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# # # # Aligning Science Across Parkinson’s represents a major new funder for Parkinson’s research. They are focused on basic biology research and require their grant holders to take a very collaborative, interdisciplinary, “open science” approach. In their first 2 years of funding, the organisation has awarded almost US$300 million in grants. That is kind of… how should I put this?… a lot! In today’s post, we will look at the research projects being funded by ASAP in 2021. # # # # |
Source: iFunny
In a world of instant gratification for no effort or justification, I like people who have a little bit of foresight. Particularly when their goal is for the greater good (even if it is simply to make someone smile).
For example, in 2006, David Hampton (one of the owners of Hampton Lumber) and employees Dennis Creel and Mark Vroman, decided to do something that would take years to develop, but now amuses folks driving down Highway 18, between Grand Ronde and Willamina in Oregon.
They ‘planted’ a 300 foot wide smiley face on a hill side, by planting larch conifers which are predominantly orange/yellow in a specific arrangement, among the usual evergreen fir trees. Years later, the result is:
Source: Reddit
Another example of some inspiring farsighted thinking that is more related to our interests here is the Aligning Science Across Parkinson’s (or ASAP – click here to read a previous SoPD post on this initiative):
And recently the organisation made a major announcement.
What did they announce?
They announced this year’s round of grant funding for Parkinson’s research.
ASAP have awarded $132 million to 14 research teams (involving 68 labs across 10 countries)
That sounds like a lot. Is it?
Well, let’s put it into perspective: In 2016, the US National Institutes of Health (NIH – the world’s largest funder of medical research) allocated $161 million to Parkinson’s research:
NIH Parkinson’s research funding (in millions). Source: NIH
So by awarding $132 million, ASAP has almost allocated the same amount of funding to Parkinson’s research as the entire US Government did in 2016.
And this comes on top of last years grant funding of $161 million from ASAP (Click here to read a previous SoPD post).
This represents a serious shift in Parkinson’s research funding. We are talking major funding for many of the labs involved – potentially career changing stuff.
More importantly, it is the kind of research funding that will hopefully allow researchers the freedom to be bold and audacious. To take a few risks and try something radically different.
What kind of research is being funded?
ASAP takes a very basic biology approach to their funding.
After years of clinical trials not succeeding to slow the progression of PD, ASAP is seeking to go back-to-basics and ensure that our ‘first principles’ are right about what we know about the condition.
The funding this year was focused on a specific theme: Circuitry and Brain-Body Interactions
Researchers were asked to proposed projects that would explore “how communication between the brain and areas outside the brain are affected over the disease course” (Source).
I am not sure how many applications were received for this round (probably a lot given the pot of funds potentially available), but the review committee decided to award grants to 14 projects.
In no particular order, these are the projects that got funded:
1. Redefining Parkinson’s Disease pathophysiology mechanisms in the context of heterogeneous substantia nigra neuron subtypes
The dopamine neurons of the substantia nigra are particularly affected by Parkinson’s (approximately 50% are lost by the time motor symptoms appear), but there are different sub-populations of dopamine neurons in this region of the brain and a really thorough analysis of which subtypes are lost in Parkinson’s could provide insights into disease mechanisms (and possibly therapeutic angles).
Substantia nigra. Source: Sheffieldneurogirls
This project will be exploring whether the substantia nigra is comprised of dopamine neuron subtypes that are “pro-motor” or “anti-motor” (that is, encouraging movement vs inhibiting motion). It will then be asking if selective loss of pro-motor dopamine neurons help to cause the imbalance associated with Parkinson’s. This research team is led by Rajeshwar Awatramani of Northwestern University in Chicago, and in 2020 he (and collaborators wrote a very good review on the topic of dopamine neuron subtypes – click here to read the report).
