About Associate Professor Fasséli Coulibaly
I always knew I was going to come to New Zealand and Australia... only I thought it would be with a French rugby jersey rather than a lab coat. Research brought me here and I have now been here in the Southern Hemisphere for almost 10 years.
My first taste of research dates back from 1998 as part of a double MSc degree in Chemistry (Montpellier, France) and Biotechnologies (Bristol, UK). I was able to fulfil one of my long-time dreams for my MSc internship: to join the Pasteur Institute in Paris; home of Louis Pasteur himself, Jacques Monod, Françoise Barré-Sinoussi... There I was fortunate to meet Marie Flamand, a molecular virologist with a contagious passion for emerging viruses, who offered me a position in the Arbovirus and Haemorrhagic Fever unit, despite my total lack of lab experience. This was the time when Ebola virus re-emerged in central Africa. The Pasteur Institute was in the spotlight their work on the origin of the virus and a brand new Biosafety level 4 laboratory in Lyon expanded its research capacity on haemorrhagic fevers. Thus, I was already seeing myself travelling across Africa to chase these viruses. But, of course, the biochemist that I was got assigned to a structural biology project rather than Dustin Hoffman's role in Outbreak. It seemed that my most exciting prospect was going to be growing dengue in a Biosafety Level 3 lab. As disappointed as I was, this was probably the turning point of my career and led me to engage in research that would allow me to see virus so much closer than if I had travelled the world to chase them!
The initial project at Pasteur was carried on in collaboration with Felix Rey, a young group leader at the French CNRS returning from Steve Harrison's laboratory at Harvard Medical School. In a few years, Felix had single-handedly created a world-leading laboratory, achieving a true convergence between a profound understanding of the virus world and excellence in X-ray crystallography. In 1999, I started a PhD with Felix on the study of the infectious particles of birnaviruses, emerging pathogens of poultry and salmon. After consulting with Jorge Navaza, the guru of molecular replacement and inventor of AMoRe, and harassing our electron microscopist Jean Lepault, I was able to solve what turned out to be first structure of an icosahedral viral particle determined in France. The birnavirus structure revealed a unique architecture that radically changed our view of the biology of this viral family. Beyond, it suggested a bold evolutionary scenario linking complex RNA viruses such as human rotavirus to simple insect viruses. Up until now, seeing "my" virus on the cover of Cell remains one of the most rewarding moment of my scientific path.
In 2004, I took a research fellow position at the University of Auckland to join Ted Baker's laboratory. This choice certainly departed from the classical career path in France... Yet, I never regretted this decision from a personal or professional point of view. In Ted Baker's laboratory, I initiated work on poxvirus assembly and virulence that I pursue here at Monash University, and contributed to the study of Streptococcus pyogenes pili. These hair-like appendages had only been discovered recently in Gram-positive bacteria and represented an attractive vaccine target for common human diseases. This work primarily carried out by an outstanding PhD student, HaeJoo Kang, resulted in the first structural characterization of a Gram-positive bacterial pilin. This research opened a new field of research that focuses on stabilizing isopeptide bonds, a previously overlooked feature predicted to exist in hundreds of bacterial surface proteins (Science, 07).
At the same time, Peter Metcalf had another challenge for me, where he was trying to determine the structure of the smallest crystals analysed by X-ray crystallography. These infectious crystals called polyhedra are common in insect viruses but were largely uncharacterized because of their extremely small size. Intense research allowed us to push the boundaries of X-ray microcrystallography and determine the structure of cypovirus polyhedra directly purified from infected insects (Nature, 07). While at Monash already and still in collaboration with Peter, I determined the structure of the second class of polyhedra suggesting evolutionary convergence between polyhedra of RNA and DNA viruses (PNAS, 09). Comparative analysis revealed common molecular characteristics that may explain the propensity of these proteins to crystallise in vivo, an attractive feature in view of protein crystallization for structural studies.
