The last half of the 20th century saw a sea change in our capacity to fight disease and improve health. The bedrock for this development was the consistent support for biomedical research, and the nation has benefited from scientific discoveries that have been translated into treatments for previously untreatable conditions.
For example, the discovery of how to effectively use penicillin revolutionized the treatment of infections and saved the lives of men, women, and children. Determining the structure of DNA provided the basis of modern gene therapies for disorders ranging from sickle cell disease to cancers, and the introduction of technologies that power non-invasive diagnostic scans have dramatically helped us to identify disorders early and accurately.
Academic medical centers and universities across the United States play a large role in biomedical research discovery, translation of findings, and implementation of new treatment and prevention strategies.
Since our inception in 1998, Women’s Health Research at Yale (WHRY) has initiated and supported such research on health conditions that directly affect communities all over the country. In particular, we have focused on advancing our understanding of women’s health and on sex differences in health and disease that inform our understanding and treatment of disorders in women and men.
The Practical Benefit of Research
All biomedical research begins with a fundamental question that needs to be addressed. Such questions target gaps in our knowledge about the prevalence and demographics of disorders, the factors that cause disorders, as well as how to treat or prevent disorders.
Women’s Health Research at Yale’s Pilot Project Program funds innovative and interdisciplinary studies that answer these types of questions with regard to women’s health or sex differences in health, and more than 100 Pilot Project studies have been completed on a multitude of topics critical to improving health, quality of life, and longevity. Five examples of topic areas in which studies have generated practical benefit:
Cardiovascular Disease
Recognizing that cardiovascular disease (CVD) is the leading cause of death among women and men in the U.S., CVD has been an area of investigation since the center’s inception through the current day.
For example, among our inaugural Pilot Projects, Viola Vaccarino, MD, PhD, revealed for the first time that women who had coronary bypass surgery were nearly twice as likely as men to be readmitted to the hospital, develop infections, report lower physical functioning, and experience more depressive symptoms.
This seminal work informed clinicians and researchers of the increased risk of bypass surgery for women and provided the groundwork for subsequent investigations on the biological and social factors that could be modified to change these outcomes.
Currently, one of our CVD projects, led by Samit Shah, MD, PhD, assistant professor of medicine (cardiology), centers on the important goal of understanding and detecting heart attacks due to microvascular or “small vessel” disease, which are more common in women than men.
Routine testing for someone with symptoms of heart disease focuses on the most common cause of a heart attack, which is a blockage in the major arteries that supply blood to the heart. However, heart attacks can also be caused by a lack of blood flow in the small vessels of the heart. Here, there is a great need to remedy the underdiagnosis of different types of heart attacks that are more common in women.
Shah’s two-year funding from WHRY tested the use of his novel method to detect small vessel disease and coronary vasospasm in over 175 women presenting with symptoms of heart attack at Yale New Haven Hospital.
First using routine coronary angiography and evaluating for large vessel blockages, Shah then assesses the ability of the blood vessels to open or dilate by injecting a medication called acetylcholine, which can unmask the diagnosis of coronary vasospasm. After that, a wire 14/1000th of an inch is used to measure pressure and flow in the small vessels that infiltrate the heart to diagnose coronary microvascular disease.
Using this new technique, more than 80% of women who underwent Shah’s advanced testing protocol received an accurate diagnosis and comprehensive treatment plan, which led to symptom relief and increased quality of life. This work was published in the Journal of the American Heart Association.
Based on these findings, a Cardiovascular Diagnostics Innovation Fund named for Dr. Shah was created in early 2025 to support his efforts to develop his technique for commercialization. Shah was also awarded a 2025 Blavatnik Fund for Innovation grant to further Angiomedix, his company aimed at revolutionizing the diagnosis of heart disease.
The importance of studying sex differences in cardiovascular disease was again highlighted in a recent announcement from 58 cardiology journals including Circulation, European Heart Journal, JAMA Cardiology, and Journal of the American College of Cardiology. Moving forward, the journals recommend those submitting manuscripts for publication describe how sex was considered in their study design and analytic approach and that data are reported for both women and men. This work was begun by the White House Initiative on Women’s Health Research.
