Earlier this year, a San Francisco-based biotech company – called Cortexyme – published a research report that grabbed my attention.
The study presented data supporting an alternative theory of the cause of Alzheimer’s – one in which a bacteria involved in gum disease appears to be playing a leading role – and evidence that the company’s lead experimental compound COR388 could have beneficial effects in the treatment of the condition.
While the study was intriguing, what completely blew my mind was the fact that the company had already tested COR388 in a couple of Phase I clinical trials, and since then they have initiated a large Phase II/III trial.
In today’s post, we will discuss this new theory of Alzheimer’s, look at what Cortexyme are doing, and how this could relate to Parkinson’s.
The dashed lines show associations. Source: Slideplayer
Before we start today’s post, a word on ‘associations‘.
Please remember while reading this material that association does not equate to causation.
So if I write something like “researchers have found an association between a type of bacteria that causes gum disease and Alzheimer’s”, it does not mean that someone with either condition necessarily has the other. It only means that they have both simply appeared in the same individuals at a higher than chance rate.
So what is today’s post about?
A very interesting report in which researchers have found an association between a type of bacteria that causes gum disease and Alzheimer’s.
At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during April 2019.
The post is divided into seven parts based on the type of research:
So, what happened during April 2019?
In world news:
10th April – Scientists from the Event Horizon Telescope project announced the first ever image of a black hole. Located in the core of the Messier 87 galaxy (53 million light years from Earth), this supermassive black hole has a mass 6.5-billion times that of the Sun! The black hole’s boundary – the event horizon – is around 2.5 times smaller than the shadow it casts and measures just under 40 billion km across (about the size of Neptune’s orbit!!!).
10th April – Fossil fragments found in the Callao Cave in the Philippines revealled the existence of a new species of human, Homo luzonensis. The species is named after the island – Luzon – where it was discovered.
15th April – During Holy Week, a devastating fire engulfed the roof and main spire of Notre-Dame Cathedral in Paris.
24th April – I am a big fan of Martin. Several years ago his video of the Marble machine took the internet by storm and since then I have been following his regular vlog updates on the construction of the new and improved Marble machine X. This week he took the new machine for its first test run – still has parts missing, but this is mesmerising to watch. If you don’t follow him you should!
In the world of Parkinson’s research, a great deal of new research and news was reported:
In April 2019, there were 730 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (3134 for all of 2019 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).
The top 9 pieces of Parkinson’s news
Microglia are the resident immune cells in the brain – they maintain law and order when trouble kicks off. And when things get really bad, these cells change shape, become “activated”, and start to absorb toxins, debris and anything else that they feel should not be there – via a process called phagocytosis.
And they are ruthless in this task.
When we are young, these cells function very well at maintaining a general sense of ‘homeostasis‘ (or stable equilibrium). But as we age,… well, let’s just say things start to slip a little.
Recently a group of researchers at Stanford University have discovered by inhibiting a single protein, called CD22, they can restore microglial homeostasis in the ageing brain, and this had beneficial effects in a model of Parkinson’s.
In today’s post, we will look at what microglia are, what phagocytosis is, and what these new CD22 results could mean for Parkinson’s.
My father often says: Ageing is not for sissies.
And as the birthdays have started to mount up, I’ve come to better understand what he means.
There are days when I feel like an old man trapped in a 27 year old’s body. For the record, I’m 27. And for the record, I’m going to be 27 until I die (27 was a great year!).
An amazing journey. Source: Topsimages
While some are able (and foolishly gleeful) to avoid taxes, until recently no one has been able to escape the rentless march of ageing. Until recently, the vast majority of us have been resigned to our fates. And until recently, the fountain of youth has only existed in the realm of the Hollywood movies.
The force is strong with this one. Source: Reddit
Recently there has been an enormous amount of research focused on stopping ageing and preventing death (both of which are being viewed as “curable diseases” – click here to read more about this). Now to be honest, much of this is still quackery.
But there does seem to be progress being made in the biology of extending ‘healthspan’ (as opposed to lifespan).
And some of that research could have implications for Parkinson’s.
One of the characteristic features of Parkinson’s is the loss of dopamine neurons in the brain. One experimental approach that is being explored for treating the condition involves investigating biological pathways involved in the early development of dopamine neurons.
By re-exposing the dopamine neurons to supportive, growth-encouraging proteins that are present during early development (but absent or reduced in adulthood), researchers hope to be able to rejeuvinate these cells and make them healthier.
In a recent post, we discussed one such developmental supportive protein: Glial cell derived neurotrophic factor (Click here to read more about this).