2. Understanding and manipulating cellular and circuit-level vulnerability to neurodegeneration in Parkinson’s Disease
A certain portion of people with Parkinson’s will gradually over time develop cognitive issues, resulting in dementia (Click here to read more about this). This project aims to understand the mechanistic pathology linked to Parkinson’s progression to dementia. Specifically, Dr Thomas Biederer of Yale Medical school (the team coordinator) and collaborators will be investigating how alpha-synuclein pathology progressively impairs cellular network function in the cortex region of the brain. It will involve molecular, anatomical, and circuitry science, plus a little mathematical modeling.
Dr Thomas Biederer. Source: Yale
3. Circuit mechanisms for dopamine neuron vulnerability and resilience in Parkinson’s Disease
A lot of the attention in Parkinson’s research is focused on the dopamine neurons and other vulnerable sub-populations, but this research project – which is led by Prof Nicole Calakos of Duke University – is interested in the interconnected and interdependent neighbouring cells. Could the connections to other neurons and non-neuronal cells (glial cells) be playing a role in the cell loss associated with Parkinson’s?
Specifically, the team will be looking at “the extent to which circuit components outside of the dopamine neurons themselves can serve as new targets to slow the progression of dopamine neuron death in Parkinson’s“.
4. Mapping the modulatory landscape governing striatal dopamine signaling and its dysregulation in Parkinson’s Disease
This project focuses on the striatum – which is one of the main target regions of the dopamine neurons – and the cells and molecules in this region. They would like to determine what modulators within the striatum directly control how dopamine is released and whether dysregulation of these factors could be influencing progression in Parkinson’s.
Prof Stephanie Cragg of Oxford University is coordinating the group and their hope is that their research “could provide new knowledge toward ways to restore normal function“. The details are scarce, but this project could be stemming from interesting research that was published last year by Prof Cragg and colleagues, which found that maladaptive plasticity in early Parkinsonism impairs dopamine output in vulnerable striatal regions (Click here to read that report).
Prof Stephanie Cragg. Source: Oxford
5. Dual Role of Neural Activity in Parkinson’s Disease
This project is going to try to identify the earliest changes in brain activity in Parkinson’s and use their nature to try and work out potential mechanisms. Their hypothesis is that abnormalities in neural activity are not simply exposing Parkinson’s symptoms, but also causing the disease. Prof Robert Edwards (of the University of California, San Francisco) and his team of collaborators will use two models of Parkinson’s (one based on the PD-associated protein alpha-synuclein and the other based on “a direct increase in activity”) and explore interactions with known Parkinson’s genes.
6. Reconstituting the lost nigrostriatal circuitry in Parkinson’s Disease
Oh boy! This is an interesting choice.
One of the most exciting areas of restorative research for neurodegeneration at the moment is in vivo reprogramming of cells. This approach involves changing the fate of a particular cell inside the brain. The research typically looks at changing astrocytes (the resident helper cells) into neurons (the cells that are primarily lost in neurodegenerative conditions).
Source: Nature
Last year, there was a lot of excitement generated in Parkinson’s research by two reports on this topic (Click here to read an SoPD post on this topic). To help make things even more interesting there has been drama in the background associated with the first two studies (Click here to read more about that). But subsequent replication experiments have failed to achieve the initial findings. That study rather proposed that the transformed neurons were not changed and had simply been neurons all along (Click here to read that report). So what is really going on?
Prof Xiang-Dong Fu of the University of California, San Diego – the lead scientist involved with one of the initial exciting research papers – is now leading this team to better characterise exactly what is occurring. If they do find that astrocyte to dopamine neuron conversion is possible: “once fully developed, we hope to be able to effectively reverse the disease phenotype in Parkinson’s patients”.
Lofty ambitions? We shall see. This project represents one of the few ASAP grants that has obvious translation potential. Still very blue sky stuff, but closer to the clinic than other projects – most of which are primarily focused on basic science. As I said, it is an interesting choice by the grant reviewers.
