The Molecular Version of Hodor

The gatekeeper of the cell

Photo by Hennie Stander on Unsplash

Hodor got his name from his repetitive speech.

He could only vocalize one word: hodor. An episode shows how he previously had a life where he could speak like every other kid. Back then, he went by the name of Wylis. After a seizure episode, his speech centres were affected. The only word that he could utter was “hodor”. That’s how he got his name.

A loyal servant of the House of Stark, he has been by Bran Stark’s side ever since Jaimie Lannister pushed him from the window to continue with his lascivious desires. Hodor then carried Bran everywhere, in life and through to his death.

In the final season, we learned about his earlier days, when he could speak normally, and the genesis of the speech impediment. He had to hold the door to give Bran a chance to create distance between him and the White Walkers. As he held the door, the scenes began to flash back. His instruction was simple: hold the door. Like an unsullied soldier, he obeyed the command and held the door, repeating it, with all might and mental strength of will.

Hold the door.

Hold th door

Hol th door

Hodor

Eventually, he was overpowered. As a foreshadowing of his end, Hodor got his name.

Hodor’s actions are similar to what happens inside a cell, preventing it from tipping into a cancerous state. Let’s dive in.

The gatekeeper of the cell

You may know someone who has a “cataract”. It’s in quotes because sometimes, it might not be a cataract, but a white pupil reaction to light. Cataracts affect the lens. Retinoblastoma gets its name because it affects the retina. A cataract is not neoplastic — it does not typically result in cancer. Retinoblastomas do. It is therefore important that anyone with a white eye reflection be seen by an ophthalmologist to rule out the possibility of a retinoblastoma.

The retinoblastoma protein acts like the Hodor of the cell because it prevents the cell from getting into the next stage of cellular division. In particular, the replication of DNA. Before a cell divides, it needs to divide its DNA. The retinoblastoma protein prevents this process from happening as a safety mechanism.

This universal cellular switch involves the phosphate molecule. Certain cellular molecules can either be turned on by the addition or removal of phosphate. Enzymes that add phosphates to molecules are known as kinases; those that remove them are called phosphatases. Depending on the molecule, this phosphate will switch on or off a certain molecular pathway.

As for the retinoblastoma protein, the phosphate is needed to inactivate it. In the absence of phosphate, retinoblastoma prevents cells from dividing. When phosphorylated, they allow the unchecked replication of the cell. Without regulation, we get an outburst of cellular replication. This is a hallmark of cancer.

Recall how Hodor held the White Walkers at bay, preventing them from accessing Bran, who was a threat to their movement. Remember too that Hodor could only stop them for a while before they eventually overpowered him. Hodor was also simple-minded, capable of only a single word. Brave but averse to violence. And loyal to a fault.

The retinoblastoma (Rb) protein is no different. It is simple, holding the door that stops the unchecked replication of the cell. The simplicity is seen through the biochemical reaction of phosphorylation. While Hodor persists, “hodor”, the retinoblastoma (Rb) protein chants “phosphor.”

Relevant to this analogy is that Hodor dies protecting Bran from the White Walkers. The Rb protein is neither alive nor dead. It exists. But once they are phosphorylated, they can no longer guard the gate anymore. Since their role is completely upended, we can safely assume that they are dead, no longer functional in the cell.

The spread of the White Walkers continues converting many humans and a dragon into White Walkers (and White Dragon…coughs). In this regard, we can draw some comparisons with cancer.

Once the Rb protein is released, cancer replicates uncontrollably. It is just as strong, for its molecular size, as Hodor. Humans have 23 pairs of chromosomes, and the Rb gene is located on chromosome 13. The Rb protein has to be mutated on these two chromosomes. A mutation on one of them does not open the floodgates. The other chromosome can take over. Both have to be mutated. This formed the basis of the two-hit hypothesis of cancer activation, back when scientists rushed to understand cancer’s mechanisms.

Cancer spreads. The White Walkers spread all over. Cancer causes misery, so did the White Walkers. Cancer is virtually immortal, given the right conditions. The White Walkers were dead but somehow alive — they cheated death, as does cancer. Cancer cells have a way of diminishing the signals of apoptosis, the process of programmed cell death. They are indeed like White Walkers.

An important difference, however, is that White Walkers spread by converting a living human being or creature into one of them. The walking dead. This makes them more akin to prions, which can convert a normal protein into an abnormal protein. They do this relentlessly, often causing havoc everywhere they accumulate. Cancer duplicates and spreads through a different mechanism.

For cancer to blow up into its full effect, the Rb gene has to be silenced, but at the same time, the replicative power needs to be amplified. You can remove the brakes, but if the vehicle is not moving, brake removal has no impact. Acceleration through cellular replication, coupled with the removal of checkpoints responsible for preventing unregulated duplication graduates an adolescent cancer cell into an adult version.

The Rb gene, in this case, is a brake. Cells have two such brakes. A single one can work if the other gets faulty. When both break, the cellular duplication is amplified. The gatekeepers become overpowered, like Hodor. The technical name is tumor suppressor. In Latin, “tumor” means swelling. The swelling is a result of cellular replication. Molecules such as Rb proteins suppress tumor growth.

As a robust system, the cell has other tumor suppressors, the famous one being p53, but it is not the only one. Rb works hand in hand with p53 and has been found responsible for various cancers throughout the body, and not only the retina.

What I’m trying to say is…

Anderson .Paak and Bruno Mars are known for making their request to leave the door open. According to Hodor and the Rb gene, that might not be a good idea.

Analogies are helpful tools to understand complex phenomena. Hodor, for instance, exists in fantasy and reality.

In Game of Thrones, he was the protector of Bran Stark and a defender of the world from the invasion of the White Walkers. Inside the cell, it protects the host from cancerous growth and spread.

[embed]This song inspired some of the lines used in this article. Source — YouTube