Why Cancer Sucks.

Cancer generates a lot of fear. It is able to strike anyone, it is able to kill across all demographics.

I am writing this in response to Alan Alda’s call for geeky people like me to better communicate with less geeky people (If I Understood You, Would I Have This Look On My Face?). This is an adaptation of a lecture I have done a handful of times explaining what cancer is and why we are where we are.

Cancer generates a lot of fear. It is able to strike anyone, it is able to kill across all demographics, and it is poorly understood by muggles (ZDogg’s description of “non-medical people”). It is the lack of understanding that I want to try to address. Because a combination of fear and misunderstanding means our reactions are not always logcial. I am going to do my best to explain it in simple terms, such that you are able to answer many of the questions I get all the time: What is cancer? What causes it? How can it be prevented? How do we treat it, and why doesn’t it work out so well? If I eat a metric crap ton of kale every day, will I still get cancer?

You can’t understand what cancer is until you understand a few things about yourself. In particular, you have to understand what cells are and how they work. But don’t worry, you don’t have to become an expert in genetics, and it’s really not that complicated. But you do need to understand how things are supposed to happen if you want to understand how things can go haywire.

You probably already realize that you are made up of cells, and a whole bunch of different kinds. Your cells are all specialized to do their job, but they all have some things in common. Each cell has a control center (the nucleus) and a factory floor (the “cytoplasm”). The control center of each cell has a big book – a really big book – that has the directions for how everything is done. And not just in that particular cell, but in every cell in your entire body. No matter what type of cell it is – skin cell, muscle cell, brain cell – every page in this big book of instructions is the same. These are your genes.

The directions in the book are written in a special code – DNA. Think of DNA as letters in an alphabet. We put the letters together to make words, and then the words are put together to make sentences: genes. Each person’s big book is unique, but they are all arranged the same, with the same order of the chapters and the same basic plan, it is just that some of the wording is a little different.

Each sentence or gene is like a recipe, and it is actually a recipe to make a protein. And the book in each cell of your body has all the recipes for every protein that is used to make you. These proteins can be structural, like the one that makes the protective outer layer of your skin. Some control chemical reactions, some act as hormones; you name it, if it is a part of your cells, it is either built from one of these recipes or assembled by other proteins that are made the same way.

Think of this thing as a big, hard-cover book. When it’s not in use, it stays closed and out of the way to keep it safe. But if someone needs to read one of the recipes, they have to open the book to the right chapter. There are different chapters for different things. Remember that the book has all the information for all of you, so some cells won’t ever use certain chapters; for example, if you are in a skin cell, you wouldn’t ever open the chapter about all the stuff needed to make muscle cells contract. That’s not what skin cells do.

Because there is only one book, and it never leaves the control room, to get the recipes out to the factory floor we make copies and take them instead. Making the copies is a process we science people like to call transcription. Using the copied recipe to make a protein is called translation. Transcription and translation sound very similar but refer to very different things, so they get confused, which really sucks if you are taking a test in genetics class. But we aren’t. Which is why we will stick to making copies and following the recipe.

When talking about cancer, there is a very important chapter in the big book: cell division. Every cell has the potential to divide and replace itself. Some cells do this a lot, like your skin; and some, like brain cells, essentially don’t ever divide. Each cell has a committee that decides if and when the cell is going to divide. The committee listens to a lot of different things before reaching a decision; some messages suggest dividing, some suggest staying put. When the balance of these things tips far enough to side of “time to divide,” the cell will stop doing it’s normal work and set about the process of making a complete copy of itself.

Think how big a job this is: everything has to be duplicated. All the scaffolding, and the machines, even the building itself, you will need 2 of each component, no matter how big or small. And you have to make special equipment to move stuff around, to physically separate into two new cells. And the most important thing that needs to be copied: the big book.

As we said, the big book is pretty safe when it’s closed. If anything is going to happen to it, it’s going to be when someone is messing with it, opening it up and forcing it flat on the copier, thumbing through the pages; that’s when something is going to get spilled on it, or a page is going to be torn or something. So the parts of the book that get the most wear and tear are the chapters that are being used all the time.

