Published on 27 November 2024

Blog Thao Tran – SARS - CoV-2

«We only required the sequencing data from the virus-of-interest, and from this we
could synthesise the building blocks to construct the synthetic virus using the yeast-based platform».

How a PhD study on strategies for pandemic preparedness became a real-life reaction to the COVID-19 pandemic

The aim of Thao Tran's thesis was to develop pandemic preparedness strategies to deal with future epidemics of emerging zoonotic diseases. Professor Volker Thiel, Head of Virology, Institute of Virology and Immunology IVI and professor at the University of Bern, explained «This project became even more timely and important with the onset of the SARS-CoV-2 pandemic. The emergence of SARS-CoV-2 allowed us to test the system in a «real life» situation and Thao and the team went from viral sequence information to generating virus in just over a week, an unprecedented achievement. The methodology was also described in further detail .  Since then, both the platform and the resultant cloned viruses, have been widely shared and used by multiple research teams in many countries from Asia, Europe, Oceania, and North America. It was also the starting point for generating viruses here at the IVI which have been used to study the impact of the SARS-CoV-2 pandemic variants which have been described in further publications (Publication Nature, Publication BiorXiv). Thao’s hard work has proved to be invaluable as the jump off-point for many more projects currently underway not only in our laboratory but in projects with collaborators across the world.»

Interview with Dr. Thao Tran

• What was the topic of your PhD project?

  My PhD project aimed to establish a system that could be used to reconstruct multiple emerging RNA viruses from genetic materials, through a process called reverse genetics. The rationale behind a one-for-all system is for us to be prepared and able to respond rapidly to an outbreak/pandemic situation caused by any emerging virus.
  
  In such situations, the established reverse genetics platform could be applied to generate recombinant viruses much faster than other methods for use in virus biology studies, identification of new drugs, and vaccine development.

• What are your most important results?

  We were able to employ a yeast-based method, « a.k.a. transformation-associated recombination (TAR)» , to establish a universal cloning platform for multiple representative emerging RNA viruses, such as MERS-CoV, Zika virus, etc. On top of that, we successfully applied the TAR cloning platform to build and recover all six versions of the infectious pandemic virus SARS-CoV-2 within one week of receiving synthetic viral genetic materials. This achievement is unprecedented and through this work we convincingly showed that this novel platform satisfied many important features of a preparedness approach, being rapid, efficient, allowing high-throughput, and universally applicable. Importantly, we only required the sequencing data from the virus-of-interest, and from this we could synthesise the building blocks to construct the synthetic virus using the yeast-based platform. This dispensed with the need to obtain clinical samples and speeded up the process significantly over traditional methods where the virus must be first sent to our lab to allow further studies. The platform has since become pivotal for generating numerous recombinant SARS-CoV-2 viruses that are an essential part of our toolbox for various projects in the Thiel lab as well as by other researchers in projects in which we collaborate.

• How can they be employed in the future, why is it relevant and for whom?

  As we have shown in our work, this TAR-based reverse genetics platform is highly translatable and responsive to the global SARS-CoV-2 pandemic. As the pandemic continues to unfold, we expect to encounter more variants with genomic changes that can potentially affect transmission, replication and/or immune evasion. By manipulating this platform, we can rapidly generate and study new variants almost in real-time, therefore providing valuable information for updating vaccines and therapeutic strategies. In addition to many applications in SARS-CoV-2 research, this platform also opens up more opportunities to study the fundamental biology of many other viruses.

• What part of your work makes you most proud?

  I started my PhD as an international student with almost no knowledge and technical skills in the field, especially reverse genetics. Despite that, my PhD supervisor, Volker gave me the opportunity to take on this project. I was very happy that I could learn so much over the years - from the smallest things like which labels I should use for tubes which will be frozen, to all the bigger «how-to’s» such as interpreting scientific results, discussing technical approaches, contributing to different projects, and working together with collaborators. Looking back at my PhD journey, I am proud that I tried my best, and that I went from having limited expertise in molecular virology, to being able to secure a niche for myself and expand my knowledge and skillset in the field. It also feels rewarding and exciting, as I think that what I have learned will be a useful basis for whatever challenges I undertake in the future. More importantly, I am glad that this system was successfully established for RNA viruses; it has proven to be highly translatable and I am very proud that my PhD work has contributed to the response against the continuing pandemic. It has since provided the basis, e.g. protocols and material, for many projects at the IVI as well as other international research teams in Europe, Asia, and America. I am hoping to see more and more labs adopting this system for studies of many different viruses, in both fundamental and applied biology.

• How was your time at the IVI? What did you particularly like about it?

  It is definitely one of my favourite times and work experiences I have had so far. I am deeply impressed by and thankful for everyone I have come to know and work with. My supervisor – Volker – is very supportive and understanding in every single part of my PhD work as well as personal matters. On top of that, it was comforting and reassuring to know that anything that I did or wanted to do, I had my colleagues around who always went out of their way to help and to ensure that things would usually work out successfully in the end. Although this, in principle, was my PhD project, the achievements of this work would have never been possible without contributions from the whole team. I want to take this small Q&A as an opportunity to acknowledge all of my colleagues at the IVI/IVB/other institutes, and especially Volker for the tremendous amount of support I have been given over the past years. It is a big honour for me to be a part of this!

• Where do you go from here?

  I think the skillset I learned and developed during my PhD will be useful for my future work, whether it is in academia or industry. In the near future, I am planning to take on a few postdoctoral positions at different universities, and I would like to focus more on the application side of virology. For the long term, it depends on many things, but I would be open to either staying in academia or moving into industry.

• Infographic : transformation-associated recombination (TAR)

  The reverse genetics platform could be applied to generate recombinant viruses much faster than other methods for use in virus biology studies, identification of new drugs, and vaccine development

  

More informations

Thao's first publication described the race to produce the first synthetic SARS CoV-2 virus. Prior to the start of the pandemic, Thao's project had involved developing a versatile platform based on yeast allowing us to efficiently engineer and regenerate different viruses within a much shorter timeframe than classical strategies and dispensing with the need to have clinical samples of the virus-of-interest. The concept for her PhD project, funded by HONOURS – an EU Innovative Training Network was co-conceived by her PhD supervisor – Prof. Volker Thiel (Head of Virology, Institute of Virology and Immunology and professor at the University of Bern), and her PhD advisor – Prof. Jörg Jores (Head of Veterinary Bacteriology at the University of Bern), with the goal to develop strategies to react to future outbreaks of newly emerging zoonotic diseases.