Patients not patents

# # # # Patent protection provides an inventor/discoverer with an exclusive right to prevent or stop others from commercially exploiting the patented invention for a set period of time. Patents are supposed to encourage innovation by providing the patent holder with an unchallenged opportunity to develop and profit from an idea. But it could be argued that patents are increasingly generating more problems than they are solving. In addition, they have led to the hording of data, which reduces collaboration and further limits progress. Luckily there are some ambitious efforts trying to change this. In today’s post, we will discuss some examples of these efforts. # # # #

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The Venetian Patent Statute. Source: Wikipedia

Patents are a form of intellectual property that provide the holder with the legal right to block others from manufacturing or selling an invention during a limited period of time. In exchange, the patent holder will publicly disclose the invention.

The use of patents began on the 19th March, 1474 when the the Venetian Patent Statute was established in the Republic of Venice.

The republic of Venice (in red) across the Mediterranean. Source: Alchetron

The Venetian Patent Statute provided that patents may be granted for “any new and ingenious device, not previously made“, IF that invention was considered useful.

More recently, some folks in the research and legal worlds have started arguing that patents themselves are no longer “useful”.

Patents are suppose to encourage innovation, but in the US alone, the costs brought on by patent trolls (these are holding companies that acquire strategic patents and use legal threats to extract steep royalties) now amounts to 12% of business R&D spending (Source). It is literally blocking innovation rather than stimulating it – if there is no certainty of a profit to cover the cost of royalties, there will be no innovation.

Patent troll. Source: Medium

And patents also inhibit medical research.

Many biotech firms will stop working on novel potential therapies (and even block others from working on them) because there is not a long enough period of time left in the patent to make a “business case” for supporting it.

As we have discussed in a previous post here on the SoPD, 30% of all Phase II clinical trials do not continue on to Phase III not because the therapy fails in terms of efficacy or safety, but rather the companies behind the agent can not find a business model that will justify continuing.

Pause and think about that for a moment.

1/3 of all Phase II trials…

…because limited profits can be made.

This is crazy. What can we do?

Simple: We stop patenting stuff.

What? But… Wait,…what?

Yeah, we no longer patent anything. Rather, we embrace open science and share everything freely.

What?!? Seriously: What?!? How would that even work?!? And what is open science???

Open science is an effort to make scientific research accessible to all levels of an inquiring society, both amateur or professional. No hording of data or publications behind paywalls, no limiting of innovation via patents.

Instead, we share everything freely.

Source: Nature

And when we say ‘share everything’, it means EVERYTHING.

Think about this in different ways.

For example, think of it in terms of the sharing of failures. Most scientific experiments end in failure – it is the very essence of experimental research – but in medical research most of those failures are never shared: Scientists typically only publish positive data. Their careers depend on positive results that advance our understanding of the world around us. But this begs the question: How many experiments have been repeated because no one shared their failed experimental results? And those ‘failed’ data might be useful to someone else, who is looking at a problem from a completely different angle or simply after large datasets.

Also think of ‘share everything’ in terms of the really hard tasks we are attempting to address in understanding the human brain. As Dr Viviane Poupon – President and Chief Executive Officer of Brain Canada –  points out, the brain is so complex that in order to really understand it, an ‘open science’ approach becomes a prerequisite (Click here to read more from Dr Poupon).

Dr Viviane Poupon. Source: themontrealer

Are there any examples of this no patent/open science approach actually being attempted?

Yes, there are. A lot of serious folks are already taking this approach.

One of the best examples is the Agora Open Science Trust – a Canadian-based charity dedicated to creating affordable new medicines using an open science approach.

Source: Agora

One of the big advocates of this project is Prof Aled Edwards, who is the Chairperson of the Agora Open Science Trust and has long been a pioneer in open science and its application to biomedicine and drug discovery.

Prof Edwards. Source: Eurekalert

He is the founder and Chief Executive of the Structural Genomics Consortium, a research organisation that applies open science  to protein science, chemical biology and drug discovery. He leads the six SGC laboratories from the SGC headquarters in Canada.

Here is a recent video from Prof Edwards about the use of open science in drug discovery – it is a fascinating eye-opening presentation (he starts around 10 minutes into the video):

The Agora Open Science Trust has several programs to encourage open science, including reproducibility in biomedicine, policy and advocacy, open science grants, and affordable medicines. And on way they are trying to support affordable medicines is through their biotech venture, M4K Pharma.

Source: M4K Pharma

What is M4K Pharma?

M4K Pharma is a wholly owned subsidiary of the Agora Open Science Trust. It is attempting to discovery and develop of a treatment for diffuse intrinsic pontine glioma – a rare and fatal pediatric brain cancer, for which no chemotherapies provide any benefit.

