In early October, when Dr. Victor Ambros and Dr. Gary Ruvkun won the 2024 Nobel Prize in Physiology or Medicine for their discovery of microRNA, March of Dimes scientists past and present around the world celebrated the win of two of their own.
Dr. Ambros, a molecular medicine professor at UMass Chan Medical School, and Dr. Ruvkun, a genetics professor at Harvard Medical School and a researcher at Massachusetts General Hospital, jointly received the March of Dimes Prize in 2016. They represent the 22nd and 23rd March of Dimes alumni scientists to win the Nobel Prize.
In addition, Dr. Ambros was a recipient of the 1985 Basil O’Connor Starter Scholar Research Award. That grant propelled his research, including work surrounding microRNA, also known as miRNA, which Drs. Ambros and Ruvkun discovered almost by accident and published about in 1993. It's this same accomplishment—the discovery of tiny RNA molecules that affect the way genes are expressed, usually silencing them—that earned them the March of Dimes Prize.
The scientists’ two 1993 papers on the discovery in Cell were transformative for genetics and molecular biology. The findings opened a floodgate of opportunity for scientific research into the biology of disease, and diagnostics and therapeutics for a range of conditions, from birth defects and preterm birth to cancer, heart disease, Alzheimer’s and Parkinson’s disease, and more.
Working as post-doctoral fellows at the Massachusetts Institute of Technology (MIT) in the late 1980s, the pair was studying the C. elegans roundworm, and the genes responsible for its development. After identifying two partner genes of interest, lin-4 and lin-14, the men, both of whom had moved on from MIT to Harvard at that stage, examined how the genes interacted, and were met with surprise.
The gene lin-4 behaved strangely; instead of blocking lin-14 in the way the scientists expected, through a protein, it suppressed it by “direct interaction between the two genes’ RNA strands,” according to Massachusetts General Hospital, where Dr. Ruvkun has a research laboratory. Plus, the mysterious lin-4 RNA was shorter than any RNA the pair had ever seen; it was only 22 nucleotides long. After publishing the findings, the pair continued to study miRNA in parallel. In 2000, Dr. Ruvkun and his team discovered the second miRNA, let-7, and learned that it is present in many animal species on earth, including humans.
“Ambros and Ruvkun’s seminal discovery in the small worm C. elegans was unexpected, and revealed a new dimension to gene regulation, essential for all complex life forms,” read the Nobel Prize passage on the win.
Although the study of the role of miRNA in pregnancy is only 15-20 years old, the molecules appear to be excellent early predictors of pregnancy complications. They are involved in the early embryo, the placenta, in fetal growth, in birth, and more.
“They are reporters that tell us what biological processing are happening,” said Dr. Vasso Terzidou, a clinician-scientist at the March of Dimes Prematurity Research Center at Imperial College London, whose focus is miRNA in adverse birth outcomes like preterm birth. “And though we don’t yet know exactly what they do, we rely on their activity to give us a snapshot into the health and trajectory of the pregnancy.”
Dr. Terzidou and her team have shown miRNA expression profiles to be reliable risk predictors of preterm birth, small for gestational age (SGA) babies, and more.
Tiny miRNAs are the gatekeepers between messenger RNAs, or mRNAs, which translate your DNA into messages, and recipient proteins, which help carry out those messages in your body. miRNA under- or over- expression results in the inability of mRNA to translate its message into proteins, which results in either silencing or activation of genes. Usually, miRNA is overexpressed, and genes are silenced.
Since 2005 alone, March of Dimes has distributed $4.6 million in research grants to study miRNA in the context of maternal and infant health, with scientists investigating their role in preterm birth, preeclampsia, embryonic development, congenital heart defects, other birth defects, genetic disease, and more.