Community Research and Development Information Service - CORDIS

H2020

SMILE Report Summary

Project ID: 738774

Periodic Reporting for period 1 - SMILE (Synchrotron Miniaturization enabling Innovative Laboratory Equipment in soft x-ray tomography.)

Reporting period: 2017-01-01 to 2017-10-31

Summary of the context and overall objectives of the project

Societal issue being addressed:
Cancer now accounts for a quarter of all deaths in the EU and it has recently overtaken cardiovascular disease as the number one cause of death in men over 50. Despite billions of Euros of investment in cell biology, science has barely scratched the surface in understanding what is happening within a cancerous cell to make it multiply uncontrollably as the disease spreads through the body. Cell shape and the shape of its internal organelles, are seen as important influencers on cell signalling and gene switching that triggers cancer growth. 3D imaging of the internal structure of whole, intact, cells is playing an increasingly important role in helping scientists to understand cancer as it allows them to accurately and non-intrusively measure and monitor organelle shape.

Role of soft x-ray imaging:
The only technology available today that can image through a whole cell, without needing to slice it or stain it, is soft x-ray imaging, which is carried out using a soft x-ray microscope. The problem is that the soft x-ray illumination required for a soft x-ray microscope is only available from electron accelerator facilities, called synchrotrons. Only four of these billion dollar, football stadium-sized facilities exist that have a soft x-ray beamline and only approximately 100 research groups from a target addressable market of 3,000 disease research organisations have been able to get access, having had to queue for up to twelve months to do so.

SiriusXT's Innovation:
SiriusXT’s innovation has been to miniaturize the synchrotron into a small chamber that will that will easily fit on a laboratory bench. This patented source of soft x-ray illumination, when integrated with a microscope similar to that used at the synchrotrons, will give our target addressable market of 3,000 disease research organizations access to this imaging modality in their own labs, at a fraction of the cost of a synchrotron.

Overall Objectives of Project SMILE
i) to demonstrate a reliable miniaturized source, which is capable of producing sufficient soft x-ray illumination to image a whole cell in 3D in under 60 minutes
ii) to build and demonstrate a soft x-ray microscope, using the miniaturized soft x-ray source.
iii) to carry out a Pilot evaluation of the soft x-ray microscope at the Crick Cancer Research Institute in London

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Work performed in first ten months of the project (Jan to Oct., 2017):

During this period the focus was on designing and building a soft x-ray source that is sufficiently reliable to work for a minimum of forty hours without need to replenish consumables or make any adjustments in an end user environment. A Failure Mode Effect Analysis (FMEA) of the prototype source that was built prior to the start of the project identified areas that needed to be improved in order to achieve these goals. The design work focused both on increasing the soft x-ray source reliability as well as its performance, the latter being defined in terms of the number of soft x-ray photons per second and the diameter (full width half max) of the photon beam at the Intermediate Focus (output) of the source.

By October, 2017, ten months into the project, the soft x-ray source performance had been validated in terms of photon numbers and intermediate focus diameter, however more mechanical development effort had been needed in order to maintain a reliable source performance over a longer period of time (40 hours) without needing to replenish consumables or to recalibrate the system. The need to redesign some mechanical modules in the microscope resulted in some project schedule slippage. To deal with this, more senior mechanical design resources and a senior Engineering Manager, with strong experience project management experience were hired. The soft x-ray source is now working to specification, both from a performance and reliability perspective. It is currently being integrated with microscope optics, similar to that used at the synchrotrons, to produce the microscope.

The results obtained from the soft x-ray source testing has been shared with the operators of the European synchrotrons and they have been very supportive with advice on how to integrate the microscope optics for best imaging performance. SiriusXT personnel have also worked closely with operators of cryo-imaging laboratories, who have developed expertise in cryo- cell preparation for electron microscopy applications as well as for soft x-ray imaging at the synchrotron beamlines. By October, 2017, we have the capability to screen cryo-prepared grids, populated with cells, on a fluorescence microscope and to then transfer the frozen cells in a custom-designed transfer box to the cryo stage of the microscope.
The results of this cryo-cell handling work has been described and published on the SiriusXT’s LinkedIn page and on the Cryo Microscopy LinkedIn Group page, which has over 1,000 members interested in cryo-cell microscopy.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Over the past ten years or more a number of organisations have attempted to design and build a commercial 'bench-top' soft x-ray source, that would be capable of generating sufficient soft x-ray photon illumination to 3D image a biological cell in less than one hour, however, all attempts to date have failed. The SiriusXT prototype source, built prior to the start of project SMILE, demonstrated an ability to produce the illumination levels necessary to achieve this goal but it was insufficiently reliable to be considered a commercial product. One of the goals of project SMILE was to redesign the prototype source in order to increase the reliability of operation. Once complete, this will be the only soft x-ray illumination source of its kind and will have clearly surpassed state-of-the-art.

This will allow SiriusXT to build a commercial, bench-top, soft x-ray microscope, fulfilling a well defined market need for such a product. In so doing, SiriusXT will open up soft x-ray imaging as a commercially viable lab-based technique for a target market of over 3,000 disease research and drug discovery organisations. It will be the only imaging modality available to cell imaging laboratories for generating high resolution images of the complete internal structure of whole biological cells, without having to slice or stain the cells. It will provide scientists working on identifying the root causes of diseases, such as cancer, Alzheimer disease, Huntington disease, etc., a unique insight into the internal function of the diseased cell, increasing their knowledge of these diseases and accelerating the development of effective cures for these diseases.

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