Cancer
Another early area of focus for WHRY that has grown over time is cancer research, the second most likely cause of morbidity and mortality in the U.S. for women and men. To date, 25 WHRY projects have examined cancers that are unique to women as well as cancers and their treatments that affect women and men differently.
For example, in 1998, it was known that mutations in the BRCA1 and BRCA2 genes were risk factors for occurrence of breast cancer. However, in a 15-year follow-up study of women who had been diagnosed with breast cancer, Bruce Haffty, MD, professor of diagnostic radiology, showed for the first time that these gene mutations also predicted an increased risk of recurrence compared to women without these mutations. This risk extended to both the initially affected breast and the non-affected breast.
This landmark discovery was published in The Lancet, providing women and their doctors with crucial information regarding options for follow-up and prophylactic treatment. It also paved the way for new methods that use molecular and genetic data to inform treatment that reduces radiation therapy resistance and improves outcomes.
Another discovery focusing on a type of cancer associated with BRCA 1 and 2 mutations, ovarian cancer, was found through a WHRY Pilot Project by Peter Glazer, MD, PhD, the Robert E. Hunter Professor of Therapeutic Radiology and professor of genetics. His laboratory had found that a lupus antibody (known as 3E10, which defends the body against foreign substances) can penetrate cancer cells and make them more vulnerable to radiation treatment and chemotherapy. Glazer applied for Women’s Health Research at Yale funding to begin the process of uncovering the biological basis for how this occurs – the first step necessary in using this finding to a develop a treatment intervention.
The basic work of this grant began a process that successfully led to identifying the biological underpinnings of how the antibody entered a cancer cell. With this information, Glazer now has designed a drug intervention to potentially treat ovarian cancer that develops from inherited mutations to the BRCA2 gene (which suppresses tumor development). Currently, his novel process of using this antibody as a cancer therapy is being tested in clinical trials.
In a third example of a Pilot Project focused on cancer, Pamela Kunz, MD, professor of medicine (medical oncology), determined sex differences in the adverse effects of treatment for gastrointestinal cancer known as neuroendocrine neoplasm (NEN). Though rare by incidence, these cancers are often considered chronic cancers because they grow more slowly than other cancers, requiring patients to be treated over many years.
Clinical observation has shown that women are more likely to develop adverse effects from treatments for these cancers. Kunz and her team have now examined and analyzed large national clinical trial datasets and have provided clear findings that women experience more adverse effects from chemotherapy and radiation treatment than men. This results in worse health outcomes, poorer quality of life, and increased costs of care.
Now, having shown sex differences in the effects of standard treatments, Kunz is focused on determining the gene variations associated with NEN that can predict patient response. This effort is designed to tailor therapy to specific persons and, in turn, reduce side effects and improve therapy outcomes in these patients who endure long-term cancer treatments.
Stroke
The third leading cause of death for America’s women and another area of WHRY research is stroke. Women’s Health Research at Yale investigator Lauren Sansing, MD, MS, professor of neurology, used her Pilot Project to determine whether there are differences in the way women and men respond to an intracerebral hemorrhage (ICH) – a rupture of a blood vessel in the brain – the second most common type of stroke. Previous studies indicate women experience more severe symptoms than men in response to ICH, yet limited data are available on why this occurs.
Sansing’s Pilot Project showed that women experience a greater immune response than men when a brain blood vessel ruptures, as evidenced by an increased presence of interferons (proteins produced by immune cells that combat infection). In addition, she found that sex differences in this initial inflammatory response increases with age.
In translating these findings, she is now assessing sex-specific therapies in a model system that provides immune responses to improve outcomes. This research, illustrating that sex differences occur at the molecular level, paves the way for clinical trials that are tailored to women and men.
Human Immune Response
The importance of understanding human immune response in all disorders, particularly infectious disorders, coupled with the onset of the COVID-19 pandemic, prompted funding for a first-of-its-kind study on sex differences in the immune response to COVID-19.
Early reports at the onset of the SARS-CoV-2 outbreak suggested men were dying from COVID-19 at a greater rate than women. In response to these reports, Akiko Iwasaki, PhD, Sterling Professor of Immunobiology was awarded a WHRY Pilot Project to determine whether and how sex differences in the immune response to the coronavirus accounted for this outcome in the pandemic’s earliest days.