In today’s post, we will look at a different type of developmental protein which is having interesting effects in models of Parkinson’s. That protein is called Sonic Hedgehog.
The humble fly (Drosophila). Source: Ecolab
No one should ever be allowed to say that fly genetists don’t have a sense of humour.
When it comes to the naming of genes, they have had a great deal of fun. A gene is a section of DNA that can be copied into RNA (which may then provide the instructions for making a protein), and each gene has been given a name. Some names are boring – such as leucine-rich repeat kinase 2 (or LRRK2… Boring!) – while other names are rather amusing.
For example, there is one fly gene called indy, which stands for I‘m Not Dead Yet. Flies with genetic variation in this gene have longer than average lifespans (Click here to read more about this).
Another amusingly named gene is Cheap Date. Flies with a genetic mutation in this gene are very susceptible to alcohol (Click here to read more about this).
There is also Ken and Barbie – genetic variations in this gene result in a lack of external genitalia (Click here to read more about this). There are lots of great gene names: “lunatic fringe”, “headcase” and “mothers against decapentaplegia (MAD)”. Like I said, fly genetists have a lot of fun.
But one of the most popular gene names in all of biology is a gene called Sonic Hedgehog.
What is Sonic Hedghog?
As the amazing Australian Parkinson’s Mission project prepares to kick off, across the creek in my home land of New Zealand, another very interesting clinical trial programme for Parkinson’s is also getting started. The study is being conductetd by a US biotech firm called resTORbio Inc.
The drug being tested in the study is called RTB101.
It is an orally-administered TORC1 inhibitor, and it represents a new class of drug in the battle against Parkinson’s.
In today’s post, we will look at what TORC1 is, how the drug works, the preclinical research supporting the trial, and what this new clinical trial will involve.
Rapa Nui. Source: Chile.Travel
Today’s post kicks off on an amazing south Pacific island… which is not New Zealand.
In 1965, a rather remarkable story began in one of the most remote inhabited places on Earth – the mysterious island of Rapa Nui (or “Easter Island”).
And when we say ‘remote’, we really do mean remote. Did you know, the nearest inhabited island to Rapa Nui is Pitcairn Island, which is 2,075 kilometres (1,289 mi) away. And Santiago (the capital of Chile) is 2,500 miles away – that’s a four-hour+ flight!!!
Rapa Nui is the very definition of remote. It is as remote as remote gets!
Does Amazon deliver to the town of Hanga Roa? Source: Atlasandboots
Anyways, in 1965 a group of researchers arrived at Rapa Nui with the goal of studying the local inhabitants. They wanted to investigate their heredity, environment, and the common diseases that affected them, before the Chilean government built a new airport which would open the island up to the outside world.
It was during this investigation, that one of the researchers – a University of Montreal microbiologist named Georges Nógrády – noticed something rather odd.
At the time of the study, wild horses on Rapa Nui outnumbered humans (and stone statues).
Wild horses roaming the east coast of Rapa Nui. Source: Farflungtravels
But what was odd about that?
Georges discovered that locals had a very low frequency of tetanus – a bacterial infection of the feet often found in places with horses. He found this low incidence of tetanus particularly strange given that the locals spent most of their time wandering around the island barefoot. So Georges decided to divide the island into 67 regions and he took a soil sample from each for analysis.
In all of the vials collected, Nógrády found tetanus spores in just one vial.
Something in the soil on Rapa Nui was extremely anti-fungal.
In 1969, Georges’ collection of soil samples was given to researchers from the pharmaceutical company Wyeth and they went looking for the source of the anti-fungal activity. After several years of hard work, the scientists found a soil bacteria called Streptomyces hygroscopicus which secreted a compound that was named Rapamycin – after the name of the island – and they published this report in 1975:
Title: Rapamycin (AY-22, 989), a new antibiotic
Authors: Vézina C, Kudelski A, Sehgal SN.
Journal: J Antibiot (Tokyo). 1975 Oct;28(10):721-6.
PMID: 1102508 (This report is OPEN ACCESS if you would like to read it)
It is no understatement to say that this was a major moment in biomedical history. So much so that there is actually a plaque on the island commemorating the discovery of rapamycin:
Why was the discovery of ‘anti-fungal’ rapamycin so important?!?
Nuclear receptor related 1 protein (or NURR1) is a protein that has been shown to have a powerful effect on the survival of dopamine neurons – a population of cells in the brain that is severely affected by Parkinson’s.
For a long time researchers have been searching for compounds that would activate NURR1, but the vast majority of those efforts have been unsuccessful, leaving some scientists suggesting that NURR1 is “undruggable” (meaning there is no drug that can activate it).
