An estimated 80 million* people worldwide live with a degenerative brain disease. That number is expected to rise rapidly over the coming decades as our growing population ages, lifespans increase and environmental toxins rise. The burden of trying to care for all those individuals will put an immense strain on our economies and test the social fabric of human civilization.

At present, there is almost nothing medical science can do to slow, let alone stop, these conditions. We have produced a few therapies that alleviate some symptoms of a few diseases, but next to nothing that addresses the diseases themselves. So, at the moment getting diagnosed with one typically means a gradual loss of independence and productivity, and most of the individual’s remaining days spent grappling with an ever-mounting assortment of symptoms. Eventually, life itself becomes a daily struggle.

But, if we make the right decisions today we can change that fate.

What follows is my opinion of the kinds of programs and initiatives societies should be investing more in now to speed up the development of better therapies and give those individuals diagnosed a better quality of life. I do not think this is the definitive list so I welcome any thoughts, comments or suggestions regarding anything that should be added or changed.

(* I could not find a figure for this, this number came from simply adding up Google search results for ‘number of people diagnosed with X’ (Dementia, PD, MSA, HD, MND, MS) and rounding up assuming I missed a few and that many, particularly in the third-world, go undiagnosed. If anyone has a more accurate figure please let me know.)

Neurotherapy Programs/Centers

The only thing proven to prevent or slow the degenerating brain is a healthy lifestyle and plenty of exercise. Though the optimal ‘dose’ is unknown, the trend lines seem to indicate that the further these factors are pushed, the better the results.

An ideal center/program would give patients access to the resources and specialists they need (physiotherapists, speech therapists, occupational therapists, etc.) while enabling them to learn what they need to know to optimize the wide variety of dietary and lifestyle factors that play a role in these diseases.

Here is one indication of the benefits to be had from this kind of program from the CAMCarePD study run by Dr. Laurie Mischley:

(Anther great model to emulate is ParkinsonNet in the Netherlands, makes me wish I lived there.)

Basic Science

The biggest hurdle we face in developing better therapies is that we don’t understand the basics of brain biology very well. Turns out, it is really hard to fix something if you don’t know how it works. A critical part of this effort will be figuring out how to integrate all that we are learning from the plethora of emerging fields in biology into a cohesive whole that can give us a sense of how our biological systems work (eg. genomics, proteomics, immunology, infectiology, toxicology, glial biology, microbiome, etc. etc.) Thankfully there are a number of giant collaborative international projects on-going tackling this (though we could use more). Some examples include: The Allen Institute, Chan Zuckerberg Initiative, and ASAP (more from them coming soon!),

And if anybody has any doubts as to why basic research is so important, watch this great explanation from the team at Numberphile.

(Another particular project that I like is Target 2035, we need more of this kind of ambitious long-term thinking).

Neuromodulation Technologies

“Brain-computer interfaces are the technology that will change reality for those enduring neurological disorders. It’s the potential of this technology to restore quality of life, rather than enhance it, that makes our work necessary.”

That quote is from Clayton Bingham in the TEDx talk below that includes a great overview of neuromodulation and its potential to treat a range of neurological disorders…

And here is a handy schematic of some of the neuromodulation techniques currently available…

Open Science

This short video I recently found explains the why and the how of open science much better than I can.

A great example of open science in practice is The Neuro at McGill, particularly Thomas Durcan who recently authored this article explaining why he is giving away all of his data. I hope more will do the same.

Better Human Disease Modeling

Much of the reason why we have failed so miserably to treat brain diseases is that we can’t really study them. We have been unable to access living human tissue, so we have been forced to use animal models, none of which come close to capturing the complexity of the human brain.

Thankfully, our ability to grow cells has made giant leaps this century, enabling many innovative new methods to better simulate some aspects of our brains. These include brains-on-chips, and, my personal favorite, organoids…

Also, we might finally be able to study real live human tissue…

Reproducibility Initiatives

“Science, however, is never conducted as a popularity contest, but instead advances through testable, reproducible, and falsifiable theories.”

― Michio Kaku

Somehow this crucial aspect of science has been missing from a lot of biology. Thankfully there are projects starting up to address them, like the upcoming Parkinson’s Reproducibility Initiative. However we will need a lot more of this as a surprising amount of science doesn’t translate to the real world simply because the experiments done were never properly validated.

(Also to note: there is a critical distinction between something being replicable and reproducible.)

(Another important note from Prof. Karen Raphael: “I would emphasize the point that reproducibility is NOT enough: We need external validity: That is, we need evidence that reproducible research findings (from labs, from clinical trials) work in the real world where just about NOTHING is controlled. So-called “Pragmatic Clinical Trials” are an effort in that direction. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126119/”)

Clinical Trial Reform

Clinical trials are painfully inefficient ways of testing a hypothesis. Put another way…

One under-explored avenue is N-of-1 trials (here is a great recent review).Where I see the most potential here is in helping patients and doctors better manage symptomatic therapies. There are so many variables that contribute to how symptoms express themselves, it is often very difficult to know how to optimize the medications patients take. A rigorously develop N-of-1 methodology that patients can apply themselves, coupled with self tracking tools, would help immensely. After all, the only way that any patient really knows if any drug is suitable for them is by conducting their own unofficial N-of-1 trial on themselves when they start taking it.

