Simplifying Microbiology meets Medium Writers Challenge Contest 2021

Scheduling an Appointment with Death

A microbiological perspective on death that can make or break a living being

Writing Prompt Tag: MWC Death

Triggers Present: Death, suicide, and cancer

You must have read or heard about the term apoptosis during high school biology classes just like me. A rather simple word hiding a cascade of intricate cell signalling pathways that can only be triggered when the cell is in dire need to protect the multicellular organism. It is the kind of death we all take lightly since it is not visibly happening before us unless you took a time-lapse video of it at the lab. But, that event saves everyone from a horrible mistake being carried on at a molecular level and maintains balance, keeping you off death’s door.

What is Apoptosis?

Apoptosis is the process of programmed cell death — taken from the Greek word meaning “falling off”, like leaves from a tree as dying cells tend to go round and get squeezed out from the sheet of living healthy cells.

The cell organises its own death when it has reached its prime, has gotten infected, has faced too much stress, or has suffered irreparable damage, all in the name of protecting the organism’s overall health.

Figure 1- Electron micrographs showing apoptosis. (A) The cell undergoes apoptosis in a culture dish. It appears almost round, lost its nucleus, and has a lot of tiny vacuoles. (B) A phagocytic cell from the immune system ate up an entire apoptotic cell in a developing tissue. Scale= 10 μm (micrometers). Source- Molecular Biology of the Cell, Alberts et al., 6th Edn.

Here are key features which can help you spot an apoptotic cell!:

• Cell shrinks and condenses
• Cytoskeleton collapses
• The envelope of the nucleus disintegrates
• Nuclear chromatin condenses and breaks

Often, the cell will also bulge outwards while dying, or if it’s a big one, it will break into tiny membraned blobs with special chemical signals on them, forming apoptotic bodies. These entities call a nearby cell or a macrophage for a quick cleanup. A swift and clean death has already occurred, even as you read this post.

Take a peek at the short time-lapse video below where the human prostate cancer cell line named DU145 cells are being forced to undergo apoptosis by a chemotherapeutic drug called etoposide. One of the many differences between a cancer cell and a regular healthy cell is that cancer cells don’t undergo apoptosis.

Video 1- The DU145 cells look flat initially (yellow with a red nucleus), but start to contract and bulge (purple and black) and burst into many small apoptotic bodies because etoposide broke the cells’ DNA. Hence, triggering apoptosis. The cells are false-coloured to indicate their thicknesses.

Who knew death looked this interesting under a microscope!

Importance of Apoptosis

Whenever someone hears the word ‘death’ on media, it could most likely be bad. Getting the 13th card, the Death card, in a tarot reading may unsettle some with its illustrations of skulls, skeletons, and other imagery signifying death, like the Reaper, but it's not always what you think it means. The Death card is often misunderstood as a bad omen. You will be surprised that it is one of the most positive cards in the tarot deck because it means metamorphosis, change, and endings. There is no beginning without an end.

Death around us is often saddening and painful, although, there is a bright side to it right here.

I: Foetal Blob to Developed Limbs

Have you ever thought that why we don’t have webbed hands or how our limbs are separate from our torso? Thank apoptosis for that. You must have seen what a developing embryo looked like, a curved tiny looking guy in a foetal position with spade-shaped hands, and limbs stuck to the torso. The cells which are not required at all, say, skin webbing between our fingers, goes away during embryological development. And when the baby is born, they have perfectly shaped limbs and digits, looking healthy and normal.

Figure 2- Apoptosis sculpting the digits in a developing mouse paw. (A) Paw is stained with a special dye where only the apoptotic cells appear as bright green dots between the digits. (B) Interdigital webbing disappears after a day with only a few apoptotic cells remaining. Scale= 1 mm. Source- Molecular Biology of the Cell, Alberts et al., 6th Edn.

Wondered where the frog’s tail goes after the tadpole stage to a fully developed adult? Apoptosis got rid of it because frogs really don’t need tails.

Figure 3- Metamorphosis of a green frog. It starts from fertilised frogspawn to tadpole, and finally forming into a regular healthy adult frog. Source- By LadyofHats — Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=20465759

II: Quality Control Service

Apoptosis aids in general development by eliminating cells that are abnormal, non-functional, misplaced, or simply dangerous to the organism’s health.

For example, developing T and B cells from the adaptive immune system get eliminated if they show an affinity to self-antigens during the self-tolerance test. It is a big no-no as it may lead to an autoimmune disease. Only the ones that do not attack the non-foreign antigens get to stick around.

III: Keeping Organs the Same Size

In a grown adult human, like yourself, you may have noticed that your pancreas and other organs don’t get any bigger. The cells divide to replace the old and damaged ones, but some have to undergo apoptosis to maintain the organs’ right size and shape. If it were to replicate continuously and not die, then I would have some bad news for you, my friends.

