A sperm cell does not carry anything unnecessary. In order to advance as fast as possible in the race to reach an egg cell first, the cell is completely stripped during its development. “Like packing a backpack for a long walk,” says Tzviya Zeev-Ben-Mordehai, “you only take what is absolutely necessary. I find it fascinating, that minimalism of the sperm cell.”
Zeev-Ben-Mordehai is an associate professor at the Bijvoet Center for Biomolecular Research at Utrecht University. Using advanced microscopes, she examines the cellular structure of sperm cells from various mammals, and soon also from humans.
What is so special about sperm cells? “Well,” says Zeev-Ben Mordehai, “sometimes people think that there isn’t much left to discover. Under the normal light microscope they do indeed look like fairly simple cells, consisting of a head and a long tail. But with the ultra-high resolution of the microscope we use, you suddenly see the enormous complexity of the sperm cell.”
What makes cryomicroscopy such a powerful tool?
“With cryo-electron tomography you can make a CT scan of the cell, as it were. The computer generates an image in which you can study the cross-sections of a frozen cell slice by slice, just as you can with a CT scan of the body. This is done in such detail that you can sometimes see the individual proteins.
“Once the scans have been made, you first have to annotate all structures on those black-and-white images: determine exactly which cell parts you see. You can then make three-dimensional reconstructions of them in the computer so that you know what the cell parts actually look like.
“The advantage over conventional electron microscopy is that you don’t have to preserve, cut or stain the specimen; actions that can damage the structure, giving you a distorted image. What we see with cryo-EM is exactly how the parts actually sit in the cell.”
The specimen is frozen in the microscope
Tzviya Zeev-Ben Mordehai shows how fast freezing is done. She fills an open thermos with liquid nitrogen, in which is a smaller metal container that is filled with liquid ethane. “It has to be ethane to make the preparation freeze fast enough,” she explains, “with just nitrogen it’s too slow. It has to go so fast that no ice crystals can form.”
The preparation is suspended over the liquid with tweezers. Then she presses a foot pedal, causing the tweezers to fall down like a guillotine. When frozen, the specimen is placed in the microscope where the shadow image of an electron beam can make the smallest details of the cell visible.
What have you discovered?
“In reproductive medicine it has always been a mystery where the second centriole in the fertilized egg comes from. Centrioles are parts of cells that are important for the cell to divide. For that you always need two; centrioles that each attract half of the chromosomes. It was clear from previous research that the ovum has no centrioles, and until recently they have always been able to find only one in a sperm cell.
“With our cryomicroscopy we have now seen what it is all about. The second centriole looks very different from normal. Instead of the normal barrel-shaped rigid structure, this centriole resembles a bowl, which can also move very smoothly. In the sperm cell it is just below the head around the nucleus of the whiptail. We suspect that there it has a crucial secondary function in the locomotion of the cell.”
It may sound crazy, but an egg is too big to study with cryomicroscopy
And what happens to this weird centriole after conception?
“That’s a good question, we don’t really know yet. After fertilization you can still see the tail of the sperm cell in the egg for a while, and we would love to see what is happening in the cell. It may sound crazy, but an egg is too big to study with cryomicroscopy. You can’t freeze that cell fast enough because of its size. We are working on a solution, but we are not there yet.”
Could this research also contribute to doing something about male infertility?
“Yes, we hope to find something at a fundamental level that hinders fertility. For this we have now started a collaboration with a fertility clinic of the UMC Utrecht. The IVF success rate is low, 25 percent in young women, and it only gets worse in older women. That is quite a heavy burden for couples who wish to have children.
“In male infertility, the cause is unknown in two-thirds of cases. Sometimes icsi is still a solution, in which a sperm cell is injected directly into the egg. Under the microscope you can see immobile or misshapen sperm cells, but if you don’t know what’s wrong and you continue to perform artificial insemination, there is a risk that you will pass on a defect to the next generation undetected. We really need to understand this better.”
Conversely, you also hope to find a target for contraception in men. Is that realistic?
“I think so. If we better understand how it works, we can also disable it. Mobility is super important for sperm cells. But the moment they have just been created and are stored in the epididymis, they cannot swim yet. If we find out what is essential to this maturation process, our fundamental work, others can start developing a male pill.”
You were only allowed to enter the lab if you did research on corona
How do you like it as a foreign researcher in the Netherlands?
“Very well! I like to work internationally. It is not for nothing that my group of three PhD students and a postdoc includes a Dutchman, a Filipino, an Indian and a German. We speak English among ourselves. I like that cultural diversity because it always brings new ideas that complement each other. I am also on an advisory board for the Faculty of Science in the field of diversity.”
Has corona still got in the way of the work of your department?
“At one point, all laboratories had to close due to the lockdown measures against corona. We were not allowed to do anything and were obliged to stay at home. There was one exception: you were only allowed to enter the lab if you were doing research on corona. Many scientists then changed their research in order to continue working. I thought about it for a while, but didn’t do it.
“We were lucky that we already had many of our measurements ready, all that was left was to work out and write down the results. That resulted in four beautiful publications last year – not bad in my opinion.”