Withholding judgement in grand strategy & finding new identities
By: Meher Roy
Tags: Strategy, Chemotherapy, Judgement, Evolution, Game of Thrones

I feel great today, especially after the sukshma-yoga done with Kiran*. Sleep eluded me last night, mainly on account of night infusion.

Friends

I am grinning since I got a remarkable gift: A personal message from Grand Maester Pycelle from the Game of Thrones. Julian Glover, who plays the character, was also the voice of Aragog in Harry Potter. The video goes into how his character was developed subtly in the series and found his identity.

It struck a chord since I am also searching for my new identity: https://youtu.be/r-ey_LVjp0w

This gift comes from the fabulous team at Solana. They have built the most performant live crypto network with trailblazing new financial capabilities such as an open-source exchange. Raj, Dominic, and Anatoly, cheers!

I am also grateful to have Rishabh in Basel. He flew down from the US to get us through the first chemo push and filled in some of my fatherly roles for Zubi**. His connections to doctors from different research institutes broaden our network of advisors that we can consult during my illness. He is a budding Biotech VC, so reach out to him if you invest in that area.

Chemoplan

Yesterday, I took the systemic chemotherapy cocktail consisting of three drugs — Vincristine (C1), Daunorubicin (C2), and Cyclophosphamide (C3). They plugged in some additional C2 into my cyborg port today and will do so tomorrow as well.

The three drugs are primarily administered to stop cells from dividing and thereby creating new cells. My leukemia blasts have a constant need to divide and proliferate. They have infested most of my bone marrow (90% of all cells in bone marrow were blasts) and a large portion of my blood. Of course, the need for cell division is also a feature of many healthy parts of the body, such as my reproductive system, hair follicles, intestinal linings, and so on. The fact that cell division is both an essential feature of the blasts and one of the normal bodily processes leads to the potent curative effects and side effects of chemotherapy.

Cell division is a complex process with 5–6 sub-steps. The three agents interfere with the different sub-steps in cell division and are therefore able to affect the division of the blasts. It is as if we’re attacking the blasts and normal dividing cells with weapons that work in three different ways — a knife, a pistol, and a rocket launcher.

Consider Vincristine (C1). Its mechanism of action is to disrupt the formation of microtubules in dividing cells. Just like our bodies have a skeleton to provide structure and stiffness, cells have microtubules to provide physical structure and move cells. Microtubules for both daughter cells must be formed during cell division, and these structures then pull the two cells apart. Microtubules are molecular machines for structural support and pulling cells apart. Vincristine stops the formation of proper microtubule structures required for cell division.

Onto Daunorubicin (C2) targets a specific molecular machine, called Topo-Isomerase, working during DNA duplication. DNA is the long-term memory of every cell, and it stores instructions to make a wide range of cell components. Division requires the entire DNA of a cell to be duplicated. One of the wonders of DNA is how it is folded compactly in the cell. Origami is used to fold 3 meters long human DNA into compact structures called chromosomes whose dimensions are in the deca-nanometer range. Whenever operations (reading, copying, maintenance) need to be performed on DNA, the origami on that operated piece of DNA must be undone. Structures near the opened piece of DNA develop stresses that must be resolved. Topo-Isomerases are molecular machines that rectify the mechanical stresses resulting from the undoing of origami during the duplication of DNA. Daunorubicin impairs the functionality of one of these machines, thereby bringing DNA replication to a halt.

The third Cyclophosphamide (C3) majorly works by disrupting the chemical structure of the DNA itself. DNA structure uses two types of glues for its formation — strong glues (covalent bonds) and weak glues (hydrogen bonds). Certain parts of DNA are only weakly glued together as these structures need to be periodically separated and then brought together again during normal operations (reading, copying). Cyclophosphamide works by strongly gluing parts of DNA that should typically be only weekly glued. This inhibits DNA replication and leads to cell death.

Chemicals like C1, C2, and C3 have many more effects than the ones described. We’ve covered here the main known mechanisms by which these agents work to halt the spread of leukemia. It is fair to say that humanity doesn’t know everything about what these agents do in-depth. Now, onto my thoughts for the day.

Withholding judgment in grand strategy

You are in the office. The boss walks by your cubicle and winks at one of your coworkers. This hasn’t happened before. Possibilities swell in your mind — budding friendship (?), commemoration, or something else. A short pause, you judge it immaterial. One is in a computer game. A shadowy figure enters, far in your visual perception. Is that an ally or an enemy? You must make a judgment and act.

