Good egg versus bad egg: Understanding the makings of a high-quality oocyte
Michigan State University (MSU) AgBioResearch scientist Keith Latham has spent the past two decades closely studying immature eggs — properly called oocytes — primarily in animals, but with findings often applicable to humans.
Women are born with about 2 million eggs in their ovaries. By age 30, about 90 percent of those eggs will be gone. By age 40, only about 3 percent remain.
Michigan State University (MSU) AgBioResearch scientist Keith Latham has spent the past two decades closely studying immature eggs — properly called oocytes — primarily in animals, but with findings often applicable to humans. He began his research lab more than two decades ago to study how life begins and, ultimately, to determine what makes a high quality egg.
Long fascinated with the concept of development, Latham recounts first realizing how similar, yet different his hands were from each other and the wonderment at how that happened. This early curiosity inspired Latham eventually to pursue undergraduate and doctoral degrees in biology, and a career devoted to the detailed molecular studies of oocytes, as well as embryos and stem cells in mammals. Much of his research has been conducted on mice.
“You’re familiar with the saying ‘the best place to begin a story is at the beginning’ — that’s exactly where my research is,” said the MSU Department of Animal Science professor and adjunct professor of obstetrics. “Really, the beginning is inside the ovary in the formation of the egg. Though it may look simple from the outside, what’s happening inside the unfertilized egg is extremely complex. It contains all the marching orders for developing the ability to transcribe DNA and to regulate DNA.”
In August 2013, Latham moved his lab from Temple University School of Medicine to MSU. He and his team of lab technicians and graduate students focus on the underlying mechanisms that regulate the development of oocytes from pre-fertilization to uterus implantation. This includes the formation of spindles needed for segregating genetic material in the immature egg, and gene function and expression responsible for genome reprogramming. He also examines the mechanisms that maintain the cellular integrity and regulate messenger RNA in the oocyte and early embryo.
“We’re looking at what makes a good egg,” he said. “If your egg doesn’t have these certain criteria, it will ‘get late very early,’ as we say. We study the egg, but we also have to look at the surrounding cells and the communication between the two. If you disrupt that dialogue, you will end up with a bad egg.”
Latham and his colleagues have identified genes in mice that appear to be important to egg quality and discovered that oocytes may edit the paternal contribution to progeny characteristics. They are also studying environmental stressors on the early molecular development of mammal embryos and ties to conditions such as attention deficit disorder, Type 2 diabetes, obesity and asthma later in life.
“The topic of developmental origins of disease is one of the most exciting things to come up in biology in the past decade,” he said. “It’s the notion that things that happen to you, not only in the early embryo but in a developing egg, can have effects on health decades after birth. And that’s not because our genes are any different — it’s because our environment is.”
Faced with some criticism over the years that studies on mice have little relevancy to human medicine, Latham turned to the Rhesus monkey embryo. In 2002, with funding from the National Institutes of Health, he created the Primate Embryo Gene Expression Resource (PREGER). This national resource, available to scientists, includes such services as a gene expression database, DNA libraries, online tools and training opportunities.
“I started PREGER with the idea that if I could take a single monkey embryo, which at the time cost $5,000, and convert it into a library of 15,000 gene expressions that could be shared with other scientists, that would be a big bang for the buck,” he said. “It’s continued to evolve to be a database resource because it makes sense to extract as much data as I can and really eliminate the need for others to get embryos for basic inquiries.”
Through PREGER, researchers have been able to study the effects of the maternal diet and maternal binge alcohol consumption on oocyte quality and pregnancy outcomes in the monkey. Latham said these findings are relevant to human reproductive health and could enhance breeding productivity in farm animals.
In fact, Latham and his team are also using PREGER to examine the impact of assisted reproductive technologies on offspring growth characteristics.
“Assisted reproduction is a large and growing industry in both human clinical practice and in agriculturally important species,” he said. “Understanding how oocyte manipulations may adversely affect outcomes is paramount to minimizing risks and maximizing success.”
Latham is particularly excited about a new technology called CRISPR (clustered regularly interspaced short palindromic repeats), which allows for rapid and precise genome editing without the need for cellular cloning (with only a 1 to 2 percent success rate). Latham says this technology will lay the foundation for application of his work in agricultural species.
“Many lessons learned through the combination of mouse and monkey can be taken back to agriculture — markers of egg quality, embryo and oocyte quality, ways to intervene to make egg quality better,” he said. “But I’m rather eager to make the transition from mouse and monkey and integrate farm animals into my work. It may mean that eventually the cow replaces the monkey for me. We’ll have to see.”