Futurism, Medicine, Parkinson's
Comments 6

The End of Parkinson’s Disease and The Last Generation

For my money, one of, if not the, best movies of this century is Alfonso Cuaron’s Children of Men. Based on a book by the same name, it is about an apathetic bureaucrat thrust into playing the hero, set in a world where humanity has lost the ability to have children.

The story has become increasingly relevant, portraying what can happen when nationalist rhetoric, rampant consumerism, mass migration and authoritarian rule are taken to their extremes. But what really sets the movie apart for me is the theoretical question that builds the world the plot runs through – what would happen to civilization if we found out that the people alive today were the last humans that were ever going to be?

(Here is a great review of the movie from The Nerdwriter…)


The Age of Biology

There are all sorts of things that can be said about the impact such a scenario would have on culture and society, but watching it again got me thinking a little more generally about what it is like to live through the end of an era and be part of the last generation to experience something. At just 33, my generation is already the last that will ever know what the world was like before computers, the internet and smartphones changed so much of daily life. And now we may be living through the last years before artificial intelligence changes everything again.

Riding these technological advances is another revolution that I think will have an even more profound impact on our world, the biological revolution. Since the turn of the century, there has been an explosion of new biological tools and techniques that have opened the door to some astounding possibilities that we are now on the cusp of realizing. Within the next decade, prominent experts believe we will be able to do things like print organs for transplant made directly from patients own cellsbring back extinct species using synthetically created DNA, and even grow human brains in pigs and monkeys. And those are just the beginning of what this century of biology has in store…


But another, less morally questionable, impact of this revolution is that the people living with many chronic diseases today may be among the last generation that will ever experience them. I’ll use Parkinson’s disease as my example, but similar things can be said about various heart conditions, diabetes, arthritis, depression and many other diseases that we are on the verge of being able to either prevent, effectively manage, or cure.

What a Cure will be

So, to ensure no one else gets Parkinson’s, what we would need is a reliable way of testing for the disorders that lead to the disease, at an early enough stage, and treatments that stop these disorders from progressing. That’s it. That’s all it would take to make sure no one else ever gets PD. (Granted, getting those tests and treatments to everyone afterwards is another challenge, after all, we are technically still battling polio.)

And the good news is, both are on their way, and have a very real chance of being here within the next few decades, if not much sooner, as some experts believe.

The first 18 years of the 21st century have seen more knowledge generated about our biology than all of human history combined. While weaving all that information together has proven to be quite a challenge itself, it has already resulted in immense jumps made in our understanding of geneticsimmunology, stem cells, computational biologybrain circuitry, and many other related fields. For Parkinson’s disease, those advances have lead to significant progress in the hunt for biomarkers that will allow us to detect signs of dysfunction before symptoms appear, as well as a staggering amount of promising new therapies aimed at halting progression. (Along with a plethora of new potential drug targets should all those therapies in development fall short.)

The bad news is, these therapies will likely not be as effective for those whose disease has progressed beyond a certain point, as too much damage has already been done. Thankfully, regenerative medicine techniques, like cell replacement or gene therapy, are also making great strides and should enable affected individuals to restore some of that damage.

This Moment in History

Parkinson’s disease has likely been with us ever since we started living old enough for it to develop. Accounts of the disease date as far back as the 5th millennium BC, giving us a minimum of 7,000 years of humans experiencing the steady decline that this disease brings. Included among those humans are some pretty notable figures like Roman emperor Tiberius, philosopher Thomas Hobbes, and modern despots Hitler and Mao Ze Dong. (The latter two are especially odd for me to think about as people diagnosed tend to have a sort-of kinship with each other over this rare shared experience.)

All of which puts people who do get diagnosed in a rather unique position in history. While no one in their right mind would ever choose this fate, the silver lining of a diagnosis is that it provides an opportunity to play a role in forever purging ourselves of it. (more on this below)

The Background

I think, in taking on this challenge, it is helpful to adopt a perspective that Cuaron was trying to convey through his use of the camera in Children of Men. As emphasized in another review of the movie from philosopher Slavoj Zizek, in any narrative, the big picture is always distorted by the point of view of the characters. That is even more profoundly true when the character is our selves. It is difficult, if not impossible, to put aside what is happening to us as individuals and our families and connect instead to the larger story. People suffering with disease are well within their right to say ‘who cares about this moment in history, how does any of that help me today?’

