Whitehead Institute researchers are uncovering answers to longstanding questions about sex differences in autoimmune and neurodegenerative diseases

This article honors Women’s History Month.

In 1905, when geneticist Nettie Stevens peered through her microscope, she made a startling revelation: two delicate X-shaped structures nestled within the cells of female mealworm beetles, but only one X structure and a smaller Y-like counterpart in male beetles.

This groundbreaking discovery helped unlock the daunting mystery of sex determination. Stevens hypothesized this pair of chromosomes, now known as the sex chromosomes, dictates whether an embryo develops into a male or a female. But little did she know she had also just uncovered an important clue toward understanding why diseases manifest differently in males and females.

Fast forward a hundred years and scientists still don’t fully understand why females are at greater risk of developing certain conditions such as autoimmune and certain neurodegenerative diseases. Now, Whitehead Institute researchers are shedding light on this age-old question by investigating the role of X and Y chromosomes beyond sex determination, paying close attention to conditions that mostly — or distinctly — affect females, and mentoring the next generation of researchers to challenge the status quo for a better world.

The better half

The X and Y sex chromosomes in mammals originated from an ancestral pair of chromosomes with identical structures. Over time, the Y chromosome underwent degeneration, resulting in the loss of hundreds of active genes. The X chromosome preserved its original genes while also acquiring new ones.

But then, possessing two copies of the X chromosome in females meant much higher levels of gene expression from the X chromosome than in males (XY), so a mechanism called X chromosome inactivation evolved. In this process, one of the X chromosomes in females is randomly silenced in each cell, ensuring both sexes have an equal dosage of genes located on the X chromosome. Whitehead Institute Member David Page has been studying genetic differences stemming from sex chromosomes between males and females to understand their impact on the prevalence, severity, and progression of certain diseases.

Work from the Page Lab has revolutionized the scientific understanding of the X and Y chromosomes by revealing their role as influential regulators of genes. Scientists have found that these sex chromosomes can dial up and down the expression of thousands of genes on the other 22 pairs of chromosomes in a cell, impacting cell function across the entire body and beyond just the reproductive system.

Now, Page, who is also a professor of biology at the Massachusetts Institute of Technology and a Howard Hughes Medical Investigator, is taking his lab in a new direction: unveiling the subtle, yet powerful, distinctions within females' pair of X chromosomes. In a recent paper, former Page lab postdoc Adrianna San Roman and colleagues described that the inactive X chromosome is not, in fact, a passive copy playing backup for its more active partner; instead it can modulate expression of genes on the active X chromosome.

This overlooked dynamic between the pair of X chromosomes has widespread implications for how scientists understand and treat conditions that disproportionately affect females.

A misfired immune response

Like most biological processes, silencing of genes on the less active X chromosome in females isn’t foolproof. In recent years, researchers have found one more clue on sex differences in disease: when certain genes manage to evade the silencing mechanism on the active X chromosome , it disrupts the normal functioning of the immune system. This may be one of many factors heightening women’s risk of developing autoimmune diseases like multiple sclerosis (MS).

This immune-mediated neurodegenerative condition, which is nearly three times as common in females than males, starts off as a misfired immune attack; disease-fighting cells are dispatched to attack the myelin sheath, a protective layer of fat and protein wrapped around the slender bundle of nerve fibers that extend from the body of a neuron. As this protective wrapping deteriorates — a process known as demyelination — the nerve fibers begin to fray. This disrupts communication between neurons and hallmark symptoms of MS — challenges with cognitive, sensory, and motor function — begin to emerge.

Researchers have thus far identified over 200 genetic variations that can heighten one’s risk of developing MS. Most, if not all, of these risk variants are associated with immune system dysfunction. But now Whitehead Institute Member Olivia Corradin, who is also an assistant professor of biology at Massachusetts Institute of Technology, is taking a unique approach to unravel the mysteries of MS: investigating if — and how — certain genetic risk factors might be rendering the brain less resilient to withstand the injuries inflicted by the immune system.

“In order for neurons to get re-myelinated, all the myelin debris from the demyelination process has to be cleared away first and that's the role of a type of cell called microglia,” Corradin explains. “We’re really excited to look at a couple of new gene targets that are directly involved in myelin debris clearance and might be dictating how the brain responds to the immune attack.”

Currently, there is no cure for MS, and available treatments focus on symptom management. However, Corradin's research has the potential to unveil new therapeutic targets that enhance the brain's capacity for recovery following an autoimmune assault, thereby altering the course of the disease.

Fingerprinting behavior

Corradin isn’t alone in investigating the brain to decipher complex health conditions. Whitehead Fellow Allison Hamilos is deeply immersed in neuroscience, and her research aims to understand how disruptions in neural circuits contribute to the symptoms of psychiatric and neurological diseases.

Hamilos' fascination with the brain was sparked by a personal experience — a concussion sustained during college lacrosse. "I'd heard about the potential vulnerability of female athletes to traumatic brain injury, but was it truly so straightforward?" she reflected. This curiosity led her to delve into what resilience and vulnerability to psychiatric and neurological diseases truly entail.

It wasn’t until Hamilos began her clinical observations of Parkinson's patients as an MD-PhD that she recognized subtle nuances in movement and behavior as potential indicators of resilience and vulnerability. When brain circuits that are responsible for regulating reward and movement are disrupted, conditions like Parkinson’s, schizophrenia, and bipolar disorder emerge. Now, Hamilos is using these insights to meticulously "fingerprint" voluntary behavior in mice, so her lab can discern differences in these neural circuits between healthy and disease-affected brains.

“My interests may be different than even another female coming into the Whitehead Institute, but what I can say is that given that females have historically been under-studied, and that there are disparities across the spectrum in healthcare, part of seeing that reality is experiencing it yourself,” she says. “I think that it's an exciting moment with Whitehead’s mission to be invested in tackling issues that have not gotten sufficient attention historically because if they were to get that attention, it would make a big difference in people’s lives.”

In each instance, Whitehead Institute researchers have discovered that the journey toward comprehending — and ultimately addressing — neglected conditions that predominantly or uniquely impact women is long and winding. But it is also one filled with opportunities that can fundamentally revolutionize our understanding of health and disease.