One question I have been trying to answer for years now is, what kinds of knowledge would someone like myself have to acquire to try and understand the brain and neurodegenerative diseases? Which subjects would I need under my belt to even attempt to make sense of our brains and why some parts of it degenerate faster in some people than in others? And what could I do to possibly help others with a similar question better understand their brain or their own degenerative brain condition?
Well, I hope this doesn’t seem too disheartening, but I’ve learned that the further one digs the more untenable these questions seem. Just look at how many different layers there are to understanding the brain and how many different disciplines one would need to master to even begin trying to make sense of this three-pound lump of goo we have between our ears…
So, what should someone like me do if they wanted to know what this thing called the brain is and why sometimes in some people things go wrong?
Well, if you really wanted you could start by doing what people in other seemingly incredibly complex disciplines have done. Namely, figure out what is the most fundamental layer of knowledge then meticulously work your way up through each layer, slowly adding piece by piece as you ascended.
Okay, so if someone were to try and do that for the brain and its various diseases where should they begin?
Well, according to many biologists that most fundamental layer is genetics. That is where life is thought to encode all the information needed to make us what we are and that is where we will find mutations that may be our best clues into the starting point for the diseases we know.
Two questions that need to be answered then would be, what is genetics and is it really as fundamental to life and degenerative brain diseases as most believe?
Well, let’s look…
One clue as to the relevance of genetics in studying degenerative brain diseases (at least as this applies to what might be relevant within an individual’s lifespan) came just a few months ago when the world learned about the result of a trial in Huntington’s disease (HD). HD might be the clearest example we have of a direct association between genetics and neurodegeneration. If you have above 40 repeats of a certain marker (CAG) on a gene we call HTT you will get HD. Almost no where else in the field of neurodegenerative diseases do we have such a clear association.
(Please note that despite some of the language used above HD, like PD, is not a single disease)
But, as we learn again and again, correlation does not mean causation. This might be intuitively a difficult thing to grasp, but just because you have a marker that may predict a disease with near certainty that does not necessarily mean that that marker is the cause of the disease in question, nor does it necessarily mean that targeting it therapeutically will help any given individual with that disease.
One of the reasons I have been told as to why this is is that genetics is very complicated and that we just do not know all the pieces needed yet to make the link between a given associated marker of a disease and the disease itself. That is certainly true of most things that we know about the brain because we cannot, in almost all cases, access any living human brain tissue. Doing so would be essential to understanding these things given that brain cells, unlike other cells in your body, do not divide. Meaning, the longer we live the more the genetics of the cells in your brain would differ from the rest of the cells in your body.
One question that needs to be asked then is how is it that we can claim to know anything at all about the genetics of human brains and what is the relevance of any of them to neurodegenerative diseases?
One tool commonly used in human genetics is Genome Wide Association Studies or GWAS. GWAS are essentially population wide studies of genetics that try to identify what are the genetic differences between people that have a given trait or disease and those that do not. The result of most of these studies are graphs that look like this:
Now, what is wrong with GWAS? Well, used a tool to understand population genetics there is nothing wrong as it does give relevant answers for that field. The problem becomes when we try and use GWAS to explain the genetics of any individual. As to why that is, I’ll leave that to a good friend of mine Dr. Alberto Espay to explain:
“What is the relevance of GWAS to individuals? GWASs are one of the best examples of “research because we can”. One study of nearly 38,000 PD patients concluded that 90 genetic variants explain between 16 to 36% of the heritable risk of Parkinson’s disease. How do I, only a neurologist caring for patients, translate that to anyone? Can we even begin to say that there will be a cocktail approach that will correct the collective biology associated with those 90 variants? And does it mean that we will need about 152,000 PD patients to explain the heritability close to 90%? The heritability in whom? No one knows.”
So, if genetics isn’t going to give us the answers that we once hoped it might where else could the answers for patients like myself come from?
At this point the problem quickly becomes overwhelming as there are any number of avenues one can choose to go from here. Protein biochemistry, epigenetics, bioinformatics, systems biology, all seem relevant. You could even make a good argument that to really understand the brain you need to understand how the most fundamental particles in the universe interact, thus you would need at least some understanding of things like quantum chemistry, fluid dynamics, loop quantum gravity, etc. etc.
If the list of disciplines and sub disciplines to be explored seems endless it is because it is endless. There aren’t enough words in all of the languages we have on earth to accurately describe all the pieces that make up the human brain. Meaning, even if you tried to systematically understand it but digging down into the most fundamental layer and putting it together piece by piece like a game of Lego you would soon realize that not only is there not enough time in one human’s life to do so but we will never have the language needed to describe it all.
So where do we go from here? Is this a hopeless pursuit?
No, or at least I should say, I hope not…
So, where should we look?
Well, for one we must realize that knowledge for the sake of knowledge can be, sometimes, pretty useless. This is especially true when it comes to the study of the brain and its various diseases. We can pile as many words and stories onto the brain and its infinitude of different parts as we want, but it is very likely that all that will do is add to a pile of noise that no person (or even algorithm) will ever figure out how to sift through. There is simply no end to this form of stamp collecting.
What we would really need here is a better set of heuristics. Patterns that we can recognize and decipher that might also act as shortcuts into how the various functions that govern how the brain works work.
And where could we go to look for these kinds of heuristics? Well, call me crazy but rather than sifting through an infinitude of various molecules and proteins trying to figure out what does what, why don’t we start by looking at what we know works. Otherwise, neuroscience I fear risks drifting into the realm of pseudoscience.
Now, I am not claiming to know what the answer is, but I think I have finally settled on what I believe to be is the right question to ask if we are going to have any hope in my lifetime of developing better therapies for people like me, and maybe even helping us understand some of what the brain is:
What is an oscillopathy?
That is the question….I think.
Check back soon for Part 2 where I will try to explore this question in a bit more detail and why I believe it is the right question to ask for anyone who wants to understand the brain and neurodegenerative diseases…
For those who cannot wait, here are a few articles that you can read as well as a video featuring some of the brightest minds in this emerging field of study…
Neuronal Network Oscillations in Neurodegenerative Diseases
What’s in a pattern? Examining the type of signal multivariate analysis uncovers at the group level
Long-term wireless streaming of neural recordings for circuit discovery and adaptive stimulation in individuals with Parkinson’s disease
Beta Oscillations in Working Memory, Executive Control of Movement and Thought, and Sensorimotor Function
Case Report: Chronic Adaptive Deep Brain Stimulation Personalizing Therapy Based on Parkinsonian State
Circuit Mechanisms of Parkinson’s Disease
Oh, and thank you to Dr. Ro’ee Gilron and the rest of the team at Rune Labs for patiently answering all my many questions on these things and more over the past couple weeks.
Dear Benjamin, I am happy that your health has permitted you to resume your blogs.