What a Tiny Worm Tells Us About Human Pregnancy

Biotechnology

What a Tiny Worm Tells Us About Human Pregnancy

• November 15, 2024

Human reproduction is a complex, iterative process, and one of the least understood stages is embryo implantation-the moment when a fertilized egg attaches to the uterine wall. Implantation failures are a significant cause of miscarriages and other challenges to successful pregnancies, and a leading factor when in vitro fertilization misfires.

It's difficult to study in humans, though, due to the ethical and technical challenges in directly intervening in or observing a pregnancy.

Now, a breakthrough study from MDI Bio Lab led by Hyemin Min, Ph.D., and published in the peer-reviewed journal Development, offers a new way to explore the intricate cascade of molecular events that are vital for a human embryo's successful implantation.

A Worm's Role in Studying Embryo Implantation

Min and her colleagues in the research group of Dustin Updike, Ph.D., didn't directly study these dynamics in human beings - they instead relied on a surprising stand-in; the tiny, transparent roundworm, Caenorhabditis elegans.

"C. elegans is commonly used as a model organism because it shares fundamental biological pathways with humans," Min says. "Although C. elegans does not undergo embryo implantation, we found that during the worm's generation of sperm, there is a cellular behavior that's similar to embryo implantation in humans."

That discovery sets up C. elegans as a new model for implantation studies, and it's particularly useful when compared to other research models. Because simply put, there are things you can do with a worm that would kill a mouse - or a human for that matter. C. elegans can survive more robust gene-editing, more radical protein manipulation and more invasive observation techniques. The worms' three-to-four day life cycle speeds data gathering. And their transparent bodies, a tenth the size of a pinky-nail clipping, offer a unique opportunity to use MDI Bio Lab's advanced microscopy to watch molecular processes unfold in real-time, in a living animal.

"If we wanted to look at this in in any other system, we'd have to look at static, fixed images of dead cells," says Updike, Min's mentor and a pioneer in reproductive research using C. elegans. "But here we can observe cells in a living animal, watch how the proteins move within them and track their dynamic interactions."

Molecular Mechanisms: Worms and Humans Share Common Pathways

Min, Updike and their Laboratory colleagues uncovered a striking parallel in the two species, involving interactions among protein molecules that allow cells to take in material from outside their membranes - a process called cellular uptake.

The mechanism is crucial in both C. elegans sperm production and in human embryo implantation. "Some of these genes and protein paths originated well before multicellular life formed, and we just have different ways of using them," Updike says.

In humans, the key interaction comes when a protein called bystin binds with another, called trophinin, to form a complex that then triggers a human embryo's adhesion to and invasion of the uterine wall.

In worms the pathway involves a set of proteins that bind together, called BYN-1 and GLH-1, to trigger a type of cellular uptake that enables material left over from other processes to be engulfed and removed, clearing the way for sperm generation.

Scientists consider BYN-1 in worms to be a "homolog" for bystin in humans - conserved through evolution and nearly identical in form. And although GLH-1 is not a homolog for human trophinin, the MDI Bio Lab team discovered that GLH-1 and trophinin share a rare combination of amino acids seen in only a handful of other known proteins.

"We observed that BYN-1 in C. elegans directly binds with GLH-1, which shares molecular characteristics with trophinin, and this interaction is crucial for cellular uptake processes," Min says.

In both species, the researchers found, the process is characterized by an unusual movement of proteins from deep within a cell to its outer cytoplasm, and by cell migration from one location to another.

Beyond Implantation: Cancer and Future Studies

Min notes that in humans, the pathway is also implicated in a cancer cell's ability to spread (metastasize), raising the possibility that C. elegans could play a new role in cancer research.

She emphasizes that further work is needed to more fully understand how the worm's cellular uptake functions relate to human implantation and to cancer cell proliferation.

But Min is hopeful, saying that the findings could help address challenges such as recurrent implantation failure during in vitro fertilization. "Discovering a conserved pathway in C. elegans allows us to study the mechanisms of implantation in a controlled and accessible model," she says.

Min has returned to her native Korea, but she plans to continue work with the Updike lab - and C. elegans.

"Moving forward, we plan to continue studying how BYN-1's role and mechanisms contribute to the developmental processes of C. elegans, their broader biological implications and the potential for identifying additional targets that may aid in reproductive therapies," she says.

The effort was a full-court press by the Updike Laboratory team; the publication's authors include Min and Updike, as well as Emily Spaulding, Ph.D., Catherine Sharp, Pankaj Garg, Esther Jeon, Lyn Miranda Portillo and Noah Lind, all working at MDI Bio Lab when the reserarch was under way.

• biomedical research
• C.elegans
• development
• Dustin Updike
• Hyemin Min
• implantation
• IVF
• Microscopy
• repeat implantation failure
• reproduction
• updike lab

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