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Imaging life from Molecules to cells - building knowledge on Cryo-electron microscopy methodologies

Periodic Reporting for period 2 - IMpaCT (Imaging life from Molecules to cells - building knowledge on Cryo-electron microscopy methodologies)

Reporting period: 2020-12-01 to 2023-02-28

Proteins are building blocks of life and they often form complexes with essential roles in the cell. Their structure and regulation allow for the great variety of molecular functions constantly at work to maintain the living state of every cell and organism. Therefore, access and expertise to modern methodologies in structural biology is essential for the study of life itself.

Dysfunction of proteins or their complexes are associated with a wide variety of pathologies, making them excellent drug target candidates. Many pharmaceutical drug discovery and development pipelines are based on the structural characterization of the components and their complex. Thus, knowledge of their 3D structures is essential for a rational drug design.

Extraordinary advances in instrumentation, sample preparation and image processing methods have brought forward the potential of direct imaging of individual molecules using Cryo-Electron Microscopy (CryoEM), allowing structures of a wide range of macromolecular complexes to be determined at near-atomic resolution, as well as obtaining an unprecedented level of detail in cell imaging by tomography.

To bring CryoEM knowledge to UNL - ITQB NOVA, and consequently to Portugal, collaborations were established with three research Centres in Europe, with proven track record and expertise in CryoEM applications: Spanish National Research Council - National Centre for Biotechnology (CNB-CSIC, Spain), University of Helsinki - Institute of Biotechnology (UH, Finland) and Weizmann Institute of Science (WIS, Israel).

The main activities performed through IMpaCT, involved a close collaboration between researchers in the consortium to transfer knowledge in CryoEM methodologies from the partners to UNL researchers, allowing them to become independent and capable end-users. Thus, IMpaCT was a fundamental instrument to develop the applications of CryoEM to life sciences research at UNL.
The activities planned to be developed within IMpaCT were severely affected by the COVID-19 outbreak in early 2020, requiring mitigation actions to ensure their implementation. This involved a 6-month extension of the project, with an adapted Action Plan and budget adjustments as specified in a Grant Amendment.

Three workshops were carried out (Figure 1), open to Early Career Researchers (ECRs) from all partners as well as independently funded external users. We highlight that the second and third workshops, initially planned to take place onsite during 2020, had to be delayed and replanned due to the health and travel restrictions imposed by the COVID-19 pandemic outbreak.

All six planned exchange visits of UNL ECRs to the partners (Figure 2) visits were conducted, and it was possible to include a seventh short visit.

UNL received 5 expert visits by the three partners and one Scientific Advisory Board (SAB) member. Besides delivering seminars, these experts also interacted with ECRs to discuss ongoing CryoEM projects and provide advice. The final three visits coincided with the installation of the new Cryo-TEM, and these experts also discussed best practices for the implementation of the new facility with the local INL staff.

CryoEM expert scientists were invited to present 6 seminars (Figure 3), four of which were delivered in virtual format. For both onsite and virtual visits, there were opportunities for interaction between the guests and the ECRs at UNL. The virtual seminars were advertised on the IMpaCT web site and social media and had a broad audience included participants from the all the partners in the consortium as well as attendants from all over the world.

Several courses for the professional and career development of ECRs (Figure 4) were organized and held mainly online (due to the COVID-19 outbreak), open to IMpaCT members as well as other UNL (ITQB NOVA) participants and provided participants with important soft skills to help them improve their publication and grant writing skills.

Four visits by UNL Research Support Staff elements to the UH and CNB-CSIC partners were carried out as planned.

Several activities were organized to make ECRs aware of the potential value of their research, and which steps should be taken to protect and exploit any IP that might arise from their results. These included a Mini-symposium and seminars in virtual mode (Figure 5), to promote closer interactions between academia and industry, foster potential collaborations with stakeholders outside of academia and to promote a possible future exploitation of project results. These activities provided ample opportunities for ECRs to interact with CryoEM researchers in the industrial sector, as well as with specialists in IP protection and creation of start-up companies.

Dissemination activities during IMpaCT consisted mainly of scientific communications (in either oral or poster formats) at national and international scientific meetings (Figure 7). Several scientific publications are lined up, ready for journal submission a few months after the end of IMpaCT.

IMpaCT was present in social media, its activities were disseminated on the website (www.itqb.unl.pt/impact) Twitter (@ICryoem) and two Instagram hastags #IMpaCT_team and #cryoem_impact were used.

CryoEM dissemination to the public and to students was accomplished by several outreach activities (Figure 8), such as visits to schools and higher education institutions, but also OpenDay/OpenLab activities, in which the public/students visited us.
The project started with a Portuguese Research community with a strong track record in X-ray crystallography and synchrotron-based spectroscopies but with very little experience in CryoEM, so scientific projects did not benefit from an integrated structural biology approach in which CryoEM is nowadays considered essential.

Despite difficulties during the COVID-19 pandemic, the project was able to adapt to a new “remote operation” mode in all its training activities, extending its scientific network beyond initial expectations, and profiting from the increased availability of researchers to attend online events without the need to travel, thus further promoting international cooperation.

All the training activities undertaken within the project reinforced the skill set of the participating ECRs, and this empowerment will undoubtedly be very important to their future careers, by opening new job and funding opportunities in the field of CryoEM.

IMpaCT succeeded in promoting the construction of fruitful and sustainable networks that will assist the establishment of national and international collaborations and the capacity to attract new and pertinent funding opportunities.

The IMpaCT coordinators were deeply involved in the purchase of the first Cryo-TEM in Portugal. The installation was finished in January 2023 (Figure 9), and the CryoEM-PT kick-off meeting took place in early February, after the final meeting of IMpaCT (Figure 10). Both events were organized at the INL.

Finally, all partners and the SAB members believe that a high-level technical capacity is essential to efficiently benefit the new CryoEM facility and to help secure the position of the Portuguese Scientific community in the CryoEM roadmap. UNL (ITQB NOVA) is hiring a PI to head a new research group in CryoEM, and the next challenge is to secure funding for additional researcher or technical positions, to retain some of the ECRs who were trained within IMpaCT.
Dissemination of scientific results
Mini symposium on Pharmaceutical Cryo-EM applications and Cryo-EM & Biotech seminars
Examples of the career development short courses for early-stage researchers
IMpaCT team at the kick-off and final meetings
Examples of early-stage researchers exchange visits
Workshops organized by IMpaCT
Examples of seminars organized by IMpaCT
Outreach activities
IMpaCT team members at the inauguration of the Glacios Cryo-TEM at INL