Illustration: Susan Crawford
Some of Arthur P. Arnold’s scientific epiphanies — pivotal observations on the biological roots of sex differences — came from studying songbirds. In the mid-1970s, Dr. Arnold, who holds a PhD in neurobiology and behavior, was at The Rockefeller University investigating the neurological circuits that control singing behavior in zebra finches, when he and colleagues noticed something: Regions of the brain that controlled singing behavior were much larger in male finches than in their female counte rparts. At the time, major sex differences hadn’t been observed in the structure of vertebrate brains, but in the years that followed, consistent differences were uncovered in other major vertebrates, including monkeys, mice and humans.
Now director of the Laboratory of Neuroendocrinology at UCLA’s Brain Research Institute and editor-in-chief of the journal Biology of Sex Differences, Dr. Arnold studies the biology underlying these sex differences. He says that, for decades, the prevailing theory about the source of these differences centered on sex hormones — hormones produced in the male testes and female ovaries. “However, there were eventually problems with the hormone theory,” Dr. Arnold says.
If the theory held true, he explains, then adjusting hormone levels in animals (giving male hormones to females, for instance) should have resulted in corresponding changes in brain structure. That, however, didn’t happen in all cases; other ideas were needed to explain sex differences.
Scientists speculated that sex chromosomes — the two X chromosomes that make an animal female (XX) or the single X and Y chromosomes found in males (XY) — might be influencing the development of sex differences. However, since sex chromosomes determine if an organism has testes or ovaries (and, therefore, how much of each sex hormone is produced), teasing out whether or not sex chromosomes were independently causing sex differences was a challenge.
Again, a songbird pointed the way.
In the 1990s, Dr. Arnold’s lab came across a rarity: a gynandromorphic zebra finch. Gynandromorphs, most commonly seen in the insect world, are organisms that have both female and male characteristics. This particular bird was genetically male on the right side of its body and genetically female on the left. However, the bird’s hormone levels were the same throughout its body.
If the hormone theory had held true — if hormone levels controlled the development of brain structure — then both sides of the bird’s brain would have been morphologically the same. But the gynandromorph’s male and female sides showed the same structural differences that Dr. Arnold had previously observed in other finches.
Computer illustration of human chromosomes. The X chromosome is larger than the Y chromosome. Females have two X chromosomes and males have one of each.
“Studying the songbirds told us that the sex chromosomes were playing a larger role in biological sex differences than we realized,” Dr. Arnold says.
Dr. Arnold’s lab now develops animal models that help investigate the roles that sex chromosomes and hormones play in the development of sex differences. It’s an endeavor that has taken on greater urgency in recent years, as evidence has mounted that differences exist in the way males and females experience disease. Researchers have found sex differences in disease susceptibility (autoimmune diseases afflict far more women than men, for instance, while men are more vulnerable to diseases of mental development). Differences have also been noted in the way some diseases progress in men and women, and symptoms and side effects of diseases and treatments can vary depending on the sex of the patient.
In 1993, such findings spurred the National Institutes of Health (NIH) to mandate that both men and women be included in all NIH-funded clinical research, a move designed to address persistent underrepresentation of female subjects. In 2014, the NIH went even further and is developing plans to balance the two sexes in funded studies on animal models and cell lines. NIH director Francis Collins and Janine Clayton, director of the NIH’s Office of Research on Women’s Health, explained their reasoning in a May 2014 Nature commentary. Disparities in representation in preclinical research, they said, threatened to “[obscure] key sex differences that could guide clinical studies.”
A third of the studies cited by the directors were authored by investigators at UCLA, where researchers have been blazing trails in the study of sex differences in disease. The commentary also singled out one of Dr. Arnold’s animal models for its utility in advancing research in the field.
At UCLA, that model and other approaches have led to groundbreaking findings. Studies led by Karen Reue, PhD, professor of human genetics, have shown that sex chromosomes play a role in weight gain and obesity, and a team led by Mansoureh Eghbali, PhD (FEL ’01), assistant professor of anesthesiology at UCLA, has shown that sex chromosomes make a difference in cardiovascular and pulmonary disease. For instance, they found that having two X chromosomes hampers recovery from heart attacks.
Neurology professor Rhonda Voskuhl, MD, has shown in mice and humans that sex chromosomes and hormones both play roles in multiple sclerosis (MS), a disease that appears four times more often in women but progresses more severely in men. Her findings have spawned two clinical trials: One uses a key estrogen of pregnancy to treat women with MS, and a second uses testosterone to achieve the protective effects of higher male-sex-hormone levels for men with the disease.
The advancement of this work from basic biological findings to clinical trials underscores the ultimate goal of sex-difference research: to use what we’re learning about the mechanisms underlying these differences to develop new treatments for disease. A field that first took its lead from bird brains is now making a difference in human health.
Veronica Meade-Kelly is a science writer at The Broad Institute of MIT and a frequent contributor to Harvard Medicine magazine.