Male infertility is on the rise, with significant declines in sperm quantity and quality occurring across the human population worldwide in the past two decades. The reason for this is poorly understood, but scientists suspect spermatogenesis – the process by which sperm develops – is a crucial piece in this puzzle.
Paula Cohen, professor of genetics at the College of Veterinary Medicine (CVM) and associate vice provost for life sciences at Cornell, is leading one effort to solve this puzzle. Thanks to an eight-year, $8 million, multi-institution grant from the National Institutes of Health's National Institute of Child Health and Human Development, Cohen and her collaborators will untangle the complex genetic rulebook for making sperm, while also looking for hidden causes of infertility related to spermatogenesis.
As director of the Center for Reproductive Genomics, Cohen unites Cornell's scientific experts on reproductive health and fertility, and emphasizes the genetic and epigenetic mechanisms that lead to healthy egg and sperm cell production.
This grant will tackle the questions of spermatogenesis in three phases: RNA regulation; investigating "junk" RNA; and monitoring RNA modifications. The project also has an K-12 educational outreach element.
The newly funded research builds on decades of cutting-edge reproductive science at Cornell, as well as Dr. Cohen's leadership of the highly successful Center for Reproductive Genomics on campus. The new award from the NIH will support several exciting basic and clinical research projects that hold tremendous promise for advancing human reproductive health."
Robert Weiss, associate dean for research and graduate education at CVM
Cohen and Charles Danko, the Robert N. Noyce Associate Professor in Life Science and Technology and a member of the Baker Institute for Animal Health, head up the first portion of the grant, aimed at understanding how RNA is regulated during spermatogenesis. That includes how certain RNAs are made at certain times, and what might happen if they aren't created in the right order – or at all.
"Spermatogenesis is an amazing process," Cohen said. "There are so many steps the cell needs to go through, and each step has a very different genetic program."
Because sperm cells have so much genetic action happening in such a short period of time, they make the perfect test subject to better understand how RNA is regulated in general. "In terms of regulation, what a sperm cell goes through is phenomenal," says Cohen. "If we want to understand these processes better, the sperm is a really fascinating system to use."
Investigating "junk" RNA
Once RNAs are made in the sperm cell, there's still the matter of how they behave and where they go. For this part of the mystery, John Schimenti, professor of genetics, and Andrew Grimson, associate professor of molecular biology and genetics (both in the College of Agriculture and Life Sciences), will be collaborating to unravel these questions. They'll work with Dr. Kathleen Hwang, a urologist at the University of Pittsburgh School of Medicine.
Specifically, they'll be looking at a mysterious portion of messenger RNA (mRNA) known as the three-prime untranslated region (3'-UTR) – a "tail" at the end of the mRNA strand that was long considered to be "junk" RNA. Studies have shown that, in fact, 3'-UTR is suspected to be the mRNA's instruction manual.
Scientists have already found that sperm cells have a lot of variation in the length of their 3'-UTR tails, but no one knows exactly why this variation exists. "There is some evidence that 3'-UTR length can affect infertility," Cohen said.
Monitoring RNA modifications
With Schimenti, Grimson, and Hwang helping to identify possible 3'-UTR defects, an additional branch of the grant will look at what might be cause of those defects. This project is headed up by Dr. Samie Jaffrey, the Greenberg-Starr Professor of pharmacology at Weill Cornell Medicine. Jaffrey is an expert in epitranscriptomics, a new branch of epigenetics that looks at the modifications that can impact RNA and how it functions.
Different proteins monitor these modifications – "readers, writers and erasers," Cohen calls them. "This opens up a massive can of worms," she said. "If you alter these reader, writer and eraser proteins in the RNA, they can all result in infertility in mice – and are really important for spermatogenesis. In the future, if we knew there were certain RNA modifications that caused infertility in men, we could screen for them."
Ultimately, when the grant concludes, Cohen and her colleagues will have uncovered new insights to sperm development – which will in turn shed light on many crucial problems, including infertility and IVF.
"Everything we do here," she said, "adds to our arsenal to help patients trying to have a baby."