Dr Janine Scholefield

JScholefield_Finding NEMO: Using super-resolution microscopy to diagnose disease-in-a-dish

Dr Janine Scholefield
Scholefield is part of the gene expression and biophysics group at the CSIR. After completing her PhD in human genetics at the University of Cape Town, she spent three years as a Nuffield Medical Fellow at the University of Oxford. Since returning to South Africa, she has specialised in modelling ‘disease-in-a-dish’.

About the talk: Understanding the biological mechanisms of disease has never been more important in the pursuit of developing treatments and cures for both infectious and non-communicable diseases. But to better understand how pathogens are able to hijack our cellular processes for their own benefit, we must better understand the basic molecular pathways themselves.

It is becoming increasingly apparent that a multi-layered complexity in the architecture of our cells dictates our response to cellular attack or damage. Yet, there is arguably less known about the details of the invisible responses of our own cellular pathways than the depths of our oceans.

Historically, we have disingenuously conjured the image of a cell akin to a ‘bag’ of stochastic protein interactions. However, a developing hypothesis in the field proposes that there is a high degree of architectural order in the cell which reduces such randomness and biological noise, instead creating a biological binary on/off switch. But how is the cell able to create its own red-to-green traffic light “GO” signal, if it is simply made up of proteins swimming around the cell?

One of the most critical pathways in our cells is called the NFkB signalling cascade – perhaps the most important one we have. This is because every cell in the body must have an innate ability to respond to an outside stimulus or attack. Whatever form that signal may take, essentially our healthy cells will respond by moving the protein NFkB from the cell body (cytoplasm) to the DNA storage area (the nucleus). There, it will activate many genes that lead to the cell’s protection. Although extremely simplified, in this way, we stay healthy.

A recently proposed theory in the field suggests that an intermediate protein linking the signal from the outside of the cell to the successful movement of NFkB to the nucleus, might be able to do this by forming higher order structures that would be able to act as that guardian – waiting for a minimum threshold of signal to arise before switching on a green light of activation. Importantly, there must also only be a limited number of these structures to ensure there isn’t an overreaction.

The protein in question is called NEMO. And though it has long been studied, due to the limitations of biological experimentation, we had no simple approaches on how to prove the existence of such higher order structures. However, a year ago, Eric Betzig, Stefan W. Hell and William E. Moerner were awarded the Nobel Prize in chemistry for developing super-resolved fluorescence microscopy. Our laboratory custom-designed the very first and to date, only such microscope in the country. Using this technology we have been able to identify the first visual proof of these higher-order structures acting as pre-formed guardians of the immune response.

Scholefield will expand on some of the research, which utilises these techniques to better understand crucial cellular interactions, and how they identified never-before-seen structures of the immune response.

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