Well, it doesn’t. All that scientific progress isn’t going to help you today, or tomorrow or the day after that. But, it does add a little credibility to a phrase people diagnosed often hear that ‘now is the best time in history to get diagnosed with Parkinson’s’. After all, it’s one thing to be told something is true, it is another to understand why it is true. I count myself lucky that of all the generations of people to get this disease, I have a chance of being part of the one that ends it. That understanding has given me the resolve to embrace the daily grind that this disease imposes and do what I can to push research forward so that I have a chance of being among the last generation to know what Parkinson’s disease was like.

 

What needs to be done

To get us there, here are the most important things that I think need to be done…

 

  • More focus on today – We need more research into what people diagnosed should be doing daily to stave off decline. There is a seemingly endless list of diets and supplements and lifestyle choices that influence the course of our disease, but each is fraught with ambiguity. We need some clarity, yet only a tiny fraction of funding goes towards trying to figure this out. For people diagnosed, this is our most pressing need. We need better information on what we should be doing today to ensure we have the best chance of still being healthy enough to benefit from the therapies to come.

 

  • Better ways to measure progression – We need a faster, more adaptive method of measuring if therapy X or supplement Y works than randomized control trials. RCTs take years and too often fail for reasons that have nothing to do with the therapy in question. It is the gold standard by which we measure if something is working, but surely we can do better. We also need better ways of allowing patients to independently monitor what effect a lifestyle change or new medication is having. Thankfully, in addition to all the work going into biomarkers that might solve some of these problems, there is quite a bit of work going into leveraging wearables and other new technologies that might allow us to better monitor disease progression.  (Click here for one such promising approach) But I fear the NIH will demand we use a RCT to test whether any of these methods are actually better than RCTs.

 

  • Identify subtypes of PD – Each of the new therapies in development will likely benefit certain groups of people with PD more than others. A lot of work is being done into identifying genetic subtypes, but just taking into account genetic factors will likely not be good enough in the majority of cases due to their low prevalence and penetrance (with some rare exceptions, most people with known genetic risk variants for PD will never get the disease). We need more holistic means of taking into account all of the variability we see in an individuals disease.

 

  • Better disease models – We have learned a lot from the models we have, but need to do a better job across the board of making sure we use the right model to answer the right question. Too often hypotheses get dumped simply because they were tested on the wrong model. Labs around the world need to more quickly embrace new models that more closely resemble the human form of this disease rather than sticking with old ones simply because they are more readily available.

 

  • It’s the environment, stupid – Most accept the environments out-sized role in the disease, yet we still devote a tiny fraction of research to it. We also continue to spray our fields with pesticides and use chemicals and solvents known to significantly increase the risk of PD. Genetic pathways may be easier to study, but will only ever tell us so much. There is a lot of talk about the need to study gene-environment interactions, but little actual work being done on this front.

 

 

  • Diversify spending – Genetics is great and has revealed a lot, but it will only take us so far and it takes up an enormous proportion of existing funding. Time to tip the scales towards other promising fields where we are only beginning to understand the upper limits of what they will be capable of. (These days, my vote would go to more immunology)

 

  • Speed up drug discovery – Once a biological pathway is identified as contributing to the disorder seen in people with PD, it then takes years, sometimes decades, to get to a molecule that can effectively target it. I have no idea how, but if somebody clever enough wants to make a lot of money, figure out a faster way of doing this. (I hear quantum computing may be the answer?)

 

  • Back to the basics – The recent advent of a wide assortment of biological tools has allowed us to peer into the universe of our cells inhabit with unprecedented clarity. Down there is a swirling chaotic mess of cells, proteins, nucleic acids, etc. constantly communicating with each other in an elaborately orchestrated attempt to keep us alive and well. However,  there are still too many unknown moving pieces and too many gaps in our understanding of how those pieces we do know interact with each other. We cannot get complacent with the knowledge we have and think we know enough, as some seem to. All the therapies in development, and all of the targets that have been identified, are simply our best guesses about how to fix the disorder we see down there. They may work, they may not, nobody knows. In case they don’t, we need to keep exploring that microscopic universe to make sure that, if needed, our future guesses will be more informed than our best guesses today are. (And because we should just know more about the alien world all around, and inside, us)

 

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(Banner image is a scene from Children of Men taken from TribecaFilm.com)

6 Comments

  1. Hank says

    Really interesting article. I very much enjoyed reading, thank you.