Scientists have proven this by observing a live rat’s liver fully return to its original state after a portion was sliced off. In another experiment, a rat was given phenobarbital, causing the liver to increase in size via cell division. When the drug administration was stopped, the organ reduced back to its regular size within a week like it was no big deal.

IV: Removing Cells Beyond Repair

Cells with busted organelles or any other form of severe damage which cannot be fixed will choose apoptosis. In the case of minor DNA damage or other stresses, a special protein named tumour protein p53, or simply p53, can stop the cell from doing its normal activities, fix the damage and continue on as usual (See Fig. 4). When the issues are super serious, p53 will hop in to stop everything and initiate apoptosis to prevent cancer from occurring. It is not called the guardian of the genome for no reason! Either removing that single protein completely or having it mutated will result in cancer.

Figure 4- The p53 pathway is where p53 gets activated by being freed from mdm2 protein when certain stress signals like DNA damage, cell cycle abnormalities, and hypoxia are detected. Depending on the severity, p53 will either repair and save the cell or begin apoptosis. Source- By Thierry Soussi — Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1867723

V: Death to the Old Ones

Did you know that the cells in your body have a limit on the number of times they can divide? This limit is known as the Hayflick limit, where the cells divide around 40–60 times, enter cellular senescence, meaning, no more cell division, and finally go into apoptosis.

Figure 5- A simple diagram showing the Hayflick Limit. The telomeres (red nubs) are at the ends of a chromosome pair (blue). They gradually shorten with each division event till they almost disappear, and the cells eventually reach senescence. Source- By Azmistowski17 — Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=40694154

Each time a cell divides, the telomeres at the ends of the chromosomes get shorter until it reaches the critical length, marking the end of cell division. Going past the critical length will cause DNA damage, leading to cancer and other ailments. Therefore senescence and apoptosis are essential for maintaining an organism’s health.

Figure 6- Human chromosomes (grey) capped by telomeres (white dots). Source- By U.S. Department of Energy Human Genome Program — http://science.nasa.gov/media/medialibrary/2006/03/16/22mar_telomeres_resources/caps.gif, Public Domain, https://commons.wikimedia.org/w/index.php?curid=5234303

VI: Ridding Of the Virally Infected

Natural killer cells (NK cells) from the innate immune system and the killer/cytotoxic T cells from the adaptive branch share a common style of killing away virus-infected cells, that is by activating apoptosis.

Figure 7- Apoptotic activation by NK cell or T killer cell in a virally infected cell. Source- Molecular Biology of the Cell, Alberts et al., 6th Edn.

Either an NK cell or T killer cell approaches a cell infected with a virus and concentrates the perforin proteins to perforate at a localised spot only on the target (See Fig. 7). Afterwards, granzymes are released within the infected to start apoptosis by activating caspases for the caspase cascade. This kills the cell along with the uninvited guest. Once apoptosis begins, there is no stopping it and the damage is irreversible.

My Thoughts and Thanks

To me, death has most negatively impacted my life, be it strangers, pets, neighbours, and family members, and my heart hurts for them. Science has been a great companion, always sharing information and showing ways I could try to make this world a better place, from a scientist at the lab to a science communicator writing this article. Amongst all the sorrow, apoptosis appeared to be the most positive form of death of all. Killing some to save the many. A meaningful, and beautifully orchestrated suicide is what I would like to call it.

I want to thank everyone who has read my work and supported it, that means a lot to me. My little spot on Medium wouldn’t have existed if it weren’t for the support of my family and friends, my passion for microbiology, and my desire to share knowledge with everyone around me.

Dying for more? There’s plenty more where that came from! 😉

Glossary

Multicellular- An organism made of many cells; example: humans

Electron micrographs- Images from an electron microscope

Vacuoles- Specialised organelles mostly seen in plant cells, and momentarily in animal cells

Phagocytic cell- Cell that can eat; cells from the human immune system include neutrophils and macrophages can do this

Cytoskeleton- Protein fibres that give shape to a cell and other functions

Nucleus- A well-defined enclosed region in a cell that holds the genetic material, which is DNA

Chromatin- DNA molecule combined with histone proteins to give ‘beads-on-a-string’-like appearance

Adaptive Immune System- Found commonly in vertebrates; involved in wiping out intruders with antibodies and killer T cells and has immunological memory, but takes time to attack

Hypoxia- Insufficient oxygen supply in cells or body part

Telomeres- Nucleotide repeats with special proteins at the end of the chromosomes for protection

Chromosome- Highly condensed chromatin after supercoiling event

Innate Immune System- Found in vertebrates and many organisms; has a variety of immune cells and several other mechanisms to immediately handle the infection and activate the adaptive system

Sources

• PART IV: INTERNAL ORGANIZATION OF THE CELL, Chapter 18: Cell Death. From the textbook Molecular Biology of the Cell, Alberts et al., 6th Edn.
• PART V: CELLS IN THEIR SOCIAL CONTEXT, Chapter 24: The Innate and Adaptive Immune Systems. From the textbook Molecular Biology of the Cell, Alberts et al., 6th Edn.