Death in the service of life

Every living cell is embedded with "software" that instructs the cell to lose itself to know when its continued existence threatens the entire organism * At the Weizmann Institute, this mechanism is studied

Head under water, arms and legs stretched tightly back - this is, more or less, all that is required of a swimmer who wants to be swept by the current. The sperm cell, on the other hand, requires a much greater effort - it activates mechanisms similar to those that cause programmed cell death. Every living cell is embedded with "software" that instructs the cell to lose itself knowing when its continued existence threatens the entire organism. This software ("apoptosis") helps the body get rid of old, damaged, or potentially destructive cells - such as cells infected with a virus or cells that have undergone a cancerous transformation. To carry out the death sentence, protein-cutting enzymes from the "Caspases" family are activated. From this moment, so the prevailing approach holds, the snowball cannot be stopped. Once the caspases have been activated - the cell is doomed to certain death.

Not long ago it became clear that it is a controlled activation of the apoptosis mechanisms that enables the late stage of sperm cell development in the "Drosophila research" fly (Drosophila). This discovery emerged from post-doctoral research carried out by Dr. Eli Arma, at Rockefeller University in the USA. Dr. Arma, who recently joined the department of molecular genetics at the Weizmann Institute of Science, showed that only after the apoptosis mechanisms are activated in them, the sperm cells, which are grouped in clusters of 64 cells that are connected to each other ("spermatids"), separate into independent units of individual sperm cells. For this purpose, the protein "glue" that connects the cells is broken down, and most of the cellular "soup" (cytoplasm) and cell organelles are collected and thrown into a membrane-encased structure known as a "waste bag", where they are broken down by caspase enzymes. At the end of the process, mature sperm cells are formed, which can fertilize an egg and lead to the creation of a new life. Disruptions in the process cause male infertility.

One of the points that Dr. Arma sought to clarify is how the sperm cell escapes the destructive activity of the caspases, or, in other words, how the caspase enzymes know how to distinguish between waste intended for decomposition and proteins essential for the existence of the sperm cell. What are the control mechanisms that limit the activity of caspases, in space and time, and prevent them from causing damage, and even death, to the developing sperm cells?

It is known that in healthy and normal cells the activity of caspases is limited by means of certain inhibitory proteins, which function as a brake system. When the green light is given to activate the programmed death mechanism, the inhibitory proteins break down and go out of action. Thus the inhibition is removed, and the processes of apoptosis are carried out. Dr. Arma and his colleagues revealed another control pathway that regulates the activity of caspases during the development of the sperm cell, and in the process provided new data on the functioning of these enzymes. The findings, which may also contribute to the understanding of the causes of infertility in humans, were recently published in the journal PLoS Biology. The researchers scanned the genomes of more than a thousand different cell lines of sterile fruit flies, in order to locate the genes that activate the caspases in the final stage of sperm cell development. Thus they were able to identify 22 genes required for the activation of caspases. Two genes from this group code for proteins that "release the brakes" that inhibit the caspases. One of these two proteins is called Cullin-3. The choline protein family is known to be responsible for marking proteins with an identification tag - a ubiquitin molecule - which sends the marked proteins for degradation. It turns out that choline-3, together with two other proteins, marks the caspase inhibitors with the destruction tag. Thus, choline-3 enables the activation of the caspases, and gives the signal to break down the clusters of sperm cells.

These findings for the first time link the proteins from the choline family to the control of caspase activity, and show that the structure that produces choline-3 plays a central role in the activation of caspases in the process of creating mature sperm cells. The researchers found evidence that mutations in choline-3, or in the other two proteins, prevent the development of mature and normally shaped sperm cells, therefore causing infertility. In the research he is conducting at the Weizmann Institute of Science, Dr. Arma plans to identify the factors that inhibit the caspases that are sent for degradation by choline-3. How, then, do the sperm cells escape the destructive activity of the caspases? The scientists hypothesize that the breakdown of the inhibitors and the activation of caspases is limited to certain sections of the developing sperm cell. The activation of caspases is avoided in places where it may cause damage. Since choline-3 is also involved in the normal development of sperm cells in humans, these findings can contribute to understanding the causes of infertility in men, and to the development of ways to treat this phenomenon.