Let’s take a minute and think about the things that can go wrong. First, the workers on the shop floor might read a recipe wrong and screw up when they make whatever it is they are supposed to be making. With this type of error, the effects are pretty minimal, because the next time the recipe is used things will be back to normal. And so long as the instructions in the big book are correct, the next copy of the recipe will be correct, and we all go on not really picking up on the problem. It’s like buying a toaster that doesn’t work: you just go back to the store and get another one.

But what if I mess up something in the big book? Then the problem sticks. Now everything that cell does from then on relating to that error is wrong. And every time the cell divides, the big book – and whatever errors that have developed – gets copied, passing on the problem to the next generation of cells. Now I go back to get another toaster, and this one doesn’t work either! Or the next one! WTH?!?

If I mess up a chapter in the book relating to something the cell never does, what happens? Exactly nothing. If I mess up the chapter about plumbing fixtures but the plant is busy making electrical supplies, no one will ever know. Even though every subsequent cell has the same errors, if no one reads that chapter, no one ever knows.

But what about if it is in an important chapter? What if someone spills an entire cup of coffee in the “how to make skin pigment” recipe in a cell that is supposed to make skin pigment? Then that cell is not going to make skin pigment correctly, nor is any further cell that comes from it. The big coffee stain gets copied right along with the big book.

Nevertheless, this essentially goes unnoticed. Why? Because you are made of a LOT of cells, something on the order of thirty trillion. So if just one is doing crappy work, meh. Also, most things in your body are regulated like a thermostat. That is to say, there is some signal – a decree from upper management – that some product is going to be made. And that decree stays in place until the managers are satisfied. So in this case, other cells would cover up the shoddy work of the cell with the coffee-stained book, and since you are really big with lots and lots and lots of cells, you won’t notice.

Where we run into problems is if someone gets careless with the chapter on cell division.

Remember that committee? They are acting on stuff that is all covered in this very important chapter. Different cell types have different sensors and measurements that feed information to the committee. Skin cells look at different stuff as compared to muscle cells or blood cells when they are trying to decide whether or not to divide. So the chapter is actually really complex, and it is cross referenced with other chapters, and there are a lot of ways it can get messed up.

Let’s imagine there is a section in the skin cell division chapter called “don’t divide when you are right next to another skin cell.” This is the section that keeps your skin nice and flat, instead of having cells pile up on top of each other; they divide until they bump up against a neighbor, and then settle in. One day, this page in the big book gets torn. Now this “don’t divide when you are right next to another skin cell” signal – which is a don’t-divide signal – is going to get ignored. That means the guy on the committee that is supposed to be paying attention to what is going on and, he just keeps voting to “divide,” no matter what.

The thing about the division committee, it’s not just one vote, it’s a group decision. So even though a page got torn and we have one vote always saying “divide,” the cell is not out of control. But all things considered, this particular cell is going to divide a little bit more often. And every time it does, the torn page is copied, and that error gets passed on to the next generation of cells.

Because these new cells divide a little bit more than usual, each of them has the big book opened to the cell division chapter a bit more often, and this just increases the chances for something else to happen, another spilled drink or a page that gets folded over. And with each little incident, the chances that votes on the committee get skewed goes up progressively. If this continues, there may come a time where the committee no longer cares about any of the signals or data it is supposed to be looking at, it’s just going to be voting for division continuously. This is pretty much what cancer looks like: the cell has lost its normal regulation of division. It generally stops doing what it normal does and just gets on with dividing, each time making new cells that have all of the same errors, each subsequent cell having no control over division, and the process just goes on and on.

This new population of cells has no regard for the normal structure of your body, so early on they grow in lumps we call tumors, which literally means swelling. As the lumps or masses grow, they can interfere with stuff. A tumor in your colon can block the flow, causing obstruction. A tumor in your lung can keep air from moving where it should. A tumor in your brain can be fatal just because it is all in a solid case (your skull) and has no room to go anywhere.

And these messed up cells can also end up spreading around your body to distant sites, where they do the same thing, growing and dividing without regulation.

There are a few things I am leaving out for the sake of brevity (there is more detail at the end, if you are a glutton for punishment ***), but this really is the underlying concept that will allow you to better understand what cancer is, how is starts, and why it is so difficult to treat.

