The National Institutes of Health has selected Wayne State University School of Medicine researcher Leonard Lipovich, Ph.D., for its coveted Director’s New Innovator Award, a five-year, $2.3 million grant he will use from the National Cancer Institute to test a hypothesis that could lead to breakthrough methodologies to improve human health.
The project will identify primate-specific long non-coding ribonucleic acids, or lncRNAs, that are functional in cell growth and cell death, within the framework of human estrogen receptor positive breast cancer. The goal of the project, which has broad relevance to other nuclear hormone receptor pathways in human disease, is to reveal the extent to which non-conserved RNA genes contribute to cancer pathogenesis in humans.
Dr. Lipovich is a Detroit resident and an associate professor of the WSU Center for Molecular Medicine and Genetics and of the Department of Neurology.
The New Innovator Award mechanism was created by the NIH to support exceptionally creative new investigators who propose highly innovative, high-risk projects that have the potential for unusually high impact. Approximately 40 New Innovator awardees are selected each year. The small number of awards, along with the relatively high award amounts and the unconventional nature of the funded research, makes the program considerably more exclusive than the NIH’s more common R01 funding mechanism.
“Life, Death and Function: The Primate-Specific Long Non-Coding RNA Transcriptome,” will test whether evolutionarily young lncRNA genes – present in humans and some or all nonhuman primates, but absent in non-primates – are directly functional in positioning human estrogen receptor alpha positive breast cancer cells along the apoptosis-proliferation axis.
Long non-coding RNA is abundant in human cells. Long non-coding RNA genes often lack sequence conservation even between closely related species, in contrast to protein-coding genes, which are highly conserved across distant evolutionary lineages. Over the past several years, the Lipovich lab has been highlighting the primate-specificity of lncRNAs in diverse disease systems.
Targeting primate-specific lncRNAs therapeutically should result in fewer side effects than disrupting conserved pathways that current cancer drugs use. For selective chemotherapeutic agents that kill only breast cancer cells but not normal cells, pslncRNAs constitute a promising class of targets. The reason: these RNAs are young and have not yet had the time to deeply embed themselves in conserved protein-based networks over evolutionary time. Drug side effects may be a consequence of perturbing those conserved networks, Dr. Lipovich added.
“This is nothing less than a paradigm shift in cancer biology. Ever since Richard Nixon's lost ‘War on Cancer,’ proteins – and mouse models – have dominated the study of cancer,” he said. “Here, we systematically interrogate the contribution of non-protein-coding genes to cancer, with a focus on those that do not even exist in commonly used animal models.”
He is the first researcher from Wayne State University to receive the competitive award, which is so sought after he believed office staff was joking when they informed him of the honor.
“I am on the verge of realizing that a transformative, career-changing experience is already underway,” he said.
Dr. Lipovich, a proud graduate of Stuyvesant High School in New York City, received his bachelor’s degree from Cornell University in 1998, his doctorate from the University of Washington in 2003, and joined the School of Medicine faculty in 2007, working to build an internationally visible, high-profile research program. He is the only Wayne State faculty member to be selected by The Royal Society to chair one of its International Scientific Meetings, the lncRNA meeting that will take place outside of London in September 2015. Dr. Lipovich is also a funded co-investigator of ENCODE, or Encyclopedia of DNA Elements, the international consortium that serves as the official successor to the original Human Genome Project. He is in his second decade of working with the Japan-based Functional Annotation of the Mammalian Genome, or FANTOM project, and this year he joined the CHARGE, or Cohorts for Heart and Aging Research in Genomic Epidemiology, Consortium, singlehandedly bringing all these major international efforts to Wayne State through his laboratory.
“I have been arguing ever since the late 1990s, when I was a graduate student, that primate-specific, non-coding RNA genes are not junk, and that they can cause human disease,” he said. “I am profoundly and emphatically grateful for this opportunity to finally address exactly the problem that I've spent the past 15 years studying – the functional and mechanistic contribution of primate-specific long non-coding RNA genes to human phenotypic uniqueness, including human diseases that lack non-primate animal models.
“What ultimately inspires me the most is the potential of this project to empower a new era of post-genomic therapeutics,” Dr. Lipovich added. “I have a deep and abiding interest in actually improving human health and the human condition through therapeutic targeting of disease-causing lncRNAs, such as those that will be pinpointed by the newly funded work.”
Dr. Lipovich will attend the 2014 High Risk-High Reward Research Symposium, to be held Dec. 15-17 at the NIH campus in Bethesda, Md., as part of the award. The symposium will showcase presentations, poster sessions and networking opportunities for awardees.
The research will be supported by National Cancer Institute Award 1DP2-CA196375.