7. Gut-to-brain circuit contributions to Parkinson-like phenotypes in disease models
The gut-to-brain influence on Parkinson’s is a hot topic at the moment (Click here to read a previous SoPD post on this topic), and this year ASAP are funding a number of projects exploring this area. Firstly, Prof Viviana Gradinaru of the California Institute of Technology is leading a team that seeks to “characterize the anatomical and functional bases of gut-brain circuitry dysfunction in Parkinson’s“. They are curious to see how environmental and genetic factors impact the connections between the neurons in the enteric nervous system (the nerve surrounding the gastrointestinal system).
Dr Viviana Gradinaru. Source: Breakthough
8. Alpha-synuclein effects on gut-brain circuits and pre-motor symptoms in Parkinson’s Disease
In another gut-to-brain project, this group is taking the research one step further by examining the influence of sleep and menopause on the system. Sleep is disrupted in many cases of Parkinson’s and women have reduced risk of developing Parkinson’s compared to men. This team – led by Prof Michael Kaplitt of Weill Cornell Medicine – want to determine what cells are responsible for gut-to-brain spread of abnormal alpha-synuclein and how this disease spread affects normal vagus functions (and vice versa). And they will be exploring the effects of sleep and menopause in this context.
9. Role of enteroendocrine cells in the origin of Parkinson’s pathology
In the gut, there are specialized sensory cells known as enteroendocrine cells. They come into direct contact with gut bacteria and the various environmental agents hanging out in our gastrointestinal system. This team, led by Prof Rodger Liddle of Duke University is examining whether enteroendocrine cells might be the source of misfolded alpha-synuclein protein and aid in its transfer to the central nervous system (Click here for a review by Prof Liddle on enteroendocrine cells, and click here for another review on how these cells might be involved with Parkinson’s)
Prof Rodger Liddle. Source: Duke
10. Olfactory circuits: Alpha-synuclein-rich neurons respond to environmental triggers at the origin of Parkinson’s disease
Loss of smell is often considered one of the early ‘prodromal’ features of Parkinson’s. This team being led by Prof Michael Schlossmacher from the Ottawa Hospital is hoping to determine whether environment-a-synuclein interactions and inflammation in the nasal cavity can act as triggers for disease initiation.
The researchers are interested in what role the Parkinson’s associated protein alpha synclein might play in our ability to smell. And whether an interaction between certain environmental agents (such as viruses) can initiate alpha synuclein aggregate formation and associated neuronal circuit dysfunction.
11. Basal ganglia networks in Parkinson’s disease
This project sounds particularly interesting – A strange feature of Parkinson’s has always been the ability of people affected by the condition to display remarkable motor abilities under special circumstances (eg smooth walking with certain cues). This is known as paradoxical kinesia. This team – led by Prof Peter Strick of the University of Pittsburgh – will use a multidisciplinary approach to characterise the basal ganglia and cortical motor areas of the brain to determine the underlying mechanisms of paradoxical kinesia. This research may also have implications for the placebo effect we often see in clinical trials.
12. Distributed circuit dysfunction underlying motor and sleep deficits in a progressive model of Parkinson’s disease
Parkinson’s is believed to start a long term before the actual motor symptoms appear. This project is seeking to explore the relationship between the early progressive dopamine depletion and distributed circuit dysfunction underlying motor and sleep symptoms of Parkinson’s. To do this, the researchers led by Prof James Surmeier at Northwestern University in Chicago, will be using a genetically engineered mouse that “faithfully reproduces the human staging of pathology in key brain circuits”
Prof James Surmeier. Source: Feinberg
13. Activity and connectivity drive neuronal vulnerability and disease progression in Parkinson’s disease
One curious feature of Parkinson’s is that many of the vulnerable regions of the brain involve cells that produce neuromelanin – the brain-version of a pigment called melanin, which is found in the skin, eyes, and hairbrain-version of a pigment called melanin, which is found in the skin, eyes, and hair (giving them their colour).
A better understanding of the role that neuromelanin is playing in Parkinson’s (and between these vulnerable populations of neurons) could have significant impact on our knowledge of the condition. This very international team will be led by Prof Miquel Vila from the Autonomous University of Barcelona (Click here to read a previous SoPD post about Prof Vila’s research on neuromelanin).