Source: CBC

Nearly every child diagnosed with the disease dies within two years. But it is one of those rare and fatal conditions that industry pharmaceutical companies generally don’t see a business plan for.

You can listen to this podcast of M4K Pharma’s Owen Roberts discussing the idea of open source drug discovery in this video here:

 

The task of developing a treatment is formidable, but M4K Pharma is attempting to do this within a open science framework. Until COVID-19 struck, they were sharing everything and regularly presenting updates on their work. For example:

Looking at the company’s Youtube website, it appears that after several years of very regular video updates, COVID-19 has slowed the news flow down (the last update was November 2020), but hopefully as things adjust to the new normal we will soon learn about what developments the team at M4K Pharma have made.

Fingers crossed.

Interesting, but what does any of this have to do with Parkinson’s?

Well, it would be encouraging to see this applied to Parkinson’s research. And recently the Agora Open Science Trust has attempted this.

In September 2020, the Agora Open Science Trust’s Medicines for Neurodegenerative Diseases (M4ND) initiative made a $90,000 grant donate to Professor Jean-François Trempe of McGill University to investigate PARKIN protein as a potential therapeutic target for the treatment of Parkinson’s (Click here to read the press release).

What is PARKIN?

PARKIN is a protein that has numerous functions inside of cells.

It is also called a ‘PARK gene’, as tiny genetic variations within the region of DNA that provide the instructions for making this protein (such sections of DNA are called genes) can put people at more risk of developing Parkinson’s.

The structure of PARKIN. Source: Wikipedia

PARKIN is one of the largest genes in our DNA, and variations within it were the second genetic risk factor to be associated with Parkinson’s. Individuals who develop Parkinson’s and also carry a PARKIN mutation in their DNA, are often diagnosed with the condition at a very young age (before 40 years old). This form of PD is referred to as PARKIN-associated Parkinson’s.

Biologically speaking, what does PARKIN do?

PARKIN is an enzyme. It functions as an E3 ubiquitin ligase.

What is an E3 ubiquitin ligase?

Let’s address each part of this.

Firstly, a ligase is an enzyme that initiates the joining of two molecules. It forms a new chemical bond between them.

Ubiquitin is a marvelous little protein that – as the name suggests – is ‘ubiquitous’ in all cells, and it affects all aspects of cell biology. It works its magic by being bound to proteins through a process known as ubiquitination.

The structure of ubiquitin protein. Source: Wikipedia

Ubiquitination can change the way a protein functions – like turning on a light switch – or it can be used to label an old/damaged protein for disposal.

This short video nicely explains ubiquitin:

It is important to understand that ubiquitin is involved in all kinds of biological processes, including:

• Apoptosis (cell death)
• Cell division and multiplication
• Degeneration of neurons and muscular cells
• DNA transcription and repair
• Immune and inflammatory response
• Stress response pathway

So PARKIN attaches ubiquitin to other proteins and is involved with lots of cellular processes?

Exactly. Specifically, PARKIN is an E3 ubiquitin ligase – referring to the third step in the  ubiquitination process that is described in the video above.

But how is PARKIN-associated with Parkinson’s?

As I briefly mentioned above, PARKIN/PARK2 was the second gene to be associated with Parkinson’s (alpha synuclein/SNCA being the first). Tiny variations in the region of DNA (PARK2) that provide the instructions for making the PARKIN protein are some of the most common genetic risk factors for individuals with young-onset Parkinson’s (or YOPD).

There isn’t one single PARKIN genetic variation associated with Parkinson’s. Rather, there are currently 10 common mutations in the PARKIN gene that can give rise to early-onset Parkinson’s. And it should be noted that PARKIN has also been associated with different types of cancer – there are 13 cancer-related genetic variants (PARKIN is recognised as a tumor suppressor – click here to read more about this).

Importantly, only two of the Parkinson’s related PARKIN variants are associated with an increased risk of cancer (they are R24P and R275W – red+black arrow heads in the image below).

Comparing PARK2 Cancer and PD associated mutations. Source: Nature

Thus it is important to know exactly where your mutation is, if in fact you have one. And even if you have the R24P and R275W mutation, it does not necessarily mean that you are definitely going to develop a particular type of cancer. It simply means that you are slightly more predisposed to it than someone without that PARKIN genetic variation (and please remember that a lot of genetic variations are required for a cancer to start!).

It is not something to worry about, but it is good to be aware of this association and to have regular check ups.

What does PARKIN-associated Parkinson’s look like?

