each group, comparing their performance on memory tasks that rely on different parts of the brain. Her lab is looking not just for cognitive function that has worsened — which, if it occurs, will be subtle — but also performance that hasn’t changed, or that has improved. Of course, lifestyle factors are taken into consideration, too.“It’s a complicated picture,” says Einstein. “Estrogen doesn’t act alone, ever. That’s the beauty of estrogen. That’s why I love it.” The new $1-million chair will allow the lab to broaden its research, looking at other variables. As part of the chair, Einstein, the former art history major, is also planning to promote understanding of women’s brain health through artist’s representations and poetry.She hopes this research will spur new thinking about the role of ovaries and the assumption that they have no purpose beyond reproduction. “I think ovarian removal is cultural. It has biomedical reasoning behind it, but you can imagine societies that might do something very different.”But her primary goal, she says, is to understand something fundamental about the role of hormones in the brain. Much less is known about estrogen than other hormones like testosterone.“I love ignorance. I embrace it. Most of the time we’re looking for the next gap in knowledge, but I think ignorance is where we should be.”SEX DIFFERENCESBetween her positions at Duke and U of T, Einstein worked as a grants reviewer at the U.S. National Institutes of Health. Einstein led an evaluation committee that focused on the molecular basis of neurodegenerative diseases, and she noticed that most of the applications on her desk didn’t address sex in their experimental design.The NIH began requiring the inclusion of women in clinical trials funded by the agency in 1993. But preclinical research in animals, and in vitro research on cells, came with no such requirement. Later research would show that as gender balance improved in clinical trials, it worsened in biomedical research.The Canadian Institutes of Health Research, Canada’s equivalent of the NIH, began including questions about sex and gender in experimental research in 2010.In 2014, the NIH announced it would begin to balance sex in cell and animal studies, too. Einstein contributed to the scientific discussions around the policy change.Here are some examples of when sex and gender differences really made a difference:
A medication that has been effective in preventing HIV in men, tenofovir, has had disappointing results in women. This week, a study in the journal Science, which was co-led at the Public Health Agency of Canada’s J.C. Wilt Infectious Diseases Research Centre, suggested a reason why: some types of naturally occurring vaginal bacteria degrade the microbicide gel.
The hippocampus generates new neurons throughout the human lifespan, and antidepressants can regulate this “neurogenesis.” Researchers at the University of British Columbia found that antidepressants increased the density of immature neurons — but only in adult women.
Last year, a study led by a team from the Research Institute of the McGill University Health Centre followed 1,000 Canadians who had been hospitalized for major adverse cardiac events. The researchers used an index to measure where the study participants ranked in terms of typical gender roles: how much housework or child care they assumed, or their salaries, for example. They found that the patients who ranked higher in characteristics traditionally assigned to females were at higher risk of a second event — regardless of their biological sex. The anxiety and stress of female-typical roles is potentially a factor, the authors said.