In routine affairs, most of our interactions deal with short periods — seconds, minutes, hours, and days. Events happen, and we must judge those events’ value — whether they’re good or bad, and what may be the magnitude of the impact on us. Our brains make such judgments continuously, to the extent that, sometimes, we may not even realize decisions already made.

Some events are so unusual that it is necessary, nay critical, to abstain from making any quick judgments about them. The development of my leukemia is one such event. It’s tempting to judge it as an adverse event, but I must resist that temptation.

It is pretty fascinating that artificial intelligence researchers have needed to put “judgment modules” in their intelligence as well. These modules assess the state of affairs in any game the AI is playing. For instance, there is this famous AI called Alphago that bested the top human (Lee Sedol) in the ancient game of Go in 2017. This particular event was covered in an excellent documentary which I highly recommend. Inside the architecture of AlphaGo, there is a module called “the value network,” which is responsible for making quick judgments on the quality of the position AlphaGo finds itself in. The value network outputs a probability of winning from that particular position in the Go game.

This convergence of humans that naturally judge events and AIs that need judgment models to function in complex environments indicates the centrality of the judgement process to intelligence.

Some events are so unusual that it is necessary, nay critical, to abstain from making any quick judgments about them.This is especially important in grand strategy, where we’re trying to plan actions for much longer time horizons — years, decades, even centuries. Some events whose influences percolate down these longer time horizons cannot be assessed without much more data. And sometimes, they cannot be evaluated since the data to evaluate them won’t exist in this universe altogether. In grand strategy, the ability to withhold judgment is a crucial skill to master.

One feature that marks such events is that the potential advantages and potential pitfalls produced are glaringly heterogenous on two different time scales. The origin story of humanity provides us with a graphic illustration.

We diverged from our common ancestor with chimpanzees sometime around 7 million years ago. It is a matter of great interest as to what triggered our ancestors to separate physically and behaviorally from this common ancestor. There are many hypotheses, and I cover the most interesting one.

Our common ancestors lived in trees and ate fruits. In some parts of Africa, 7 million years ago, climate change happened very rapidly (over hundreds of years). The amount of forest shrunk and was replaced by dry grassland. This was the trigger for our divergence for chimpanzees. When change is gradual, populations of a species can adjust to the changing circumstances by altering population numbers over generations. If change is rapid, gradual adjustment of numbers is arduous, and other mechanisms come to play.

When trees were replaced by grasslands, some chimpanzees were forced to go and live in the grasslands. Most likely, the physically dominant chimpanzees continued to live in the trees, and the weaker ones were left to fend for themselves in the savanna. Our ancestors had a precarious situation: their strategies to get food, stay safe from predators, and their bodies were out-moded. It must have been a gut-wrenching experience to be kicked out of trees in which their ancestors, in turn, had lived for more than 10 million years.

However, this massive downfall possessed the seeds of long-term growth. Our ancestors were able to find niches where a small number of trees were surrounded by grassland. They learned to scavenge for food in the plain while using the trees for hiding. This modified lifestyle led them to travel more on the ground and learn to scavenge. Since they were scavenging from animals much more physically powerful than themselves, social coordination assumed much greater importance. We have evidence that our first tools were rough stones used to break bones left behind by larger animals after eating their meal. It points to how mental capacity developed to adapt to this new lifestyle. The need to travel more on the ground slowly gave way to more upright stances in successive generations. A couple of millions of years later, we have evidence of our ancestors becoming completely vertical to prioritize running on the ground over moving or hiding in trees. We also developed sweat glands and lost all our hair to run for a longer time without overheating. This opened up the strategy of chasing down prey in a marathon by tiring it out.

That event, that gut-wrenching event, of being kicked out from trees had glaringly different pitfalls and hidden advantages on two different time scales. The true meaning, or appreciation, of the event can only be seen in a grand time. Such events do happen in our lives, even though we are dealing with much smaller time scales (only decades) than the development of humanity itself.

The development of my leukemia is one such event. It’s tempting to judge it as an adverse event, but I must resist that temptation.It is that rare event for which judgment must be withheld. We will, I will need 10–20 years to begin to judge this event.

*Kiran- My classmate, colleague and now wife. We’ve been married for almost 5 years.

**Zubi (Zubin)- My two-year-old son.