A few important facts flow from this process that may not be obvious:

1. These problems with the big book represent acquired defects in a cell’s DNA. So for something to cause cancer, it needs to be able to mess up that DNA. Common things that do this are radiation, either from the sun or the natural background solar radiation that we are all exposed to when living on the earth. There is a lot of stuff in cigarette smoke, and this remains the most significant modifiable risk for cancer. Some byproducts of your metabolism are really reactive, you may have heard of “free radicals.” The bottom line is that you can’t escape these defects, as some simply happen because of the natural process of messing about with the genes, just like wear and tear on a big book.
2. It takes multiple errors or defects. We call them “hits.” Think of them as modifying votes on the committee. You can’t do it with just one, but if you get enough, you have a majority vote and things go wrong. Problems in other things in the cell other than DNA, like proteins, are not passed on when the cell divides, so they will not lead to cancer.
3. It is possible to be born with a messed up page in your big book. This is “inherited risk.” If this happens, every cell in your body starts out with that issue. A person like this isn’t born with cancer, but they are born with a committee that is already biased. That increases the ultimate risk for developing cancer, and also shortens the time it takes to get there. Of course it depends on which page is messed up, and which cells use that section of the book. If it is a committee member that doesn’t have a seat at the table in that particular cell type, then it doesn’t matter. This is why certain inherited genetic mutations increase the risk of certain types of cancer, and reduce the age that they occur. An example is an inherited BRCA gene mutation increasing risk of breast cancer, and patients with this mutation develop cancer at an earlier age.
4. The more a cell divides, the higher the risk of developing cancer, because the big book is open to the critical pages more and more. Because the steps to cancer progressively increase the rate of division – each time you lock down another committee member vote, things just go faster – it becomes a self-fulfilling process; it accelerates. And other things that make cells divide faster – like certain chronic inflammatory conditions – may also increase the risk of cancer. Smoking irritates the linings of air passages in the lung, which makes the cells divide more as a reaction to this irritation (on top of all the DNA-damaging crap that comes with it). This is another reason it increases the risk for lung cancer, but also helps explain why some people get cancer and some don’t; some people’s lungs are more easily irritated than others, and that changes things from person to person. We are all individuals.
5. You can’t eat stuff to protect you from DNA damage. No amount of kale in your diet will keep the big book from getting opened and copied over and over and over again. And sometimes, shit happens. That’s life.
6. You can’t eat stuff to undo DNA damage. No amount of kale will cure a cancer patient. Once it’s there, it’s a self-replicating system.

Well then, what about treatment?

In most cases, the best way to treat cancer is to cut it out while it is small. Who cares what it is and why it is, just get rid of it. Breast cancer, colon cancer, lung cancer…the goal is to catch it small and get rid of it. Because as it grows, it can spread – metastasize – to other parts of your body. And once that happens, the only way to get rid of it is with medicine that is going to affect the rest of your body, too. And that’s a problem.

Think about antibiotics. Antibiotics – like penicillin – work on bacteria. Bacteria are not like you. They are made of different stuff, and they have different chemical reactions and proteins and things that make them up. Antibiotics work on the things that are different in bacteria from the stuff in you. That means they don’t have any direct effect on your cells, they just kill the bacteria. The side effects to antibiotics are usually related to allergies, or to the killing of normal bacteria, such as those in your gut that are necessary for your digestion. But in general, we are pretty good at treating bacterial infections.

Now think about viral infections. We don’t do as well treating these. Why? Because a virus lives a different life than a single-cell organism like a bacterium. Viruses get into your cells and highjack the systems inside and trick them into making more virus. But this means there is less stuff that is different; there is virus stuff, but a whole lot of what is going on is you, it’s still your stuff. So we have some anti-viral medicines, like Tamiflu for influenza, but they don’t work as well.

Cancer cells are your cells, with all of the same proteins and enzymes and stuff, they just have lost their normal regulation for division. So there is typically very little, if anything, different about them to target with a drug. So what to do? Well, there is one thing a little different between cancer cells and normal cells: cancer cells divide more. And this is what standard chemotherapy goes after; it kills cells that are dividing.