Recently, however, a research report was published which suggests this “undruggable” protein is druggable, and the activator is derived from a curious source: dopamine
In today’s post, we will discuss what NURR1 is, what the new research suggests, and how this new research could be useful in the development of novel therapeutics for Parkinson’s.
It always seems impossible until it’s done – Nelson Mandela
In 1997, when Nelson Mandela was stepping down as President of the African National Congress, some researchers in Stockholm (Sweden) published the results of a study that would have a major impact on our understanding of how to keep dopamine neurons alive.
(Yeah, I know. That is a strange segway, but some of my recent intros have dragged on a bit – so let’s just get down to business)
Dopamine neurons are of the one groups of cells in the brain that are severely affected by Parkinson’s. By the time a person begins to exhibit the movement symptoms of the condition, they will have lost 40-60% of the dopamine neurons in a region called the substantia nigra. In the image below, there are two sections of brain – cut on a horizontal plane through the midbrain at the level of the substantia nigra – one displaying a normal compliment of dopamine neurons (on the left) and the other from a person who passed away with Parkinson’s demonstrating a reduction in this cell population (on the right).
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinsonian brain (right). Source:Memorangapp
The researchers in Sweden had made an amazing discovery – they had identified a single gene (a specific region of DNA) that was critical to the survival of dopamine neurons. When they artificially disrupted the section of DNA where this gene lives – an action which resulted in no protein for this gene being produced – it resulted in mice being born with no midbrain dopamine neurons:
Title: Dopamine neuron agenesis in Nurr1-deficient mice
Authors: Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T.
Journal: Science. 1997 Apr 11;276(5310):248-50.
The researchers who conducted this study found that the mice with no NURR1 protein exhibited very little movement and did not survive long after birth. And this result was very quickly replicated by other independent research groups (Click here and here to see examples)
So what was this amazing gene called?
Nuclear receptor related 1 protein (or NURR1; it is also known as NR4A2 – nuclear receptor subfamily 4, group A, member 2)
And what is NURR1?
At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during March 2019.
The post is divided into seven parts based on the type of research:
So, what happened during March 2019?
In world news:
2nd March – SpaceX successfully launch their Crew Dragon rocket on it’s first un-manned mission into space. One day later it docked with the international space station.
5th March – A second case of sustained remission from HIV was reported. This news comes ten years after the original “Berlin Patient” (Click here to read more about this).
15th March – Cyclone Idai made landfall on Mozambique, causing loss of life, mass flooding, and power outages in south-eastern Africa.
25-26th March – the International Parkinson Disease Genomics Consortium met in Lisbon (Portugal) for their annual meeting. 100+ genetics experts from around the world gathered to discuss all of their new research on the genetics of Parkinson’s – it was an amazing meeting (Click here to read a SoPD post on this meeting).
26-31st March – the 14th International Conference on Alzheimer’s & Parkinson’s Disease was held in Lisbon (Portugal). 4000 researchers from around the world invaded the city for five days of lectures & presentations. The results of many clinical trials were presented and exciting new data was discussed (a SoPD post is in the works on this meeting).
In the world of Parkinson’s research, a great deal of new research and news was reported:
In March 2019, there were 869 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (2429 for all of 2019 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).
The top 6 pieces of Parkinson’s news
Recently some researchers conducted an analysis of some postmortem brains from people with Parkinson’s and they discovered something rather curious.
Half of the brains that they analysed came from people with Parkinson’s who had been given deep brain stimulation (or DBS) to help manage their symptoms. When the researchers analysed the mitochondria – the powerstations of each cell – in the dopamine neurons of these brain, they found that the DBS treatment had helped to improve the number of mitochondria in these cells.
Specifically, the DBS treatment “seemed to have inhibited or reversed the reduction in mitochondrial volume and numbers” that was observed in the Parkinson’s brains that had not had DBS.
In today’s post, we will look at what DBS is, what the new research report found, and what these new findings could mean for the Parkinson’s community.
The worst thing. Source: Greatist
Do you know the worst thing that happens to us in life?
We wake up each day.
Every day of our lives (so far) we have woken up and been given – without any kind of justification – another 16 or so hours to do whatever we want with.
Regardless of one’s physical/mental state, this is a bad thing.
This continuous pattern is what is referred to in psychology as a ‘continuous schedule of reinforcement’. Such regimes instill complacency and – worse – expectation. They quickly lead to people taking things for granted. All of us are guilty of thinking “I’ll do it tomorrow”.