Individuals diagnosed with PARKIN-associated YOPD are usually diagnosed around 30 years of age (but this can vary greatly). The condition is slower in progression than other forms of Parkinson’s and often presents itself clinically via tremor, bradykinesia, and lower-limb dystonia (sustained muscle contractions).

Affected individuals will generally have a preserved sense of smell and cognitive deficits are rare. Interestingly, at the postmortem stage, there are few reported cases with lewy bodies (one of the fundamental hallmarks of the Parkinsonian brain).

For those interested in learning more about PARKIN-associated YOPD, click here for a thorough review of the condition.

Ok, so what are the researchers going to do with their Agora grant to study PARKIN?

Professor Trempe & his team were seeking to “accelerate the discovery of new medicines for Parkinson’s disease by developing open access molecular agents that activate the PARKIN protein“, and they would “make all molecules and associated data generated in the project freely available to the research community” (Source).

It sounds like this is the way all research should be, right?

But it doesn’t always work out that way. Often resources in research are so scarce that folks get scared and try to protect whatever they can by keeping it all to themselves.

It’s basic human nature. Hard stuff to break.

But the Agora Open Science Trust is not the only organisation pushing change.

Can you give another example?

Yes. One of the key pillars of the Aligning Science Across Parkinson’s (ASAP) is democratizing data (aka open science).

What is ASAP?

ASAP is a major research funding organisation for Parkinson’s that takes a very basic biology approach to the research that they fund (Click here to read a previous SoPD post on this topic).

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.

ASAP “will allocate financial resources that significantly enlarge the basic science effort currently supported by the government and private foundations with the goal of understanding the underlying biology of Parkinson’s“.

But, the funding comes with conditions.

And these conditions include:

• Supporting meaningful collaboration (across disciplines and geographies)
• Generating research resources (which are made freely available)
• Democratizing data (open science)

And these conditions are applied to the three themes that have been prioritised by the organisation:

Source: Elife

And there have been some wonderful efforts from the funded research teams at embracing the objective of open science. A good exampe 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. Remarkably, one of their 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.

Interesting. Are there other examples of open science drug discovery across neurodegenerative conditions?

There are a few examples – which is really encouraging.

For example, in May 2020, a group of University of Arizona students launched a biotechnology start-up called Cliacept (pronounced CLEE-a-cept).

Their goal was to develop an effective and affordable treatment for Alzheimer’s, and the focus of their work is a protein called chloride intracellular channel 1 (or CLIC1) which has been reported to be elevated in the Alzheimer’s brain.

The almost entirely female team is being led by CEO Jaesa Strong, who has postponed her post-graduation pharmacy school plans to focus on Cliacept.

Jaesa Strong. Source

How do we get more researchers involved with open science?

Easy: Don’t give them a choice in the matter.

Que?

Just as ASAP has made it a requirement of their funding, so too are other funding bodies.

Very recently, the US National Institutes of Health (NIH) – the largest funder of medical research in the world – announced that from January 2023, they will require most of the 300,000 researchers and 2,500 institutions it funds annually to provide a data-management plan for any of their grant applications, and these will making their data publicly available.

It has been described as a “seismic shift” (Click here to read more about this), and it will be very interesting to see how this changes not only the behaviour of researchers, but also the progress of innovation.

It will be a giant experiment.

So what does it all mean?

In order to better understand complex situations like the human brain and the diseases associated with it, a new and more open approach is required for scientific research. The sharing of data and tools will be key to this, which has given rise to the idea of open science.

There are dangers with terms like ‘open science’, however, as they become increasingly used by the research community. A cynic could easily argue that the use of such labels is simply ‘perfunctory’ or ‘symbolic’ (a bit like getting someone with Parkinson’s to read the lay summary of your research grant so that you can say PwP community input has been involved). It will be up to the funding bodies and associated stakeholders (such as the community affected by the associated medical ailment) to help keep the research community honest.

Another potential danger is that researchers who are already stressed and overloaded with work (teaching, researching, & clinical duties, as well as finding time to stay on top of the published research… not to mention family, etc) will see open science as yet another burden, while the universities will view the movement as an existential threat to their intellectual property holdings. Such views are based on old thinking and long established habits. If anything, opening up science could de-burden the researcher and make life easier (the adjustment to the new way of thinking may take some time though). And most universities are yet to really prove that the cost of establishing and hording IP is a cashflow positive undertaking (see Prof Edward’s video above).

As I wrote above, it will be a massive experiment applying open science to the way we do research, but it feels right and worthy.

Let’s see how things look in 5 years time.

 

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The banner for today’s post was sourced from M4ND