    ——————–
    >Descriptions of the disease date as far back as the 5th century BC, giving us a minimum of 7,000 years of humans experiencing the steady decline that this disease brings.
    ——————–

    I just wanted to clarify that this is 500 BC? If so I assume this should say 2,000 years, rather than 7,000? Or have I misunderstood somehow? I’m genuinely curious if this is a typo or if there is a 5000 year gap in my knowledge. 😂

    Like

  2. Hi Ben,

    This is a brilliant article. It’s visionary, challenging and a call to action. The metaphor with Children of Men (great film) works really well.

    You list several priorities for PD research. I find the spheres of influence concept very useful in trying to prioritise.. This aims to distinguish between what we totally control; what we partially control; what we influence; and what we can do nothing about. Another way to approach this is to understand what is urgent, and what is important. If we apply these criteria to your list, this would be my conclusions:

    MORE FOCUS ON TODAY

    The is something we can influence strongly through advocacy. This is urgent, as those of us already diagnosed don’t have time on our side. This is important as we are still at the stage where we can participate, contribute and influence. There are limited pharmacological options to delay, but quite a few lifestyle ones. We need to know the best options. Even with exercise, largely accepted as beneficial, we don’t know the optimal regime. So – urgent, important and influenceable.

    BETTER WAYS TO MEASURE PROGRESSION

    Fully agree – as PwP though, we can only influence, we can’t control. We can do lots of patient-inspired, n=1 studies but, to be brutally honest, the lead for this must come from the research community. A key challenge will be to get regulatory authorities to accept new methods. I think it’s both urgent and important.

    SUB-TYPES

    Crucial. This will take a lot of research analysis. I worry that whatever we come up remains as crude as the old tremor-dominant vs PIGD-dominant. My impression is that we are a long way from linking aetiology to phenotype and proving it clinically. Yet, if we don’t, we will continue to include heterogeneous clinical trial populations producing averaged results for potentially useful drugs.

    BETTER DISEASE MODELS

    Disease models are important, but the ones we have, especially at the cellular level, probably give us enough handles to screen out potentially positive therapeutics. Having said that, I don’t like the MPTP and 6-OHDA models, and I’m not sure they really add anything to selecting therapeutic potential. I would class this as both less urgent and less important.

    LEAD ADVOCACY

    The more $ we get invested, the better it is for research. However, we should distinguish what is done for classic research and what is done for drug development; and the source of the funding. To my mind, the big needs are:

    – commercial $ to accelerate the development of new therapies
    – sub-type classification
    – objective measurement

    By common consent, this is a golden age for PD research; as you say, we’ve learnt more in the past 18 years than all the time before. So I find myself counter-intuitively challenging whether more research money is a priority; whereas I would unambiguously say more drug development funding is needed. Influenceable, urgent and important.

    DIVERSIFY SPENDING

    This is something which is a bit like the old turning the supertanker analogy. Academic scientists are driven by the next grant, impact factors and tenure/security; as well as enabling smart people to follow their curiosity. I doubt there’s much we as PwP can do influence the detailed direction of research. From what I can see they’re doing very well as it is.

    SPEED UP DRUG DISCOVERY

    I’m not so sure that drug discovery is the big problem. Looking at the number of projects on what I’m now calling The Hope List – PD Therapies in Development, it seems the molecules are out there. The big issue seems to be speeding up the clinical development of potentially new drugs. The standard route of Phase 1 to Phase 3 is largely determined by the regulatory authorities; these aspects would be well outside our control and influence. There are five ways we can influence the acceleration of drugs to market;
    – understand sub-types and their influence on clinical trials
    – improve objective methods of symptom measurement
    – prioritise repurposed drugs with already proven safety profiles
    – get more PwP into clinical trials so that recruitment is not a rate-limiting step
    – ensure the clinical trial population is representative of the PwP population at large.

    This is urgent, important and something we can influence through advocacy

    BACK TO THE BASICS

    I’m relatively relaxed on this one, given the pace and progress of PD research. I think there is a tremendous amount going on with understanding the basics. So while it’s urgent and important, it’s being addressed.

    Hope this helps.

    Kevin

    Liked by 1 person

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