Such a continuous pattern of reinforcement does not prepare one well for a life in scientific research, where there isn’t a constant schedule of reinforcement (quite the opposite actually). Experiments regularly go wrong (reagents/equipment fail), grants/manuscripts get rejected – it can be rather brutal.
But here is where the addictive component of science comes into effect. Every so often, something works. And even better, every so often something unexpected happens – an ‘intermittent/irregular schedule of reinforcement’. An experiment will occasionally spit out a completely unexpected result, which could change everything.
These are the moments of insights that researchers are slaving for. The instant that they are the first to “walk on the moon”.
They are moments to savour.
And this must have been the state of mind for some researchers who dicovered something surprising and absolutely remarkable recently while they were looking at some postmortem brains from individuals with Parkinson’s who had been treated with deep brain stimulation.
What is deep brain stimulation?
Approximately 1 person with Parkinson’s in every 100 will have a genetic variation in a specific section of their DNA that is referred to as LRRK2 – pronounced ‘lark 2’. The variation results in changes to the activity of the LRRK2 protein, and these changes are suspected of influencing the course of LRRK2-associated Parkinson’s.
Numerous biotech companies are now developing LRRK2 targetting agents that will modulate the activity of the LRRK2 protein.
Recently, however, a research report was published which points towards a potentially accessible method of LRRK2 modulation – one of the active forms of vitamin B12 – and if this research can be independently replicated, it may provide certain members of the Parkinson’s community with another means of dealing with the condition.
In today’s post, we will look at what LRRK2 is, review the new research, and discuss what could happen next.
This is Sergey Brin.
You may have heard of him – he was one of the founders of a small company called “Google”. Apparently it does something internet related.
Having made his fortune changing the way we find stuff, he is now turning his attention to other projects.
One of those other projects is close to our hearts: Parkinson’s.
Why is he interested in Parkinson’s?
In 1996, Sergey’s mother started experiencing numbness in her hands. Initially it was believed to be a bit of RSI (Repetitive strain injury). But then her left leg started to drag. In 1999, following a series of tests and clinical assessments, Sergey’s mother was diagnosed with Parkinson’s.
The Brin Family – Sergey and his mother on the right. Source: CS
It was not the first time the family had been affected by the condition – Sergey’s late aunt had also had Parkinson’s.
Given this coincidental family history of this particular condition, both Sergey and his mother decided to have their DNA scanned for any genetic errors (also called ‘variants’ or ‘mutations’) that are associated with an increased risk of developing Parkinson’s. And they discovered that they were both carrying a genetic variation in a gene (a section of DNA that provides the instructions for making a protein) called PARK8 – one of the Parkinson’s-associated genes (Click here to read more about the genetics of Parkinson’s and the PARK genes).
The PARK8 gene is also known as Leucine-rich repeat kinase 2 (or LRRK2 – pronounced ‘lark 2’).
What is LRRK2?
Today saw the publication of one of my favourite stories of Parkinson’s research.
It is a tale of courage, serendipity, hard work, and (most importantly) an idea for a research project that came from the Parkinson’s community, but has now opened new doors for researchers and could have important implications for everyone.
In 2012, former nurse Joy Milne was attending a Parkinson’s support group meeting in Edinburgh (Scotland) when she bravely asked the scientist presenting research that day, “Do people with Parkinson’s smell different?”
What happened next is likely to become that stuff of legend.
In today’s post, we will discuss the back story, review a new research report investigating the smell of Parkinson’s, and consider what the results could mean for the Parkinson’s community.
Erasto Mpemba & Denis Osborne. Source: Rekordata
In 1963, Dr. Denis G. Osborne – from the University College in Dar es Salaam – was invited to give a lecture on physics to the students at Magamba Secondary School (Tanganyika, Tanzania). At the end of his lecture, a 13 year old student, named Erasto Mpemba, stood up and asked Dr Osbrone:
“If you take two similar containers with equal volumes of water, one at 35 °C (95 °F) and the other at 100 °C (212 °F), and put them into a freezer, the one that started at 100 °C (212 °F) freezes first. Why?”
The question was met by ridicule from his fellow classmates.
But to his credit, Dr Osborne went back to his lab and conducted some experiments based on the question, confirming Mpemba’s observation. Together they published the results in 1969, and the phenomenon (the process in which hot water can freeze faster than cold water) is now referred to as the Mpemba effect.
Mpemba effect. Source: Wikipedia
The point is: All scientific discoveries start with an observation, followed by an experiment.
And scientists do not have a monopoly on this.
There have been many cases of ‘laypeople’ – like Erasto Mpemba – making important observations. And recently the Parkinson’s world had a perfect example of this. It’s very own Erasto Mpemba moment.
What are you talking about?