On average, every woman is born with a million immature eggs, which will degenerate as she ages. No more will be produced in her life. At puberty, only about 300,000 will remain in her ovaries, and just 400 will be released during the reproductive stage, usually one for each menstrual cycle. The vast majority of other cell types don’t live that long: they age and die. Red blood cells, for example, are eliminated after four months. Neurons do last for decades, but they face many problems, such as mutations and building up of toxic proteins. However, some of the precursor cells of the egg cells — known as oocytes — will live for around half a century, preserving the woman’s DNA, and the ability to bear healthy children, intact. This amazing shielding of the future eggs used to be an enigma to science; but on Wednesday, a team from the Center for Genomic Regulation in Barcelona announced that it has discovered its unique defense strategy.
Human cells usually contain hundreds or thousands of mitochondria, tiny power banks of about one thousandth of a millimeter. Energy is formed in the mitochondria thanks to the movement of electrons between five protein complexes, and it is stored in the form of ATP, a molecule made up of 10 atoms of carbon, 16 hydrogen, five nitrogen, 13 oxygen, and three phosphorus. Human life would not be possible without this constant production.
A collateral effect of this essential process, however, is the formation of unstable molecules called reactive oxygen species, whose accumulation can cause mutations in the DNA and kill the cell. The Barcelona researchers, led by Turkish biologist Elvan Böke, observed that the oocytes skip the step that generates most harmful by-products (the first of the five protein complexes), which explains why they are capable of remaining in a dormant state for almost half a century without losing their reproductive capacity. “My mother had me when she was 26, so the cell I was born from was already 26 years old. Oocytes cannot afford to accumulate damage,” says Böke.
There is so much we don’t know about human reproduction that one in four cases of female infertility is unexplainedElvan Böke, biologist
The finding, published in the journal Nature, could help understand why many women are unable to have children. “There are so many things that we don’t know about human reproduction that one in four cases of female infertility has no explanation,” laments the Turkish biologist. Her team analyzed human oocytes as well as those of the African clawed frog, a classic laboratory animal that has been the focus of several investigations whose authors have won the Nobel Prize. This frog was the first cloned vertebrate animal in 1962, more than three decades before Dolly the sheep. The one responsible for this first cloning, British biologist John Gurdon, received the Nobel Prize for Medicine half a century later.
The authors of the new study refer to their results as “quite surprising,” because an animal cell that was capable of living without this first mitochondrial protein complex had never been seen before. In the domain of eukaryotic organisms — those formed by cells that have their instruction manual, the DNA, in a differentiated nucleus, such as animals, plants and fungi — only one similar case was previously known: that of mistletoe cells. “It is a parasitic plant that just wants to survive. And in order to survive for a long time, it curbs the harmful processes in its system. We see this same mistletoe strategy in the oocytes,” points out Böke.
The Turkish scientist arrived in Barcelona in 2017, coming from Harvard University in the USA. Her work, funded by the European Research Council with €1.4 million, is now focused on the search for the alternative energy source that immature egg cells use during their decades of latency. Biotechnologist Aida Rodríguez, co-author of the new study, uses an illustrative comparison: “As a long-term maintenance strategy, it’s like putting the engine in neutral.”
In wealthy countries, mothers are taking longer to have their first child. Biologists Deepak Adhikari and John Carroll from Monash University (Australia) emphasize in an independent commentary published in the journal Nature that these mothers present a decrease in the fertility of the egg cells, presumably caused by reactions in the mitochondria. The new study may help understand why, as the years go by, the eggs cease to be a safe haven for the mother’s DNA.