Micro-management (of disease) and the 2018 Nobel prize in physiology

One of my (too many) hobbies is to read and learn about leadership, strategy and effective communication. I developed the habit of reading leadership books after I learned about servant leadership — a methodology that teaches one to lead without power over others and without manipulation. Micromanagement in leadership is bad. But this post is not about person management — instead it is about management of very small, but very complex machines called cells.

One piece of information that will be important in understanding the rest of this post is that virtually every cell has sensors in its outer wall or plasma membrane (official name). As explained in a previous post, a large number of these sensors or receptors (official name) normally act as breaks or constraints to stop the cells from doing what they would normally do. For example, without receptors, cells will make copies of themselves as fast and as many as they can, move and invade other tissues to get more energy, release toxic substances into their environment without any regard to everything around them. In short, without receptors they become very much like cancer cells. Different types of cells have different types of receptors according to the role that they play.

A very simplistic view of receptors and how they work in a cell

How cell differentiation is micromanaged

Some (many) processes in the cell need to be micromanaged. For example, all cells in an animal come from a single cell initially — the zygote. At some point in time, we were all just one cell — we did not have a central nervous system or circulatory system. From that initial cell, every other one of our other cells was created. Even though the first few copies of that cell are all somewhat the same and unspecialized (like teenagers before choosing a career), slight differences inside the cells will lead to the expression of different genes, which in turn will lead to the specialization into different types of cells (liver cells, blood cells, neural cells, etc) — just like adults after they choose a career (figure below).

For example, retinoids (of which retinoic acid is an example) are molecules that can be sensed by nearly any type of cell. It is the individual and highly specific concentration of different minerals and proteins inside the walls of those early cells that causes early embryonic cells to specialize into different type of cells.

A single initial cell — the zygote — becomes many different types of cells. The type of cell that each daughter cell becomes is controlled by signals both inside and outside of the cell (src: bioninja). On the right, how a daughter cell perceives signals from the micro-environment and responds by expressing only a certain type of genes — those related to the creation of neuron cells, for example

But this specialization is not a random process — it can’t be otherwise it would be chaos. Instead, those early cells send signals to each other — mechanical signals (pushing other cells and offering resistance to being pushed by other cells) and chemical signals are constantly giving these early cells “hints” that either there are enough liver cells around so it’s time to stop or — to continue making more liver cells because there are not enough of them around. This nudging and micro/inter-cellular signaling is what I am calling micro-management because there is no central authority that all cells respond to.

How the central nervous system macro-manages

Any multi-cellular organism needs some sort of regulation and coordination between the cells, especially when multiple organs are involved and they need to have coordinated behaviors. For example, when an animal gets ready for a meal, several things happen: energy is redirected to the jaw, stomach, and intestine muscles; saliva and gastric acids need to be created to break up the food and its nutrients. The central nervous system (CNS) plays a central role in coordinating and synchronizing all of these activities — when food is recognized, the CNS starts a chain of electric signals which will launch all of the other events. This is what I call macro-managing.

At the cellular level, however, there is still some amount of micromanagement that needs to happen — for example, one of the signals that travels via a nerve called the vagus nerve from the CNS, causes a type of cells (called G cells) to start producing a hormone called gastrin (a chemical signal), which travels in the blood and triggers another type of cells (parietal cells) to create the gastric juices (HCl or H+) that will help digest that food (figure below).

In preparation for a meal, parietal cells in the stomach are signaled to create acid that will destroy bacteria in food. (src: apsubiology.org). On the right, a schematic of a parietal cell responding to the gastrin signal by creating gastric acid

A very important detail in this whole process is that only some cells respond to the signal by creating gastric acid. The difference is that they have a receptor called gastrin receptor. That is really important because the signals from the vagus nerve arrive at a lot of different cells (heart and the lungs also get their marching orders from the vagus nerve). If all cells responded to this signal by producing gastric acid, it would be very bad indeed! You definitely don’t want any gastric acid anywhere but your stomach.

In summary, the CNS macro-manages the digestive process but only certain cells involved in the process must respond in a certain way: the signals have to be very specific in both space and time.

As a final note on macro-management of digestion, when sugar is ready to be distributed to all cells, insulin is created and released into the circulatory system, which in turn activates the insulin receptor, which in turn causes cells to start collecting that sugar and generate ATP (the way energy is stored in cells).

Middle Management — the immune system and the 2018 Nobel prize in physiology

The immune system is somewhere in between micro and macro management. On the one hand, immune cells can touch almost any tissue and any cell. They need to because pathogens (disease-causing bacteria, virus and parasites) can hide anywhere and their job is to destroy them. From that point of view, the immune system macro-manages what goes on in the cell, making new immune cells as necessary to destroy pathogens.

On the other hand, when they do detect and mark something for destruction, they need this attack to be highly micromanaged in order to attack ONLY the disease-causing cells and leave everyone else alone. When the immune system finds a protein expressed in the surface of a normal cell, they will not immediately destroy. Instead, they will use their signaling repertoire to ask the question “do you belong here?”. Normal cells that can reply back “yes I do” are left alone. Those that miss this signal are marked for destruction (some auto-immune diseases are caused by a malfunction of this signaling cascade).

As I hope I hinted several times in this post (and others) one of the reasons why cancer cells are so annoyingly difficult to target is the lack of the constraints that all other cells have and prevent them from overwhelming the body with too many requests for energy and nutrients (which then are redirected from where they are needed to feed the tumor).

Once cancer cells acquire enough mutations, they find a way to hide themselves from the immune system by “hacking” this same system. A cancer cell that is spending all of its energy and time making more copies doesn’t have a lot of energy to make sure that DNA is being copied correctly, i.e. they stop making use of the DNA proof-checking tools that all normal cells do. As a result, a lot of mistakes happen and proteins are created that are messed up. These are good targets for immune cells because they can be used as a way for them to tell normal from cancer cells (scenario 1 in the figure below).

The 2018 nobel prize in physiology was awarded for the discovery that some cancer cells can “hijack” these immune system checkpoints that prevent destruction of cells that should be destroyed. They express on their surface a protein called PD-L1 which sends a signal to the immune cell (“In spite of all this damaged proteins you should not destroy me!”) thus inactivating the immune cell (scenario 2 in figure below).

The reason why the 2018 nobel prize discovery is so important is because now we have a way to micro-manage what happens when cancer cells hack the system — immunotherapies like ipilimumab and nivolumab block PD-L1 and other type of checkpoint inhibitors, allowing the immune system to behave as it should behave (scenario 1) even when cancer cells have developed this hacking mechanism.

How about auto-immunity?

Yes, that’s a big problem — normal cells also use PD-1/PD-L1 to send the message to the immune system that they do belong there. If we introduce PD-1/PD-L1 blockers, they will enable both the destruction of cancer cells and the destruction of normal cells. Unfortunately, several patients treated with immunotherapies have suffered complications caused by the immune system attacking their normal cells (see 1, 2 and 3 for more about this).

Because of that, immunotherapies by themselves are not the end of the story for cancer. Back to the gastric acid analogy, treatment with immunotherapies without micro-managing which cells are targeted and which ones are not can cause a lot of unintended damage.

Nevertheless, immunotherapies are a step in the right direction. Combined with a more specific micro-management of which signals to block, these therapies can indeed be very powerful.