Another intriguing attempt comes out of the Linked Clinical Trials group that is working with partners in Australia on a new type of trial that will have five arms (four drug arms and one placebo, click here to learn more.)

(btw, really looking forward to taking part in this years Linked Clinical Trials meeting in two weeks, here is my very thorough recap from last year’s meeting…)

Subtype Specific Targets Only

Most in the field acknowledge that each of the diseases associated with accelerated brain aging are not single diseases but instead are umbrella terms used to classify a spectrum of disorder. However, almost all of our attempts to solve these diseases still attack the umbrella in the hopes that something might work for all the variety of disorder clustered underneath. The emerging reality seems to be that there is no unifying disease mechanism that unites these disorders, they are clinical labels that do not accurately reflect the underlying biology.

So, does it still make sense for us to fund research into diseases like Parkinson’s or Alzheimer’s when it seems like they don’t really exist? Perhaps institutions, companies and foundations need to be more selective and work first to identify genetic/molecular subtypes and only then try to develop effective treatments for that very specific subtypes.

One great example of this is the Silverstein Foundation. (Click here to read more from the Science of Parkinson’s blog.)

Going forward we will need many, many more such efforts. However, a crucial prerequisite for this is…

Biomarker Discovery Programs

It is absolutely essential to the development of better therapies as well as tools to effectively manage these diseases that we find sub-type specific markers of disease. One of the best examples was the discovery that blood glucose levels can be used as a marker for diabetes, it completely revolutionized our ability to manage this disease.

I’ll have more to say on this in later posts as this topic will play a big role in my upcoming book with Alberto Espay titled Brain Fictions. Details (hopefully) coming soon.

(Spoiler: An important aspect missing from many ongoing biomarker programs is that they need to be completely agnostic. What too often happens in these programs is, as Werner Heisenberg (somewhat infamously) said, “What we observe is not nature itself, but nature exposed to our method of questioning.” )

(also note that there are a range of digital markers being developed that may act as useful surrogates until relevant biomarkers are founds.)

Well, that’s my opinion of the programs needed, anything you think I got wrong or missed, let me know in the comments below or contact me directly here?

One glaring omission might be regenerative medicine/tissue engineering. While the science is really cool, lately I have been wavering on whether many of them being developed for brain diseases will be able to make it through clinical trials any time soon, and, if they do, will they really be more beneficial than already established techniques. (One example is stem cell research for Parkinson’s, see this expert survey for more.)

There is also a need for society to restructure the way we fund and support biomedical research. The old-trodden ways of basic research being funded by public institutions and then taken up by big pharma when closer to being ready for commercialization makes translation difficult and greatly limits our range of options. Thankfully, there are new models shaking this up (to a degree) with the influx of venture capital money and more and more philanthropic groups entering the biomedical arena.

(Somewhat) Relevant Quotes I Like

“But the reason I call myself by my childhood name is to remind myself that a scientist must also be absolutely like a child. If he sees a thing, he must say that he sees it, whether it was what he thought he was going to see or not. See first, think later, then test. But always see first. Otherwise you will only see what you were expecting.”

― Douglas Adams, So Long, and Thanks for All the Fish

“Cherish your doubts, for doubt is the handmaiden of truth.

Doubt is the key to the door of knowledge; it is the servant of discovery.

A belief which may not be questioned binds us to error,

for there is incompleteness and imperfection in every belief.

Doubt is the touchstone of truth; it is an acid which eats away the false.

Let no man fear for the truth, that doubt may consume it;

for doubt is a testing of belief.

The truth stands boldly and unafraid; it is not shaken by the testing;

For truth, if it be truth, arises from each testing stronger, more secure.

He that would silence doubt is filled with fear;

the house of his spirit is built on shifting sands.

But he that fears no doubt, and knows its use, is founded on a rock.

He shall walk in the light of growing knowledge;

the work of his hands shall endure.

Therefore let us not fear doubt, but let us rejoice in its help:

It is to the wise as a staff to the blind; doubt is the handmaiden of truth.”

― Robert T. Weston

You were born a winner, a warrior, one who defied the odds by surviving the most gruesome battle of them all – the race to the egg. And now that you are a giant, why do you even doubt victory against smaller numbers and wider margins? The only walls that exist are those you have placed in your mind. And whatever obstacles you conceive, exist only because you have forgotten what you have already achieved.

– Suzy Kassem, Rise Up and Salute the Sun

The universe seeks equilibriums; it prefers to disperse energy, disrupt organization, and maximize chaos. Life is designed to combat these forces. We slow down reactions, concentrate matter, and organize chemicals into compartments; we sort laundry on Wednesdays. “It sometimes seems as if curbing entropy is our quixotic purpose in the universe,” James Gleick wrote. We live in the loopholes of natural laws, seeking extensions, exceptions and excuses. The laws of nature still mark the outer boundaries of permissibility – but life, in all its idiosyncratic, mad weirdness, flourishes by reading between the lines.

– Siddhartha Mukherjee, The Gene: An Intimate History