Jayakrishna Ambati, MD, and Bradley Gelfand, PhD, Describe How Sex Is Impeding Medical Progress

November 8, 2023 by

Bradley Gelfand, PhD, and Jayakrishna Ambati, MD

Jayakrishna Ambati, MD and Bradley Gelfand, PhD

Medical research that could improve patient outcomes and transform treatments is being hindered by a lack of genetic research tools that consider biological sex, two UVA School of Medicine experts argue.

Doctors and scientists increasingly have come to appreciate the importance of biological sex both in developing new treatments and in understanding fundamental cellular processes essential to good health. For example, sex chromosomes are known to play important roles in a wide range of diseases, from heart problems to Alzheimer’s.

But Bradley D. Gelfand, PhD, and Jayakrishna Ambati, MD, from the Department of Ophthalmology, maintain in a new scientific paper that genetic research resources have failed to keep up with this evolving understanding. The current approach to genetic research, Gelfand and Ambati say, simply doesn’t provide scientists with adequate clues for sex-specific discoveries that could have huge benefits. And that means a treasure trove of medical advances are going undiscovered.

“We know so much about the consequences of being male or female for many disease conditions,” said Gelfand, of UVA’s Center for Advanced Vision Science (CAVS). “What we don’t yet have a complete handle on is why sex plays such a crucial role in human health. We hope that by drawing attention to this blind spot in the research community that new tools and approaches will be developed.”

Sex in Health and Disease

Gelfand and Ambati note that there has been huge progress in including women in medical research, from fundamental lab research to clinical trials testing new treatments. The National Institutes of Health, the European Commission and the Canadian Institutes of Health Research all require scientists to consider the potential role of sex. But protein-based research, in particular, still has a glaring blind spot when it comes to sex, Gelfand and Ambati say.

That’s because important genetic research resources have not been refined to distinguish the effects of the sex chromosomes. Typically, males, you may recall, have an X and a Y chromosome, while females have two X chromosomes. These chromosomes contain our genetic blueprints – the operating instructions for our cells. The genes in our chromosomes make cellular proteins that are instrumental in carrying out those operating instructions and can play important roles in disease.

Scientists know a tremendous amount in general about the function and effects of proteins made by genes. But existing research resources often don’t make critical distinctions about proteins specific to sex chromosomes. For example, protein databases can wrongly report the presence of Y chromosome proteins in tissues that don’t have a Y chromosome.

By failing to factor in sex, these critical research resources are woefully incomplete and often misleading, Gelfand and Ambati say. Improving them could have tremendous benefits for medical research – and for patients. For example, doctors might be able to battle certain diseases in females by introducing a Y chromosome gene into tissues that lack them. Conversely, silencing a disease-causing Y chromosome gene in males may provide protection against male-biased disease processes.

“With currently available research tools that are unable to differentiate between X and Y genetic components, we simply don’t know what we don’t know,” Gelfand said. “Improving our ability to measure these could be the key to better and more personalized care.”

Ambati added, “High-fidelity resources and reagents related to sex chromosomes are critical to advance scientifically accurate conclusions about sex-based differences.”

Article Published

Gelfand and Ambati’s article has been published in the prestigious journal Science. The full perspective piece is available to read for free.

Article written by Josh Barney, Deputy Public Information Officer, UVA Health. Contact Josh about this story or to share your own research.

Filed Under: Research