Telomeres, Sex, and Hospital Infections

WSA Scholars Discuss Their Research

BY BRANDON LEVY, NIMH

Bari Ballew’s investigations on shortened telomeres may lead to a cure for a rare genetic disorder. Barbara Nicol’s efforts to understand the genetics of sex differentiation may shed light on how environmental chemicals do their damage. And Christine Jao’s use of structural biology to learn the secrets of a nasty bacterium may contribute to the prevention of hospital-acquired infections. So it’s not surprising that all three women are winners of the Women Scientist Advisors (WSA) Scholar Award and were invited to present their work at the annual NIH WSA Scholar Seminar held on March 20, 2015.

“Telomere biology and cancer etiology are closely linked,” explained Ballew, who wants to understand the relationship between the two. Telomeres are repetitive DNA sequences that protect the ends of chromosomes. She described her research on dyskeratosis congenita (DC), a rare genetic disorder characterized by drastically shortened telomeres. People with the disorder are at increased risk of developing severe life-threatening conditions including bone marrow failure and cancer.

She and colleagues at the University of Michigan (Ann Arbor, Michigan) discovered two previously unrecognized genetic mutations—in a person with DC and several family members—that impair the function of a protein encoded by the gene ACD. The protein is part of a larger complex called shelterin, which protects telomeres against damage and in some cases recruits the enzyme telomerase to repair them (Genes Dev 28:2090–2102, 2014). She hopes the discovery will influence the treatment of DC.

Ballew earned her Ph.D. in biology from the University of California, San Diego, and works in Sharon Savage’s lab in the National Cancer Institute, Division of Cancer Epidemiology and Genetics.

Barbara Nicol is exploring the genetic factors that cause mice to develop male or female sexual organs during embryogenesis. She hopes to better understand the basic process of organ formation as well as the potential implications of exposure to environmental chemicals.

Mammalian fetuses have undifferentiated precursor cells called the gonadal ridge that can develop into either testes or ovaries depending on the balance between pro-testis pathways activated by the SOX9 gene and pro-ovary pathways triggered by the CTNNB1 gene, which codes for beta-catenin.

Nicol described how knocking out the two genes SOX9 and CTNNB1 caused both genetically female and genetically male cells to develop testis-like traits, suggesting the existence of pro-testis genes that can function without SOX9. Indeed, she identified several pro-testis genes that were active even when SOX9 and CTNNB1 were nonfunctional. In addition, she observed that male cells became more masculinized than female cells when both genes were disabled.

Nicol, who received her Ph.D. in the biology of reproduction from the French National Institute for Agricultural Research and the University of Rennes (both in Rennes, France), is part of Humphrey Yao’s lab in the Reproductive and Developmental Biology Laboratory of the National Institute of Environmental Health Sciences (Research Triangle Park, North Carolina).

Christine Jao investigates methods for combating hospital-acquired infections. She has done postdoctoral work in two NIH labs since earning her Ph.D. in biochemistry and molecular biology from the University of Southern California (Los Angeles)—first in James Hurley’s lab at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and now in Susan Buchanan’s lab at NIDDK’s Laboratory of Molecular Biology.

Jao is particularly interested in how to interfere with bacterial growth by tweaking its zinc-uptake system. Bacteria need trace amounts of metals to survive; previous research focused on how infectious bacteria take in iron.

She helped figure out the crystal structure of a zinc transporter in Acinetobacter baumannii, a multi-drug-resistant bacterium that often infects patients during hospital stays. The transporter, called zinc uptake receptor D1 (or ZnuD1), resides on the bacterium’s outer membrane, making it a potential drug target.

Zinc receptors in other bacteria are likely to be similar. “So the hope is,” said Jao, “if we find a chemical that stops growth in Acinetobacter, we can also use it for other types of pathogens.”

The NIH WSA Scholars Seminar was sponsored by WSA and the NIH Office of Research on Women’s Health. The WSA committee, formed in 1993 under then–NIH Director Bernadine Healy, aims to advance the scientific careers and scientific contributions of women at NIH. Each year, the WSA selects awardees from the pool of female winners of the Fellows Award for Research Excellence for this special recognition and gives them the opportunity to present their research to the NIH community. To learn more about the history and activities of the WSA, visit http://sigs.nih.gov/wsa/Pages/default.aspx.