Spotlight on early-career investigators: an interview with Benjamin Falcon

Dr. Benjamin Falcon is a postdoctoral scientist at the UK Medical Research Council Laboratory of Molecular Biology, working to untangle the mysteries of neurodegenerative conditions such as Alzheimer's disease. He completed his Ph.D. with Prof. Michel Goedert and has developed an impressive track record of findings that progress our understanding of neurodegenerative diseases.

His work has been supported by the EU Joint Programme in Neurodegenerative Disease Research (JPND) and he was awarded the Rising Star Award 2019 by Alzheimer's Research UK, just to name a few.

Benjamin and his colleagues recently published some of their findings in the journal Nature, identifying differences between how Tau assembles in people with the head impact-induced disease chronic traumatic encephalopathy (CTE) and Alzheimer's disease.

Looking back at these successes it is not surprising that Benjamin is now busy setting up his own group at the MRC Laboratory of Molecular Biology in Cambridge.

What motivated you to become a scientist?

I became interested in high school, when we made the switch from approaching science as a series of facts to actually learning about and carrying out experiments ourselves. This got me hooked, it is quite addictive testing hypotheses in an attempt to understand how life works.

Later, during my time as an undergraduate at University College London and whilst taking Professor Stephen Davies' course on neurodegenerative diseases, radical new evidence emerged suggesting that neurodegenerative disease might spread from cell to cell, instead of occurring as separate events in individual nerve cells. To me, this new perspective offered a way to make real breakthroughs. Despite more than one hundred years of research there are no disease modifying therapies for any of these diseases and they are becoming one of our biggest health challenges.

Could you tell us a little bit about your work, what does it involve?

My work has focussed on the abnormal ordered assembly of the protein Tau into filaments in neurodegenerative diseases. Tau is the most commonly assembled protein in neurodegenerative disease, including Alzheimer's disease and frontotemporal dementia. The abnormal filaments form aggregates and these are what actually spread from cell to cell along connected pathways in the brain, leading to neurodegeneration.

Although there is clear evidence from genetic studies that protein aggregation plays a causative role in neurodegenerative disease, we still don't fully understand why aggregates form or how they lead to disease. My postdoctoral work has focussed on determining the high-resolution 3-D chemical structures of Tau filaments from human brain, using recent advances in electron cryo-microscopy (or cryo-EM).

Cryo-EM is a powerful technique that allows you to image complex protein structures in their natural state at extremely high magnification. We did this in order to shed light on the molecular mechanisms of protein aggregation in neurodegenerative disease and how we might design precise drugs or molecules targeting them.

What have been some of your major research findings?

Using 3-D reconstructions from thousands of 2-D cryo-EM images, we found that Tau protein within the filaments of Alzheimer's disease, the fontotemporal dementia Pick's disease and CTE adopts specific conformations (or folds) that are unique to each disease.

We also found that Tau filaments in CTE contain integral hydrophobic non-protein molecules and that additional polyanionic molecules on the solvent-exposed faces of the filaments are a general feature in all of these diseases. These results suggest that a combination of protein conformation and non-protein molecules defines disease-specific Tau filaments and may contribute to the distinct neuropathologies of the different diseases, something that my future lab will follow up.

What are the clinical implications of these findings?

Knowing the exact composition and structure of Tau filaments in the brains of people with neurodegenerative diseases such as Alzheimer's disease gives us the possibility of designing and improving upon small molecules that specifically bind to them.

Such molecules could be used to track the emergence of Tau filaments in the brain, such as PET ligands, as an early diagnostic strategy, or to prevent or reverse the formation of the filaments as a therapeutic strategy. Because the process of protein aggregation begins very early on in disease, before any clinical symptoms can be detected, there is a need for more sensitive, early diagnostics, if any future therapies are to have a chance of succeeding.

You are involved in the IMPRiND project, which is funded by the Innovative Medicines Initiative. Could you tell us about the work you are doing in IMPRiND?

The goal of the IMPRiND project is to find inhibitors of the cell-to-cell spread of Tau aggregates in Alzheimer's disease. We are doing this by conducting genetic screens in neuronal cell culture models.

In IMPRiND, I have been involved in the production of Alzheimer's disease-specific Tau filaments for these screens. The cryo-EM structures were key in deciding which source of aggregated Tau we should focus on.

Our finding that there is a common Tau filament fold in all cases of Alzheimer's disease, and that current methods to produce Tau filaments in vitro do not recapitulate this structure, led us to use filaments extracted directly from human brain. Next, we worked with our partners at Janssen, Eli Lilly and Cambridge University to optimise the Tau filament extraction protocol, to achieve the yield and purity required for the genetic screens.

It has been a productive collaboration, allowing us to pool our individual expertise to tackle a shared research goal. Collaborating with industrial partners enabled the project to run the much-needed big genetic screens that would not be possible to do in an academic setting. This has produced something more than either of us could do on our own.

As an early-career scientist, it has provided a valuable introduction to many of the leading European academic and industrial scientists in this field, and sparked potential future collaborations.

Is there anything you would like to add?

We are working with human tissue, because these structures are specific to the different diseases and we cannot make them in the lab (yet).

I would therefore like to thank the people who enable our work, the patients for donating brain tissue and our collaborators, Bernardino Ghetti, Ruben Vidal and Kathy Newell, who perform neuropathological and genetic analyses.

Work as Postdoctoral Scientist in Neurobiology within the group of Dr. Benjamin Falcon at the MRC Laboratory of Molecular Biology. Closing date 6 October 2019: mrc.io/2LoeuYh

More information:
www.imi-neuronet.org/interview … ind-benjamin-falcon/
www.imprind.org/
doi.org/10.1038/s41586-019-1026-5
doi.org/10.1038/s41586-018-0454-y
www.cambridgeindependent.co.uk … in-dementia-9071086/
www.cambridgeindependent.co.uk … to-dementia-9071078/
www.cambridgeindependent.co.uk … n-two-years-9050529/
www.cambridgeindependent.co.uk … r-s-disease-9052890/

Provided by Alzheimer Europe