Diving into Cell Death - Who Lives and Who Dies?

According to Judaism, in the Ten Days of Repentance, between the Jewish New Year and the Day of Atonement (Yom Kippur), decisions of life and death are made: “On Rosh Hashanah will be inscribed and on Yom Kippur will be sealed – how many will pass from the earth and how many will be created.” The liturgical prayer poem describes the vulnerability of life and the many ways one can die. This Day of Atonement poem was revived by Yair Rosenblum who composed music to it for the Gevatron folk singers group; honoring the fallen soldiers of Kibbutz Beit HaShita during the 1973 Yom Kippur War. Many others performed the touching song, including Rabbi Shlomo Carlebach, Amir Benayoun, Dudu Fisher, Avraham Fried, and IDF chief cantor Shai Abramson. The poem was also the underlying inspiration in Leonard Cohen’s Who by Fire.

Although these performances differ in their implementation, they are unified in reflecting our annual introspection. Similarly, our body is constantly making tough decisions; in order to maintain the thirty trillion cells that comprise our body, every day it must sacrifice over fifty billion cells that may harm it. “In cold blood”, so to speak, our body eliminates proteins, cells, and even tissues that jeopardize our very existence.
 

Tribute to the kibbutz in commemoration of its fallen soldiers during the Yom Kippur War. Performed by the Gevatron to music by Yair Rosenblum

"Who will die at his predestined time and who before his time” (Proteosome)

The human body is built hierarchically: organs, tissues, cells, organelles, and proteins all encoded by genes that are constructed from DNA. When the job of a protein is complete, or when the protein is damaged, it is recycled. The process begins with marking the protein with “The Kiss of Death” – a small protein called ubiquitin. Israeli scientists Aaron Ciechanover and Avram Hershko discovered the ubiquitination mechanism, which won them a Nobel Prize together with American scientist Irwin Rose.

The ubiquitinated protein enters a protein-recycling tunnel called proteasome, which is one hundred times larger than The Kiss of Death protein. Therein, the protein is recycled to its amino-acid building blocks. The elimination of proteins that have finished their job or are damaged is so vital to the cell that without this recycling mechanism the cell cannot function.

Recently, the ubiquitination mechanism of the DNA-packing protein histone was elucidated. The DNA-histone interaction is involved in the repair of damaged DNA; the discovery of which was awarded last year’s Nobel Prize in Chemistry. As DNA damage is the leading cause of cancer, deciphering the mechanisms involved in the process is pivotal for development of cancer drugs; some of which are already used clinically.

Deciphering cellular recycling mechanisms can contribute to drug development for other diseases as well. For example, last year’s Nobel Prize in Medicine was awarded to Youyou Tu for finding a drug for Malaria. However, drug-resistant strains to the plasmodium malaria-causing parasite have emerged. A recent study published in Nature identified the structure of the plasmodium parasite proteasome including drugs that will damage it but will not harm the human proteasome. The new drugs were successful in killing the parasite in mice – a crucial step required before testing their efficacy in humans. 

The Kiss of Death. The ubiquitin protein (on the right) and the protein-degrading proteasome (view from above) | Illustration by Dr. Ilan Samish

"Who by sword and who by beast” (Apoptosis)

Multicellular organisms need to concurrently maintain most cells, as well as cautiously get rid of other cells. This is done via a programmed cell death process called apoptosis. In Greek, apoptosis translates to the “falling off” of leaves from a tree – the natural leaf-shedding “death” of deciduous plants. The signal for apoptosis can originate from within the cell, or externally such as from a white blood cell. Yet, once the process begins, it cannot be stopped. The cell shrinks and is disassembled to multiple small vesicles that are swallowed by other cells, and without damaging the nearby tissue.

An important aspect of apoptosis is the degradation of proteins by other proteins – performed by a family of enzymes called caspases. Low caspase activity promotes cancer while overly high activity may result in the death of healthy essential cells, as manifested in Alzheimer’s disease and in autoimmune diseases, in which the body’s own immune system acts against it.

Programmed cell death also plays an important role in embryo development. For example, the separation of fingers occurs because cells between the digits undergo apoptosis. When apoptosis itself is damaged, due to a mutation (DNA damage) or by an invading virus, there is a chance that the cell will divide in an uncontrolled manner resulting in a tumor. Another example is the AIDS virus (HIV), which causes apoptosis of immune cells.

In 2002 the Nobel Prize was awarded for the discovery of the genes underlying apoptosis. Yet a lot still needs to be unraveled to fully understand this important process. For example, just last week a group of Chinese scientists published in Nature the newly discovered structure of a specific calcium pump – a protein involved in this process.

"Who will enjoy tranquility and who will suffer”  (Phagocytosis)

It was just announced that this year’s Nobel Prize in Medicine will be bestowed to Japanese scientist Yoshinori Ohsumi who unraveled the mechanism of “self-eating” (autophagy) and described the genes involved. In this mechanism the cell digests parts of itself by enclosing these parts in sack-like vesicles and merging them with the lysosome recycling compartment. The mechanism parallels that of “swallowing” cells of the immune system (phagocytes). These cells cause apoptosis by engulfing and swallow invading and dying cells.

Autophagy helps coordinate life with the surrounding environment. For example, when the cell is hungry it can eat its own proteins that are not required for survival, in order to reuse these building blocks for making other more essential proteins. Occasionally this mechanism enables a starving tumor to continue to thrive despite other processes that try to eradicate the malignancy. 

"Who by upheaval and who by plague”  (Necrosis)

Unlike programmed cell death, which is fully controlled, sometimes a greater damage occurs necessitating the eradication of a tissue; for example, avoiding the spread of gangrene. During apoptosis all is under control and the cellular content is not spilled out of the cell; however, in necrosis there is a traumatic process caused by injury or infection. In such a case the cell content is spilled and phagocyte immune cells swallow the debris. Necrosis may result in a need to surgically remove the dead tissue or use maggot therapy where fly larvae clean the dead tissue without harming the nearby healthy tissue.

In a review recently published in Science, David Wallach from the Weizmann Institute of Science, along with fellow American scientists, explained the connection between necrosis and inflammation stating that the interaction occurs in both directions; inflammation ignites necrosis and necrosis causes inflammation. A specific protein phosphorylates other proteins and subsequently another protein interacts with the complex to ignite necrosis including an inflammatory response that comes with it.

As Wallach states, many components have already been identified in the complex system governing the necrotic process, yet there are still missing pieces in the puzzle. Understanding necrosis accurately at a molecular level will enable us to harness it for medical use such as to eradicate tissues harming our body. 

Hence, as the poem describes, a large number of processes in our body decide: “How many will pass from the earth and how many will be created. Who will live and who will die”.  Each of these processes has a designated use – from killing damaged or unneeded proteins to eradicating a diseased tissue. A deep understanding of these processes will open the door to accurate diagnosis and treatment of an array of medical conditions such as cancer, Alzheimer’s disease, AIDS, autoimmune diseases and the list goes on.