Transparent, microscopic worms—yes, worms—may hold the key to understanding why human fertility decreases with age. In fact, genetic exchanges take place in the roundworm known as C. elegans much like they do in humans. By studying how DNA successfully (or unsuccessfully) changes in these worms, researchers can better understand age-related reproductive issues in humans, such as miscarriage, infertility, and even birth abnormalities.
Judith Yanowitz, PhD, a primary investigator at Magee-Womens Research Institute, uses worms to do just that. With help from high-powered imaging using confocal microscopes, researchers in the Yanowitz lab are able to study cell division in C. elegans and discover how errors in this process affect reproductive development over a woman’s lifetime.
What Goes Wrong With Age
Miscarriages can trace their origins back to defects in the process that Dr. Yanowitz studies: crossover formation during meiosis (meiosis itself is the type of cell division that results in the formation of egg & sperm cells.) “Crossovers are exchanges between the chromosomes that we inherit from our moms and dads. [Those exchanges] increase genetic diversity and they are also required to help chromosomes separate correctly so that you end up with the right number of chromosomes,” Dr. Yanowitz explains. “When the chromosomes don’t separate correctly, abnormalities arise.”
Errors in this separation process are a major cause of miscarriage and the underlying cause of Down Syndrome and other genetic birth abnormalities. Statistically, the risk for these developmental issues increases with a mother’s age.
Two reasons for these reproductive errors stand out: either an error in the oocyte (egg) during meiosis occurs, or an older woman is unable to maintain the configuration of chromosomes throughout the years until the egg is fertilized.
The former poses a difficult puzzle for researchers. Meiosis—where chromosomes are configured for initial segregation—actually occurs in utero. For females, this means that a woman’s eggs are set for the rest of her life during the fetal development period when she is a baby in her mother’s belly. If this is the case, how can researchers say that an error during meiosis at this early stage of life is an age-related problem?
“Crossovers occur in different places in the genome, and for reasons we don’t understand, as a woman ages, some of the positions where those initial crossovers occurred become less stable over time, ” Dr. Yanowitz explains. “For example, a crossover that occurs near the end of a chromosome is not always able to stably hold those chromosomes together in an older mom. However in a younger mom, they’re just fine.”
What does this mean for older mothers-to-be? “If we can minimize the chances of retrieving eggs with these abnormalities [in both normal fertilization and processes like Assisted Reproductive Technology (ART)], we might improve the usage of good ones [to ensure healthy development.]”
Worms & Humans—An Unlikely Combination?
To look at the impact of age on reproductive health and the development of these chromosomal abnormalities, Dr. Yanowitz’s lab turns to the roundworm known as C. elegans. At first glance there is little in common between the millimeter long, transparent worm and the complex human body, but humans are remarkably similar to C. elegans when it comes to reproductive cell division.
“The process of meiosis, where chromosomes separate and pair off with their respective match, is pretty much identical between humans and worms,” Dr. Yanowitz notes. While it takes the human body years to mature to adolescence, and another nine months after fertilization of an egg for gestation, C. elegans’ entire lifespan lasts about eighteen days. C. elegans age from egg to adult in three days, and peak reproduction takes place in the first four days of adulthood. Most lay their eggs in those first four days. Though they can be reproductive for another five days, by day nine of adulthood, the worms are basically done reproducing. “What’s interesting is that, just like in women, we start to see reproductive errors like an increase in indicators of Down Syndrome halfway through the worm’s reproductive lifespan. Though measured in years versus days, the two curves of human and worm reproductive decline (or, the capacity to have good eggs with age) are incredibly superimposable.”
Dr. Yanowitz and her lab aren’t the first to study worms as a window into human health, though they are only one of roughly 15 labs in the world currently investigating meiosis this way. C. elegans as a model system has been around since the early 1970s, when Sydney Brenner initially developed it as a model to study the nervous system.
Many of the genes that are involved in the development of the germ line have been discovered in worms, flies, even yeast. This kind of research can’t easily be done in mice or humans because of the long time frame of reproduction. Looking at this organism allows researchers an efficient opportunity to define, identify, and provide mechanistic insight into the basic developmental processes that occur similarly in both humans and roundworms. It’s work in organisms like C. elegans that propel work in higher organisms forward.
“It’s fun [research]! The worms grow on petri plates, then we transfer them with a tiny piece of platinum attached to a piece of glass, or even with a stylus-like apparatus, to move them from plate to plate.” The most interesting part of studying worms? “Because the worms are transparent we can see the developing eggs in the animal and we can see the germ line. If we use a DNA stain and magnify it at 100-400 times, we can actually see the process of meiosis as the maternal and paternal chromosomes come together.”
The Odds of Healthy Eggs
It’s almost impossible to fix pre-existing chromosomal errors, but Dr. Yanowitz’s research could play a role in improving the odds of scientists and medical professionals finding healthy eggs for infertility procedures.
The challenge in research like Dr. Yanowitz’s is that chromosomes, particularly oocytes, are pre-set. “The best way to potentially tackle the problem is likely by asking, ‘Might there be a way to identify those oocytes that have had a problem?’ and selectively eliminate those before ovulation so they’re never even chosen to be an oocyte.” While this research is still in the investigative stage, recent work from Dr. Yanowitz’s lab has suggested that errors in chromosomal crossovers cause a delay in development that also yield a “Hey, wait up! Let’s try to fix this problem!” signal. If those signals leave an identifying or permanent mark, it might be the first step in selectively eliminating problematic oocytes.
Embryo screenings are already a part of the current ART process and while it is possible to identify and cull eggs with chromosomal abnormalities in the clinic, that doesn’t mean that retrieving healthy eggs is foolproof. “We still know that women who are, say, 42-44 and come to the clinic for reproductive assistance are still encountering problems where they don’t produce good eggs. There may still be good oocytes that are there, but the frequency of retrieving them is lower.”
For older women where reproductive aging makes the retrieval of healthy eggs more of a gamble, a treatment devised from Dr. Yanowitz’s research is a bit further off. “I would imagine there might eventually be a way that something like a drug could be taken to prevent the use of oocytes that are chromosomally bad. We have to think out of the box in terms of developing the technology to do that.”
There’s still research to be done to translate these studies to clinical practice, but for Dr. Yanowitz, the ability to literally see her work come together before her eyes is exciting. “It’s inspiring that day in and day out we can look at the genetic material of the worm and realize, ‘This is what makes us up.’ That’s what keeps me going.”
Support Dr. Yanowitz’s continued research into human reproductive aging by donating to Magee-Womens Research Institute today!