Whatever happend to cancer and bad luck? The story of known unknowns

Back in 2015, Bert Vogelstein et al, wrote a really interesting theorectical paper regarding essentially "What we don't know about cancer." 

We sort of already knew what caused bad luck but we can't really articulate what it is.

 (The "Bad Luck" article itself is behind the paywall but this editorial is a really good primer on what was ACTUALLY said by the authors)

I believe, like many in my field (when I still had one) that bad luck is simply physiology that we do not understand (Yes a direct rip off of Arthur C Clarke)

Vogelstien et al caused a media explosion to start off 2015 with the bad luck line- Forbes, Huffington Post have run with it.

A year later we haven’t heard much about the stochastic models (a fancy word for random) While hesitate to wade back into this morass of jargon, layman interpretation and poor analogies- I will. I think it is important to recognize that the authors were in no way suggesting we (society) should just stop trying to prevent cancer or that individuals have no way to decrease their risk.

I also think it is important to note that this was not about media attention. Bert Vogelstein is one of the fathers of cancer research- He doesn't need media attention to get funding. The point the scientists are trying to make is that some types of tissues make more copies and that is why certain tissues have higher rate of cancer. They also acknowledge that there are areas where we have limited research and therefore may be the source of "bad luck."

One of the biological control mechanisms that is part of the randomness of cancer is an area of study call Epigenetics. This new area of study controls mutations, rate of cell divisions, amongst other "things", in a cell specific manner.

What is Epigenetics?

In a practical sense epigenetics is an in-depth look at how genes regulate each other. Genes are, at their strictest definition, the precursors to the proteins (or certain RNAs) that perform (most of) the jobs that make life possible. While genes are the stars of the show, in terms of regulation of biological processes, they are the least interesting part of the genome. The interesting part is the so-called junk DNA or more accurately non-coding DNA-as in it does not code for a protein. If genes are the stars, then non-coding DNA are the role players and the scenery that move the show forward.

The dance of how these proteins and their modifications is choregraphed is WHAT epigenetics does for the cell.

Non-coding DNA essentially act as the context for why a gene should expressed; for example certain cell specific genes will be epigenetically regulated so as to NOT be expressed in the wrong tissue. This occurs through a series biochemical and physical changes to a gene that as a group are as a group considered epigenetic regulators.

Epigenetic processes are the key to providing organisms the flexibility to respond to the environment. So what about these processes make them so important? As with any regulatory process-it depends.

The best analogy is the "genome as the book of life". If genes are the words by which an organism is "made" then epigenetics is everything else in the book. (see here for a presentation on this topic)

[I prefer the script and scenery analogy above but the book analogy fits better with the general "Book of Life" analogy for DNA]

 At the lowest level it is the sentence structure that allows the words to have meaning. At the highest level it is the chapter order that gives the story a linear order. Unlike a real book each tissue in the body can shuffle each of these elements on the fly....a choose your own adventure book based on cell type.

Keeping with this analogy the various tools that each cell uses to keep track of their progress though the choose your own adventure would be the epigenetic machinery. This machinery provides, the grammar, syntax and paragraph structure that allows the cell to respond to each potentially different path.

As anyone who has every read a choose your own adventure, part of the fun is tracing back and making a different decision. In a cell this ability to track back is vital as it allows certain cell types to re-populate after injury or during normal growth. To bring it back to cancer, the flexibility that is inherent in a choose your own adventure book leaves cells vulnerable to errors.

Imagine that each cell has their own copy of the “Book” and everytime they divide they have to make a copy of the book for their kids. The only problem is that they have to do it by had one letter at a time. Obviously, there are going to be errors but for the most part they do not change the word or change sentence meaning. On occasion though the errors do change sentence structure or alter a word. In a nutshell this is any disease; an alteration of the “Book.” Cancer is in someways a step further, just like there are verbs, nouns, adjectives, etc in language there are categories of genes. When the growth category of words are altered you get cancer or when you alter the grammar (epigenetics) that provides rules for “cancer words” then you get cancer.

What we still don’t understand is how many words need to be altered or how much can you bastardize the grammar of the genome before you get cancer. That is part of why cancer appears to be bad luck, we simply do not understand the language or the grammar rules sufficiently to judge the quality of words that we find in cells.

To put in plainer; we don’t understand genetics or epigenetics well enough yet to make predictions.

The deeper dive:

While the book analogy is interesting and useful, the beauty of the system in my opinion is that all of this is managed through biochemistry: small differences in enzyme kinetics and subtle changes in protein binding. This biochemistry leads to a wide variety of markers that can be used to denote parts of the genome.

The cell uses different types of biochemical markers for each of the particular categories; grammar, pages, chapters. Each of the different markers has a different eased of use – sort of like an e-book where how you can jump as a reader is very dependent on how the author thought you would move through the book. The ease of use is a function of the biochemical processes by which the cell adds or remove the markers. If this all seems like overkill just to express a gene...it sort of is.

All of the added layers and differing ease of use allows the cell to add very tight regulatory control. This allows the cell to mix and match different markers to make bookmarks or highlight favorite passages, often used paragraph, etc. In general the chapter markers are direct methylation of the DNA. As the name suggests it is the addition (or subtraction) of methyl groups to DNA. This alters the affinity of DNA to a subset of proteins that occlude the DNA-basically hiding the genes. Removing the methyl groups abolishes this occlusion.