Prof Miquel Vila. Source: Vilalab
14. Cortical pathophysiology of Parkinsonism
While a lot of focus in Parkinson’s is focused on the substantia nigra and associated regions, there is a lot of evidence that the activity and anatomy of neurons in the cortex are also abnormal in this condition. This project will utilise both optical imaging methods and electrophysiologic recordings to measure the activity patterns of large groups of individual neurons in the cortex.
Cortical neurons. Source: AllenInstitute
And the scientists will do this across different families of cortical neurons before and during the development of Parkinson’s to better understand the reshaping of connections between cells. The project is led by Thomas Wichmann of Emory University who has previous published research in this area – click here to read an example.
What do you think of all of the awarded projects?
It is not for me to judge. My opinion is no better than anyone else’s.
Plus it is extremely difficult to pass any kind of judgement as there is very little information available on the ASAP website in terms of what the specific objectives and milestones are for each project.
There is a lot of familiar topics (eg. alpha synuclein), but there is also a lot of breadth to the topics. Many of the groups are located within the same universities, which diminish the international collaborative nature of the initiative. But this may speak to the world-class talent that some of these institutes have gathered and nurtured (if the best in the world is in the room next door, why force people to collaborate with groups further afield? – would be the argument).
It will, however, be interesting to watch how some of these team adopt the strong ‘OPEN ACCESS’ policy that ASAP is trying to enforce.
What is the OPEN ACCESS policy?
The overall goal of ASAP is “to fund a basic research program that amplifies and coordinates the efforts of researchers around the world, both inside and outside of the existing Parkinson’s community“ (Source).
In addition, ASAP also has some major objectives which could be rather transformational for the way we conduct research. These objectives include:
- Supporting meaningful collaboration (the point of view discusses this particular topic at length)
- Generating research resources
- Democratizing data via open access
Open access refers to a set of policies that allow for research outputs to be distributed online, free of cost or other access barriers (Source). Their guiding principles are modified from the Panton Principles for Open Data in Science.
In their version, ASAP believe that:
- Science is based on collaboration – building on, reusing, and openly criticizing the published body of scientific knowledge.
- For science to effectively function, and for society to reap the full benefits from scientific endeavors, it is crucial that science data be made open.
- The ultimate value of data can often not be predicted and with advancing technologies and analytics, prior data could be reanalyzed for new insights and innovation.
Here at the SoPD, we whole-heartedly agree with the ASAP open access efforts.
Can you give an example of open access can look like?
A great example of an ASAP funded project that is embracing the objectives and the open access policy is the LRRK2 Central project.
This project – which was funded in the 2020 round of ASAP grants – has been very busy with sharing of data and information via different routes. They have been publishing reports in OPEN ACCESS journals (for example these report here and here), as well as making protocol available to other researchers (for example, methods for cell-based analysis of PINK1-Parkin pathway activation).
They have also been holding monthly research presentations – inviting individuals from outside of the team to share data. Their most recent event involved Ryan Watts (CEO of Denali Therapeutics) who presented the work that his company has been doing on LRRK2 inhibitors.
The team are also very good with social media, and have a very active twitter account.
Another example is the “Mito911” team. This project was also funded last year to explore the “mechanisms of mitochondrial damage control by PINK1 and Parkin” (Click here to read more about this).
They too hold regular webinars and have an active social media presence on twitter.
EDITOR’S NOTE: I would be very happy to highlight the OPEN ACCESS efforts other ASAP awarded groups here as well – contact me.
So what does it all mean?
The ASAP initiative represents a major new force in Parkinson’s research. Not just a significant leap in funding, but also encouraging a change of culture. It is a wonderful development. One which will hopefully bear fruit in the not too distant future.
And sticking with the tree theme that we started today’s post with, I will finish with a Warren Buffett quote:
Someone’s sitting in the shade today because someone planted a tree a long time ago.
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