The ALS RAP

Yesterday, we were delighted to unveil a new research collaboration that we believe will greatly improve the quality and pace of MND research – not only in understanding the cellular processes that cause motor neurons to degenerate, but also in helping with drug discovery and development.

The Amyotrophic Lateral Sclerosis Reproducible Antibody Platform (ALS RAP) isn’t anything to do with the musical genre. It isn’t really a research project either. Instead, it’s focusing on the importance of providing the scientific community with ‘gold standard’ tools for their research.

This new collaboration involves a group of universities that make up the Structural Genomics Consortium, working with industry partners alongside three MND research organisations: The ALS Association, ALS Canada and ourselves.

The ‘best tools for the job’

The ‘tools’ I’m talking about are called antibodies, which are used in many different ways: from pregnancy testing kits, to diagnosing diseases, and treating conditions such as cancer or multiple sclerosis. But the most common use is in scientific research.

Antibodies are Y-shaped proteins that play an important role in helping the body to control infection, by recognising and sticking to invading bacteria and viruses.

Image: Wellcome Trust

Their use in research comes from seminal work performed over 40 years ago in the field of immunology. In 1975, two Cambridge scientists discovered a way of manufacturing antibodies in the lab that would only stick to particular molecules in a highly specific way – similar to the way a particular key will only open a particular lock. This discovery revolutionised medical research and led to them sharing the Nobel Prize for Medicine in 1984.

With MND, their main use is to help scientists work out what specific proteins in the body are up to, whether it’s in the blood, cerebrospinal fluid or the motor neurons themselves.

Proteins are the building blocks of every cell in our body, carrying out virtually all the essential cellular processes. I’d estimate that over 99% of all drugs have their effect by acting on proteins, which shows how vital they are to health and disease – and how important they are as targets for treatment.

We know that with neurodegenerative diseases, such as MND, a lot of damage occurs to the proteins in nerve cells. We need to understand what proteins are affected, how much of each protein is present, where they are in the cell and whether the proteins have changed in size or shape. This information gives rise to new theories on what is going wrong in MND as well as identifying new protein targets for drug development.

Antibodies are made to be highly selective. They will only stick to one particular type of protein – or even one particular part of a protein – which means that scientists can ‘home in’ on particular proteins in individual cells and study them in exquisite detail.

The challenge in MND

A common example from the MND field is using antibodies to look at the protein TDP-43, which we know plays a role in around 95% of all cases. The picture below shows human motor neurons from people who have donated their spinal cord after their death. The TDP-43 protein within the neurons has been targeted using a highly specific antibody that allows it to be then stained (brown) meaning that it can be easily spotted down a microscope.

TDP-43 staining

The photo on the left is a motor neuron from a person who did not have MND and the TDP-43 (brown staining) is tightly restricted to the nucleus of the cell. In the middle and right hand photos of motor neurons from people with MND, the TDP-43 protein has left the nucleus and spread out to other parts of the cell, with the right hand photo showing how the protein starts to form large TDP-43 ‘aggregates’, which are the pathological hallmarks of dying motor neurons.

The above picture is a very simple example. More powerful microscopes and analysis tools can allow scientists to ‘drill down’ much further into the cellular machinery. But there are also lots of other things that can be done using antibodies, which don’t need a fancy microscope. For example, researchers are using them to look for changes in the levels of proteins in blood and cerebrospinal fluid, which could form the basis of a diagnostic test for MND.

The elephant in the room

So, we know that antibodies are essential to research. The problem is that they can be difficult to make and sometimes not nearly as selective as scientists would like. Researchers do make their own antibodies, but they may not have been rigorously checked for quality. Even if they are good, they are often made in small quantities, which means that there isn’t enough available to share with the wider research community.

They can also be expensive to make, which means that the commercial companies will often stick to developing antibodies for already popular proteins linked to more common diseases.

The result is that if scientists around the world are working with antibodies of dubious quality they will produce dubious results – and this can seriously slow down the pace of scientific progress.

A painful example from the field of cancer research wasted two years, hundreds of patient samples and several hundred thousand dollars when it was eventually discovered that the antibody was not recognising the correct protein!

We don’t think it’s nearly as bad as that in the MND research world, but we know it’s not perfect. A recent research paper compared the effectiveness of several versions of antibody to the C9orf72 protein (involved in around 15% of MND cases) and the researchers found quite a lot of variation in quality, affecting their results. If that is happening in the labs of highly experienced neuropathologists who use antibodies every day, then there is going to be even more doubt about results coming from labs with much less experience.

The solution

The ALS-RAP aims to manufacture a large supply of ‘gold standard’ research antibodies, establishing a robust, ‘industry standard’ protocol that will set the standard for future antibody production in the MND research field.

Importantly, the list of antibodies that will be created will be based on the proteins that MND researchers most urgently want to investigate. A small group of experienced MND scientists from universities and drug companies will consult with the wider research community to come up with a ‘wish list’ of priority targets.

The Structural Genomics Consortium and their industry colleagues will combine their expertise to manufacture up to 45 new antibodies for proteins on the wish list. They will then rigorously check their quality and if they hit the high standard, they will make them available to the international research community, so everyone will be working with the same ‘best quality’ research tools. This in turn will speed up our understanding of the disease process and identifying new approaches to treatment.

 

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