Heart disease kills more people of all sexes than anything else. But for more women than men, a heart attack may start with nausea, shortness of breath or extreme fatigue rather than chest pain. These symptoms are still often thought of as “atypical,” which means many women don’t get the treatment they need in time.

According to David Page, head of the Page Laboratory at the Massachusetts Institute of Technology’s Whitehead Institute, sex differences can actually be found all over the body. Women are more likely to be diagnosed with rheumatoid arthritis, lupus and multiple sclerosis, for instance, while men are more likely to be diagnosed with autism.

“Biomedical researchers have for a very long time viewed those sex differences as a kind of inconvenience that should be ignored and simply gets in the way of research,” he says.

In this documentary, which is the first episode of Scientific American’s new series, A Question of Sex, we explore discoveries being made in this small but growing area of research.

Sex is usually defined by several biological attributes, including genetic and anatomical features and hormone levels. And it does not exist as a binary but rather represents a spectrum—with typical male and female individuals on either side. (As shorthand, this article refers to those ends of the spectrum as “men” and “women,” respectively.) Sex is also separate from gender, which is defined by social and cultural characteristics and exists on a spectrum, too.

Page says that sex comes into play at the same time as environmental, behavioral, and social factors in determining health outcomes. The challenge is teasing out the relative impact of each.

Until recently, however, the vast majority of biomedical research was done only on male subjects and cell lines. In clinical research, this largely stemmed from concerns about side effects that medications could have on a possible fetus.

Page notes that scientists also thought the ovarian cycle could be a source of noise. On some other level, he adds, members of the field perhaps valued improving the health of male individuals more than female ones.

Indeed, in January 2001 eight of the 10 drugs the U.S. Food and Drug Administration pulled from the market over the previous four years had worse side effects in female individuals. Scientists still don’t know why. 

“There is a growing group of people who are very interested in these questions,” says Adrianna San Roman, a postdoctoral researcher at the Page Lab, “and many of them are women.”

San Roman studies skin and blood samples from individuals who are neither XX nor XY, to better understand how the number of sex chromosomes in a cell affects its function—whether that function is absorbing nutrients in the gut or creating movement in a muscle.

She wants more doctors to understand that each cell has a distinct genome because of the number of X or Y chromosomes and that this might be generating differences in the body before we even think about hormones or anything else.

In 1993, Congress passed a law requiring the inclusion of women in all clinical research funded by the National Institutes of Health. But in 2019 only 42 percent of articles in the biological sciences that included both male and female individuals analyzed data by sex

“We talk a lot nowadays about personalized medicine,” San Roman says, “but a lot of that work has ignored the X and Y chromosomes. And that is really the biggest genetic difference in our species.”

The members of the Page Lab believe that paying attention to these differences, cell by cell, could initiate a sea change in science and medicine.

This article is part of “Innovations In: Health Equity,” an editorially independent special report that was produced with financial support from Takeda Pharmaceuticals.