Unsolved Problems in Cell Biology: Germline Immortality

True mysteries often lie in something that we take for granted. One such mystery in biology that remains almost entirely unaddressed is germline immortality. Each of us, as a multicellular organism, was once two germ cells (one from our mother, the other from our father), each of which was once two germ cells in our grandparents, each of which was once….. Throughout this journey of the germ cells, they never died or senesced. And the implication of this, although obvious once stated, is that the very existence of each of us can be tracked back to the gonad of somebody (something) that was not Homo sapiens or even a mammal, but something like a choanoflagellate.

This magical process is vaguely called “rejuvenation” or “resetting,” but we know essentially nothing about how this can happen. Currently, the idea of rejuvenation/resetting is discussed mostly in the context of epigenetics and conferring totipotency to zygotes at the beginning of each generation, by resetting the memories of cells and preparing the genome for a new start. However, we know that the materials that constitute our genome and cells are not resistant to damage or decay; cells can accumulate many forms of damage to their genomes and the cellular components, and this damage normally leads to cellular aging/senescence. Such damage includes mutations and damaged proteins. Therefore, germ cells must have mechanisms to reset or eliminate this damage. Critically, these mechanisms must be somehow harmful or unaffordable for somatic cells or individual organisms. Otherwise, I would imagine that evolution might have found a way to reset every single somatic cell to create an immortal animal that can reproduce forever. In sum, I consider the germline’s ability to rejuvenate every single generation, as it is passed from one generation to the next, to be the most fascinating unsolved question in biology.

I am often asked why I study germ cells, a nonessential cell type not required for human health. Although germ cell biologists can snap back or respectfully disagree (whichever they prefer) by saying, “Without germ cells we’ll all be extinct fairly soon,” I wonder that being nonessential might be the very job of germ cells. Germ cells are dispensable for organismal survival, whereas somatic cells are not. There are lots of things a cell can do only when it is nonessential. I imagine two strategies germ cells could take to support their immortality, grounded on their dispensability. First, germ cells could be extremely picky about their quality control and discard any subpar cells via cell death. In this manner, the germline could protect its genome by selecting a “precious few,” while trashing anything that does not meet the highest standard. Such an approach would not be affordable for somatic cells, because development and maintenance of multicellular organisms require concerted actions of somatic cells, and therefore somatic cells’ logic will be skewed more toward survival.

Being nonessential may further allow germ cells to rejuvenate by a means that cannot be explained purely by selection. “Selection of the least damaged” described in the previous paragraph is not an active process and can only passively protect the germline from damage. However, such selection cannot counteract damage and decay that occurs to all cells, and even the least damaged cells/genomes will soon be too damaged to move on. Therefore, germ cells must have some active mechanisms that truly removes damage and rejuvenates the cells/genomes. Again, I wonder if germ cells’ dispensability (for organismal survival) might be the key. For example, after investing two cells’ worth of material, cells could divide asymmetrically segregating all “good” components into one cell and all the “bad” ones into the other cell. This would lead to one rejuvenated cell and the other, bad cell, which could be sacrificed if it is too bad because germ cells are not supporting organismal survival. Again, somatic cells might have a limited capacity to do this, because they have critical functions to perform to keep the organism alive.
These are pure speculations of mine on the mechanism of germ cells’ immortality, which may be a hilarious misconception in the eyes of future biologists. However, the very fact that these speculations might be embarrassingly wrong reveals how little we know about the immortality of germ cells.

About the Author
Yukiko M. Yamashita is James Playfair McMurrich Collegiate Professor of the Life Sciences and a Howard Hughes Medical Institute Investigator at the University of Michigan, Ann Arbor.