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The Way Forward for Antibodies in Neuroscience

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Antibodies are an essential part of everyday neuroscience research. They are a centerpoint of common analysis assays, diagnostic tests, and are even being exploited for advanced therapeutics. But antibodies have come in for criticism recently, with high profile articles calling into question the reliability and reproducibility of these essential research tools. We caught up with Bio-Techne’s Raymond Chan and Katherine Bradley to find out how providers are hoping to improve antibodies and make them fit for a more reproducible future in neuroscience. 

Ruairi Mackenzie (RM): What are the most common applications for antibodies in neuroscience?

Raymond Chan (RC):  The main way neuroscientists use antibodies is for immunodetection [e.g. immunoblotting, immunocytochemistry, immunohistochemistry] of targets.

RM: How can we improve antibodies to make them more sensitive and specific for neuroscience applications?

Katherine Bradley (KB): Neural tissue has a more complex and heterogeneous cellular and molecular composition compared to other tissue. One way to improve antibodies for neuroscience research, is to design and validate these tools for use in this complex tissue. So, when selecting antibodies, those that are pre-validated would be a wise choice – utilize those product data sheets!

RM: A recent feature in Nature pointed a finger squarely at antibodies as a contributor to the reproducibility crisis. How valid is that claim, and how can we improve the reproducibility and validity of antibodies?

RC: The claim is extremely valid, especially as antibodies are so widely used – any related issues can quickly become widespread within the scientific community. As such, the use of inconsistent and unvalidated antibodies can create a range of issues in current and future research.

At Bio-Techne, we use industry-leading antibody production standards, which follows the 5-Pillar Model from the International Working Group for Antibody Validation. This approach to antibody production standards is based on 5 validation principles:

Genetic strategies such as CRISPR KO validation

A non-antibody based, orthogonal method such as ACD’s RNAscope® ISH technology 

An independent antibody targeting a different epitope

Use of tagged or overexpressed protein

Biological or chemical modulation of protein expression

You can find out more about these validation steps here.

In addition to this, R&D Systems – a Bio-Techne brand – have 39 HLDA-approved CD marker antibody clones. Characterized by the Human Leukocyte Differentiation Antigens (HLDA) Workshops, new CD molecule antibodies are blind-tested by multiple international laboratories including rigorous Flow, WB, IHC, IP, cross-reactivity, and functional studies. Further information on the steps we take to build our antibodies for reproducibility can be accessed here.

Following the steps above ensures high validation, reproducibility, and specificity in antibodies is achieved, which is essential to maximize their potential to researchers.

RM: Our understanding of the brain has advanced hugely in the last ten years of research. How can antibodies advance in kind? 

KB: We are seeing a need for antibodies that work for immunodetection of proteins in whole tissue samples. The brain is made of neural cells connecting with each other and there is a need to be able to visualize these neural networks in order to get a better understanding of neural development and changes that occur in the pathological brain.

Neuroscientists are also needing validated tools for the specific detection of different protein conformers. A hallmark of many neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, is the abnormal accumulation of aggregated proteins in the brain. While there are methods to detect proteins aggregates (i.e. mass spectrometry), they lack the ability to look at them in spatial context.

RC: Overall, antibodies designed for neuroscience targets are being continually developed and improved, as we better understand the biology of different cells in the mammalian brain, and the neural network, and can better design immunogens, especially to difficult targets such as membrane proteins.

At the 1st International Antibody Validation Meeting, an issue with antibodies to the neurotrophin receptor TrkB was raised in one of the talks by a neuroscience lab in Aarhus University, Denmark. The R&D Systems antibody to TrkB was shown to work very well for Western blot, immunostaining (ICC and IHC) and IP, but only after having no results from 15 other commercial antibodies, at great cost and time. Sometimes, well-designed and validated neuroscience antibodies may therefore already be out there, but labs may not be aware of them.

Finally, neuroscientists have also successfully applied RNAscope ISH technology to many targets of unmet need, where antibodies are not yet commercially available, or do not perform adequately in applications of interest. Of 2200 citations using RNAscope, 650 (30%) of papers have been in the neuroscience field. This speaks to the great need we see for improved and well-validated antibodies to more neuroscience targets.