When the body is attacked by a pathogen, such as a virus, it mounts an inflammatory response to fight the infection. This innate immune response includes the production of inflammatory proteins called cytokines. Although cytokines are key to managing infection, overproduction of these proteins can cause harm. Iwasaki’s research found that male patients often had higher plasma levels of cytokines than female patients. Additionally, female patients were more likely to have a robust activation of an adaptive immune response that produces T-cells, which are white blood cells that can recognize individual invading viruses and eliminate them.
In the August 2020 issue of Nature, Iwasaki and her team published an initial biological explanation for “… the observed sex biases in COVID-19 and an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19.”
Iwasaki and her team continue to examine sex differences, now in long COVID – which is more common in women than men and in which women and men experience different sets of symptoms and distinct patterns of organ system involvement.
Alzheimer’s Disease
The prevalence and impact of Alzheimer’s disease continues to grow. Women account for two-thirds of those living with the disease in the United States, which is the fifth leading cause of death for women. Although women generally live longer than men in the U.S., this alone does not account for this difference in Alzheimer’s disease cases.
An example of WHRY studies on Alzheimer’s include a co-funded WHRY-Yale Alzheimer’s Disease Research Center Pilot Project. This study was conducted by Le Zhang, PhD, in the Department of Neuroscience and Stephen Strittmatter, MD, PhD, Vincent Coates Professor of Neurology and professor of neuroscience.
The human brain contains about 100 billion individual cells that form a variety of cellular structures in the tightly packed, interconnected landscape of the human brain. For researchers seeking precise causes of impairment from Alzheimer’s disease and other dementias, the brain’s intricacy and diversity in the molecular underpinnings of these diseases have made it difficult to devise prevention strategies and treatments.
In order to understand what is happening to people with such a complex disease, the investigators started at the cellular level and looked for sex-specific differences that exist in the brains of women and men with and without Alzheimer’s disease. Having found sex differences among cell populations in Alzheimer’s disease, they are now building upon current knowledge of abnormalities that cause cell death and how these relate to disease symptoms such as cognitive dysfunction. Such knowledge has the potential to identify hidden biological clues and produce novel therapeutic targets that will benefit women and men at risk for developing this destructive disease.
A second WHRY Pilot Project led by Carolyn Fredericks, MD, associate professor of neurology, studied the relationship of a known genetic risk factor for Alzheimer’s disease to brain circuitry in women compared with men.
Every person inherits one “APOE allele” from each parent. For women who carry one copy of the APOE-ε4 variant, the risk of developing Alzheimer’s disease can be as high as three times greater than someone without this variant. Fredericks recognized, however, that not enough is known about the impact of the genetic risk factor on brain circuitry in women compared with men. Her research evaluated a large public dataset that included brain scans and APOE test results for more than a thousand individuals who had preclinical Alzheimer’s disease – meaning, they had evidence of Alzheimer’s pathology in their brains but had yet to show cognitive symptoms of Alzheimer’s disease.
Using a technique called connectome-based predictive modeling that allows researchers to visualize communication within the brain, Fredericks and her team successfully modeled which parts of the brain had activity that was “working together” to achieve an outcome – and how that tightly correlated activity related to how much of the protein tau was in the corresponding regions. Tau is an important protein in brain health, and when it malfunctions, such as folding onto itself or becoming detached and forming tangles, it contributes to the development and progression of Alzheimer’s disease.
Over the two-year investigation, Fredericks and her team successfully developed a method for using functional connections in the brain to model and predict the location of tau in brain networks of individuals with amyloid deposits, or preclinical disease.
Opportunity Abounds
Much can be gained through biomedical research in building a base of knowledge that leads to discoveries for treatment and prevention of disorders. As women historically have been understudied and are more likely to have chronic disease and disability, investment in women’s health brings great impact.
As a recent McKinsey report indicated, if we improve women’s health over the course of working years alone, approximately 60% more healthy life years could be gained for women, thus generating more than $294 billion in the annual U.S. GDP within 15 years. Moreover, studying women’s health and sex differences in health and disease improves the lives of women, men and families, and as a consequence, the health of the nation thrives.