Because most chemotherapy kills cells that are dividing – pretty much any cell that is dividing – both cancer cells and normal cells are killed. This has several implications:

1. The side effects are generally related to killing other cells that are dividing. Like hair, which often falls out. Or bone marrow, which means chemotherapy can make you anemic (too little blood, or more specifically not enough red blood cells). Or have a compromised immune system (not enough white blood cells). Or have bleeding problems (too few platelets, little cells in your blood that help your blood to clot).
2. The higher percentage of cancer cells that are dividing at any given time (ie. faster growing tumors), the more effective the therapy. Fast growing tumors are more likely to be curable, while slow growing tumors are more likely to be indolent, but hard to cure. Lance Armstrong had an extremely aggressive cancer that had spread all over his body, but that same aggression is exactly why he was able to be cured. Some cancer patients (like some with breast cancer) may live with their disease for years or even decades, only to have the disease slowly progress, ultimately killing them.
3. Because the cancer treatment doesn’t typically kill all of the cells, it sets up an environment for evolution; that is to say, it can select for resistant cells by killing off some and leaving behind cells that for whatever reason are immune to the treatment. Then, those cells can simply divide and live on, allowing the cancer to progress unhindered. This is why we see an initial “response” in patients, where the treatment makes their tumors shrink some, but then they come back, often seemingly with a vengeance.

What about all of these new treatments? We have made huge strides in cancer treatment. How have we done that?

First, through study. Because each cell type is different, the chapters in the big book that get messed up can be different, so different cell types (like lung cancer cells vs. breast cancer cells) tend to involve different genes (although it’s ultimately the same thing: loss of the cell’s regulation of division). So different cancers tend to behave differently, and they tend to respond to different drugs differently. By studying what works on what types of cancers, we have been able to create better recipes and plans.

Second, we have started to find drugs that work on cells with specific errors in the big book. More like the way antibiotics work, this is an attempt to find things that are different in the cancer cells as compared to the normal cells. It’s harder to do than it sounds; remember that no matter how messed up they get, they are still your cells. But we have found a few things to “target” in different tumor types. With each of these targeted therapies, there are two important things we have to figure out: First, do the cancer cells actually have the specific error? If not, the treatment won’t work. We typically do tests on cancer cells to try to figure this out. Second – and unfortunately we can’t test for this – the error has to be a big part of the problem. Think of it this way: just because a cell has a coffee stain in the big book doesn’t mean the stain has been causing a problem. Maybe it is still readable. The best we can do today is to look for the stain, and then try the treatment and see if it works. But sometimes even very successful targeted treatments don’t work in certain people.

We are often faced with questions about what to do, and each decision is a bit of a gamble, balancing risks.

Unfortunately, because cancer is by definition random errors, each one is a little different, and each patient is different too. So these recipes and plans are designed to work well when we look at a group of people; we try something on 100 different people and see what works out the best on average. Because of the way doctors talk about these results, people have a tendency to confuse the meaning. For example, if I say this treatment has a 99% cure rate, that doesn’t mean that any individual is going to be cured by it. What it means is that it’s highly effective and worth the risks (everything has risks). But anyone might turn out to be the one out of a hundred that dies from their disease, despite having a “cure.”

It gets even more difficult when treatment options aren’t so good. Today, about the only way to cure a patient with lung cancer is to catch the disease early (which is not usually the case) and cut it out. Because the vast majority of lung cancer patients are long-time smokers, many of them have pretty shitty lungs and hearts to begin with. So we are talking about taking someone who might not be in the best of health to an operating room, opening their chest, and taking out something like 25% of their lung tissue. Lung tissue is pretty important stuff. And it is a big surgery, with lots of things that can go wrong – infection, heart failure, bleeding. And after all that, only about half the patients will actually be cured. The other half will have the cancer come back a year or two later. These decisions put us all in a hard place: is it worth risking death to do the surgery, dealing with the difficulties of recovery, only to have the cancer come back and kill anyway? Sometimes, these are questions we don’t discuss with the patient quite as well as we should. We have a tendency to focus on quantity of life, and maybe think less about quality of life.

But that discussion is for another day. Today I am just trying to help you to understand this difficult disease and why it is continuing to be such a pain in our collective asses. It’s complicated, and my description here is far from complete. But you can’t make good decisions, for yourself or others, without knowing what you are up against. The reality is that our understanding of the disease is outpacing our ability to treat it, simply because of the pesky fact that cancer cells are your own cells. But we are moving forward, even if it seems like it’s taking forever.

By the way, we’d go faster if we cooperated instead of competing. But that’s also a discussion for another day.