[Music] About 60 billion cells die in the human body every day.

This is about 1% of all the cells that comprise the average human body. Cell death is there for a major aspect of human biology. It is as important as cell division. The process for which new cells are generated. However our knowledge about the cell death process lags behind our knowledge of cell division. Why is that? The result of cell division can easily be detected. You start out with one cell, and after cell division, there are two. The result of cell death cannot be easily detected. You start out with one cell, and after cell death, there is no cell anymore. Because of this conceptual difference, at least, early on it was harder to detect and observe cell death than it was to detect and observe cell division. For this reason, cell death was not studied extensively for a long time. Now that we know of cell death and can analyze it research has picked up. However, our knowledge of the cell death process is still lagging behind our knowledge of, for example cell division, that's also why it is actually still hard to find chapters dedicated to cell death in general textbooks. Do all cells die the same way? No, they don't. We are slowly realizing that cells can die in different ways. And while some major cell death pathways have been identified, there are probably more to be discovered. The death of a particular cell can be triggered by that cell itself. One then refers to as intrinsic or cell-autonomous induction. Alternatively, the death of a particular cell can be triggered by neighboring cells or the micro-environment around the cell. In that case, one refers to as extrinsic or cell-non-autonomous induction of cell death. During the next six weeks, we will focus on programmed cell death. As one suspects programmed cell death is

a form of cell death that occurs in a programmed and controlled manner. It's main purpose is to remove unwanted cells. It therefore occurs intentionally. In contrast to programmed cell death Necrosis, another form of cell death, does not occur in a programmed and controlled manner. Cells die through Necrosis predominantly in response to acute injury and massive physical damage. And it affects sometimes cells in entire tissues or organs. It is therefore also refered to as accidental cell death. You will hear a bit more about Necrosis and how it is different from programmed cell in one of the next sections. Is programmed cell restricted to humans or the animal kingdom? No. Evidence for forms of programmed cell death now exists for all domains of life and kingdoms. Animals, plants, fungi, protists, archaea and bacteria. In other words protists, prokaryotes, eukaryotes as well as unicellular and multicellular organisms possess mechanisms to eliminate individual cells. For multicellular organisms, it is obvious why the elimination of unwanted cells is important. However, for unicellular organisms, it's not so obvious. Currently it is thought that such altruism, or selflessness benefits, for example, the bacterial colony making bacteria off a particular clone more competitive and therefore successful. Why mechanisms of programmed cells have evolved is therefore maybe not such a difficult question to answer. Genetically related cells whether those are individual bacteria within the bacterial colony or individual cells within the multicellular animal, the species appears to profit from the fact that individual cells are capable of undergoing programmed cell death. The more difficult question is how programmed cell death mechanisms have evolved. This question is still debated and a number of hypotheses have been proposed. There might be several answers to that question. Since the pathways used to eliminate unwanted cells in individuals of the

different kingdoms are not all the same. What might help answer this question are recent findings that factors involved in programmed cell death have functions other than in programmed cell death. These non death functions might eventually help to elucidate the evolutionary origin of programmed cell death mechanisms, in the various kingdoms. In the course we will focus on programmed cell death in multicellular animals. In multicellular animals, programmed cell death is predominantly required for development and for the maintenance of cellular homeostasis. Programmed cell death is used for sculpting. It is also used for deleting structures. And those could be structures no longer needed or structures only required in males or females. Programmed cell death is also used to adjust cell numbers and to eliminate harmful cells. And these could be cells that are either toxic to the body or cells that have been injured. In the next few minutes I will now give you one example for each of those functions, and I will give you examples from humans in particular. This is my favorite example of programmed cell death during development. The removal of the webs of skin between our digits. In utero, human fetuses have skin between their fingers and also between their toes. But these skins are removed through programmed cell death long before birth. In mammals that spend part of their time in the water, the skins between the digits of the hind foot are often retained to help the animal move in the water. For example: most otters have webbed feet. Here's a short video that illustrates this process in a developing human fetus. An example for deleting structures no longer necessary are the mammary glands in women who gave birth and are weaning their children. During pregnancy, the ductal systems of the mammary gland proliferate and form structures within the branches. These structures are called alveoli, and they are later used for milk production. Once the child is weaned, milk production stops, and the mammary gland reverts back