Sentence structure this is more complicated but in general there are 2 types of post translation modifications that are most commonly seen as having a definitive role in this process. This usually involves the structural proteins that surround DNA. These proteins are the histones and they allow 2 linear metres of DNA to be packed a volume of 0.00001 metres. An amazing feat in and of itself! Histones can be modified in a wide variety of ways too numerous to mention here. (see here for a review)

Full disclosure; my laboratory studied the role of histones in epigenetics so I am biased when in comes to how interesting these proteins are in the scheme of life

The combinatorial placement of these proteins and modifications on DNA allows for a very precise grammar to be used. So precise that cells can communicate exactly which protein should be expressed to their neighbor. Given that there may be as many as 31 thousand that is quite impressive. What are histones? that is another story for another post. The bottom line here is that these proteins control access to the DNA- as well as generally protecting cells from misusing cancer genes and/or accidently erasing instructions.

As always I love feedback and this is one of my works in progress.

What is epigenetics?

It's a question that I am often asked. The answer is complicated. Since, in my opinion, the viewpoint of the field shifts based on where the next sexy science that can generate money is coming from. 


So lets start with the word epigenetics and its semantic meaning. If we start by breaking down the word, we can see what the word and field has come to mean in the last twenty years. The first part epi is from Greek meaning above. Genetics....well realistically it is a galaxy of smaller fields dedicated to studying what genes are, how they are involved in disease and development, and how genes regulate each other. 

So epigenetics is the study of processes above genetics.........which is where the etiology fails to be useful. Hence the confusion amongst scientists and the public at large.


In a practical sense epigenetics is a in-depth look at how genes regulate each other. Genes are, at their strictest definition, the precursors to the proteins that perform (most of) the jobs that make life possible. 

While genes are the stars of the show, in terms of regulation of biological processes, they are the least interesting part of the genome. The interesting part is the so-called junk DNA or more accurately non-coding DNA. If genes are the stars, then non-coding DNA are the role players and the scenery that move the show forward. 


The dance of how these proteins and modifications is choregraphed is epigenetics. 


Non-coding DNA regions control which genes are expressed and when they are expressed. This occurs through RNA molecules, binding of proteins and enzymatic modification of these proteins. Its more complex that what I am highlighting but the core message here is that Epigenetics is about controlling access to the genome by RNA and proteins through the non-coding regions of genomic DNA. 


Epigenetic processes are the key to providing organisms the flexibility to respond to the environment. So what about these processes make them so important?  As with any regulatory process-it depends. 


The best analogy is the "genome as the book of life". If genes are the words by which an organism is "made" then epigenetics is everything else in the book. At the lowest level it is the sentence structure that allows the words to have meaning. At the highest level it is the chapter order that gives the story a linear order. Unlike a real book each tissue in the body can shuffle each of these elements on the fly....a choose your own adventure book based on cell type. Further flexibility arises from how each individual cell interprets the story that it is given.

While the book analogy is interesting and useful, the beauty of the system in my opinion is that all of this is managed through biochemistry: small differences in enzyme kinetics and subtle changes in protein binding. This biochemistry leads to a wide variety of markers that can be used to denote parts of the genome.


The cell uses different types of markers for each of the particular categories; grammar, pages, chapters. Each of the different markers that the cell can use for these categories has varying ease of use. The ease of use is a function of the biochemical processes by which the cell adds or remove the markers. If this all seems like overkill just to express a gene...it sort of is. Adding layers and differing ease of use allows the cell to add very tight regulatory control. This allows the cell to mix and match different markers to make bookmarks or highlight favorite passages, often used paragraph, etc.  

In general the chapter markers are direct methylation of the DNA. As the name suggests it is the addition (or subtraction) of methyl groups to DNA. This alters the affinity of DNA to a subset of proteins that occlude the DNA-basically hiding the genes. Removing the methyl groups abolishes this occlusion.

Sentence structure this is more complicated but in general there are 2 types of post translation modifications that are most commonly seen as having a definitive role in this process. This usually involves the structural proteins that surrond DNA. These proteins are the histones and they allow 2 linear metres of DNA to be packed a volume of 0.00001 metres. An amazing feat in and of itself!

Histones can be modified in a wide variety of ways too numerous to mention here. The combinatorial placement of these proteins and modifications on DNA allows for a very precise grammar to be used. So precise that cells can communicate exactly which protein should be expressed to their neighbor. Given that there may be as many as 31 thousand that is quite impressive. What are histones? that is another story for another post. The bottom line here is that these proteins control access to the DNA. The modifications on these proteins act to either loosen the structure and increase access or glue the proteins together blocking access.

So what you say? Well the answer is variation: variety in cells (brain VS muscle), variations between twins, variation in cell response, variety in drug response, variation in disease. Epigenetics is the root cause of variation at every level: species, organism, tissue, cells.

So until we understand how this biochemical signature is modified we can't really understand how cancers vary from person to person or in a bigger picture how we retain biodiversity.