How could you study epigenetics? Thought experiment from a dreamer

This blog is part autobiography part roadmap. 

I am often asked “Do you miss it-being a scientist”

The short answer is “I didn’t dream of being an IT consultant.”

Longer answer is, as with all things that are part of being an adult, more complicated.

• I miss discovery- the joy designing a method to answer a question and then actually knowing- for a brief moment in time- something that no one else knows.
• I miss immersing myself in a problem and building a solution.
• I don’t miss, university politics; having to know who’s ass to kiss and watching my back for potential theft of ideas.
• I don’t miss the bullshit publication process that sometimes is used for competitive reasons.
• I don’t miss trying to write a grant that appears to be both novel and safe at the same time.
• I don’t miss the bureaucracy of universities policies that protect senior faculty but burden junior faculty.

I have been “out of the game” for half a decade now but I still pay attention to science and design experiments in my head and sometimes write them down.

I was an Assistant Professor running a small lab for about 4 years, my lab was centered on a set of enzymes that control the expression of genes in response to cell signals and environmental stimuli. These enzymes are commonly known as epigenetic regulators. The work we did was pretty good given the lack of funding, the fact that the enzymes had been described literally a year before I started my lab and I was trying to combine a novel class of genes with a novel set of methods (I was part of one of the groups that published the early papers describing the histone demethylase enzymes).[Synopsis of my lab]

My real interest, however has always been in learning the answer to the fundamental question “How do you make a brain?”  

I think now, I would ask a slightly different question; which has “how do we fix the brain when it isn’t made right.” One thing that age and distance has given me is perspective or perhaps empathy I don’t honestly know the difference. I have two small children both of whom are pretty awesome- unfortunately both have inherited some of my flaws. So I am often struck by how does the brain manifest these “flaws” even if there are no major changes or developmental issues.

How would one go after such questions?

Five years ago the answer was Stem Cells with maybe some mouse genetics thrown in for good measure. Now? I would go another direction. I think the single biggest issue in epigenetic research as well as neuroscience is the lack correlation data between phenotype (what it looks like in the whole organism), genotype (what genes play a role) and biochemical output (how well does the “engine” function”). Much like astrophysics and quantum physics have mathematic models which provide probability maps for specific core particles and/or forces, Epigenetics needs probability maps for phenotype and genotype- a Heisenberg probability if you will.

As I have mentioned in other posts, epigenetics is essentially grammar for the genome. It is a big, unwieldy mess of a field that is likely at least three separate full fields that we do not have names for as of yet. Sticking with the analogy the “field” of epigenetics is at the point where Western civilization was in the late 1700s/early 1800s where we knew some words and potentially some word relationships in the Egyptian cuneiform but we were largely blind to what was actually being said in hieroglyphs until the Rosetta stone was found. To me the rosetta stone for epigenetics will be cross species mapping of real world consequences.

For example; we know that there is a link between obesity in dogs and their owners. That is a real world cross species phenotype- why don’t we look at what genes expression and epigenetic patterns are changed as both lose weight? There is still validity to the idea mammalian biology is conserved at the physiological level.

What I would do if I was starting now would be to focus on dogs as a main model; they live with us, they often eat like us, they have behaviours which at their core are similar enough to ours but distinct across breeds. Furthermore access to their health records would have less risk and potentially greater detail as most veterinarians have a depth of knowledge on their patients over a whole lifetime – and for some clients multiple dog lifetimes.

For me, I would focus on brain cancer- as a scientist it is a fascinating process to take a cell that is programmed to not multiply and make it multiply and it is a cancer type that has repercussions to ones body, dignity and family.

The lab would have five facets;

1.     Define a set of neurologic symptoms that could be tested for by a veterinarian in clinic.

a.     Use standard indications from observation.

b.     A set of typical blood markers that are used for “unhealthy’ as part of the analysis.

c.     X-rays to define rough location, size and prognosis

2.     Test brain tumour samples across gene expression, “Epigenetic profile”, potentially genome mutations

3.     Use samples to grow models tumours, testing their gene expression profile and epigenetics profile for changes in culture.

a.     Where possible have normal age specific controls across breeds (or at least a general “mutt” control)

4.     Longitudinal studies of dogs with tumors after various therapies.

5.     Map epigenetic changes in tumour versus normal as well as fresh tumour versus in culture.

I was “classically” trained as a mouse geneticist where we had the clean clear; I deleted a gene what happened to my cell type? I learned [the very hard way-  hello consulting ;{ ] that there are no one-to-one relationships in any cell type when we deal with epigenetics- it is the system that protects the cell from single points of failure.

Long term would be to identify a set of parameters that can be linked to cancer and then go back and start testing the enzymes that are directly linked to the epigenetic modifications that are related to the phenotype. 

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.