to its normal state. This reversion occurs through the programed cell death of cells of the mammary gland and mammary epithelial cells in particular. An example for deleting structures only required in males or females are the Wollfian and Muellerian ducts which form structures important for the reproductive system. In fetuses both ducts are initially formed along with the gonads. Once sex determination has taken place and the fetus knows, for instance, that it has two x chromosomes and therefore is female, the gonads develop into ovaries, the Muellerian ducts into the oviducts and the uterus and the wolffian ducts are eliminated through programmed cell death. Conversely, in fetuses with one X and one Y chromosome, and therefore a male, the gonads develop into the testis, the wolffian ducts develop into the vas deferens, and the seminal vesicles and the mullerian ducts are deleted through programmed cell death. Through programmed cell death an intially sex neutral structure is therefore turned into a sexually dimorphic structure. The vertebrate nervous system is a good example for the role of programmed cell death. in adjusting cell numbers. In the developing fetus an excess of neurons are formed. More than half of these neurons are subsequently eliminated through programmed cell death and this is critical for the generation of functional neuronal circuits and therefore brain function in general. Our immune system is critical for the ability of our body to combat all kinds of infections. This ability depends in part on the ability of immune cells to distinguish between foreign material such as, bacterial or viral proteins, and proteins from our body. Also referred to as self antigens. Immune cells that are generated, therefore need to be tested for their ability to bind to self antigens. If they strongly bind to self antigens it means they recognize them and they are therefore eliminated by programmed cell death. T cells, one important class of immune cells are formed in our thymus.

Immature T cells are also called thymocytes. With the help of dendritic cells, cells of the immune system that exhibit on their cell surface, many, many different self antigens, thymocytes are tested for the ability to bind to self antigens. Every thymocyte has a different kind of T-cell receptor complex on its cell surface, that recognizes and binds to a different antigen. If this T-cell receptor complex binds to self antigens on the dendritic cell only weakly, the thymocyte survives and matures into a T-cell. However, if the T cell receptor complex of the thymocyte binds to a self antigen strongly, the thymocyte is eliminated by programmed cell death. The selection of T cells that do not strongly bind to a self antigens is absolutely critical for the normal functioning of the immune system. An example for the elimination of injured cells are cells of our skin that have been damaged by reagents that are formed by UV light. You probably know that UV light is part of sunlight and that depending on the wavelength of the particular light, UVA and UVB are distinguished. Our skin is composed of several layers: epidermis, dermis, and hypodermis. When you go out in the sun, sunbathing, most damage to our skin is caused by UVB, the shorter wavelength UV light with the higher energy. And the damage is mainly caused in the epidermis. In cells in the epidermis that are hit hard by the UVB, small compounds are formed - polycyclic aromatic hydrocarbons, and those compounds can distort the DNA in the nucleus. This distortion leads to problems in the replication and transcription of the DNA. The cell therefore has an interest in fixing this problem. This is done by activating what is called DNA damage repair pathways. Often the injury to the DNA can be repaired. However in those cases where the damage is too extensive and repair fails, programmed cell death is induced to eliminate the cell. What happens now if programmed cell death becomes deregulated during development or during adult life?

What if too many or too few cells are eliminated by programmed cell death? Based on these normal functions during development and throughout adult life, you can probably guess, already, what the consequences of deregulated programmed cell death might be in humans. Deregulation of programmed cell death during development, either too much or too little, is detrimental to the developing fetus and will lead to abnormal development and often to an arrest in development. As an example for the role of adjusting cell numbers, I discussed the adjustment of cell numbers in our nervous system. This is really important for optimal function. Now imagine what happens if after this number has been adjusted, additional neurons are inappropriately eliminated by Programmed cell death. Optimal function is no longer possible, especially when the neurons that are eliminated are those of a certain type. This is what happens in patients with neurodegenerative diseases. For example, in patients with Huntington's disease, GABA-ergic neurons, neurons that use the neurotransmitter GABA, are lost through cell death. This loss of GABA-ergic neurons leads to a range of symptoms and eventually death. In the case of patients with Parkinson's disease, it is dopaminergic neurons that are lost to cell death. What happens if self-reactive toxic thymocytes are not removed by programmed cell death. This can be detrimental since they will mature into T-cells that can attack self antigens and therefore your body. This is what happens in auto-immune diseases, such as, Lupus. Which some of you might have heard of. And finally, cells in our epidermis that have been damaged by UV radiation, for example, in which the damage cannot be repaired, are eliminated by programmed cell death. This is done as a safe-guard mechanism. What happens if this safeguard mechanism no longer works? Then cells with damaged mutated DNA survive. Those damaged cells potentially could start proliferating again reproducing in an uncontrolled manner. If the damage for example occured in a

gene that normally restricts cell proliferation this could be the initial event that leads to the formation of a tumor. In this case, a skin tumor, melanoma. [Music]