In 2007, I attended the Lorne Conference and the meeting of the Australasian Virology society. I received the Young Investigator and the Excellence awards respectively; and thought that Australia seemed like a motivating place to work! A visit of Jamie Rossjohn's laboratory finally convinced me to join the Biochemistry Department at Monash University to establish a research lab. While this really was a one-man lab for the first six months, I benefited from a strong level of support in those critical years from fellow structural biologists but also at a Departmental level from Rob Pike. With the award of an NHMRC CDA in my first year at Monash, I could steadily expand my group over the next 4 years with project funding from the NHMRC and ARC. In addition, three grants from the Gates Foundation supported the development of a new project aiming to design ultra-stable microcapsules for HIV and flu vaccination based on viral polyhedra.
As an ARC Future Fellow (2013-16), my research now focuses on very diverse systems within the virosphere such as poxvirus-directed remodelling of host membranes; the recognition and invasion of target cells by the Hepatitis C virus; and the architecture of the replication machinery of Hendra virus. These have in common a lack of structural information hindering the establishment of a solid paradigm for these complex processes. To address ever more complex questions, I am also interested in the development of novel and hybrid methods in structural biology including X-ray microcrystallography, electron microscopy and NMR.
Whether these methods will be supplanted by the much-hyped free-electron lasers remains to be seen but I bet that, once again, viruses will be the ideal tools to establish and push the limits of structural biology... and I'll surely want to be around!
Crystal elegance reveals viral solutions
Associate Professor Fasseli Coulibaly has found beauty beneath the surface of the most brutal human diseases. His enchantment with the elegance of virus architecture has led to a pioneering study of crystallised insect virus proteins, which could provide the first vaccines to protect against complex diseases such as HIV.
Fasseli is using robust protein microcrystals, which originally occur in insect viruses, to develop a novel platform of viral vaccine delivery. The microcrystals could improve antigen delivery because they can carry the kind of complex vaccines required to fight pathogens such as HIV.
Fasseli says the microcrystals are also very stable, meaning they are well suited to developing countries where refrigeration is not guaranteed.
The research, funded by the Bill and Melinda Gates Foundation, is being undertaken in partnership with a Burnet Institute team led by Associate Professor Rosemary French.
It is based on Fasseli's 2007 breakthrough made at the University of Auckland with Peter Metcalf and Japanese collaborator Hajime Mori, which has been documented in Nature. He used X-ray crystallography to identify the structure of miniscule insect virus proteins for the first time. X-ray crystallography uses synchrotron light to analyse protein crystals in three dimensions.
X-ray crystallography is also a fundamental part of his research to better understand smallpox and hepatitis C viruses. The Australian synchrotron is essential to this work. Its intense X-ray light beams are already being used to reveal how smallpox virus protein crystals are assembled. This could potentially lead to smallpox antivirals.
'It is like switching on a light in a dark room,' Fasseli says. 'If you manage to crack the structure you can understand the virus strategies in their most intimate detail, which can ultimately lead to the development of new drugs.'
Unlike synthetically produced protein crystals, which can take years to develop, Fasseli's insect protein virus can spontaneously crystallise. This increases the protein's stability, making it ideal for use in developing countries - to which Fasseli has a personal connection.
'My father's family is from Mali in West Africa, so it is satisfying to do something that could have an impact there,' the French expatriate says.
Fasseli and his team are also developing crystals for a hepatitis C project with Dr Heidi Drummer's Burnet Institute laboratory, aimed at understanding how the virus invades host cells. This has implications for the design of new vaccines and antivirals.
Besides the potential health benefits that flow from his work, Fasseli says he is drawn to the simple elegance of this microscopic world.
'Viruses are very inventive at finding ways of going around cell defences, so this elegance in the viral processes is what I like,' he says. 'And as for the structural biology, what I really love is what we see. We reveal molecular structures for the first time, but the crystals themselves are beautiful. I love seeing them.'
Understanding how viruses assemble and interact with their cellular hosts not only helps fighting off viral pathogens but it also provides a powerful probe to analyse many fundamental processes in biology. The study of poxviruses has contributed to both of these aims. Poxviruses have been a paradigm in vaccination that culminated in the eradication of smallpox by the end of the 1970's. In addition, poxviruses have been model systems because of their complex infectious cycle and their remarkable ability to hijack and neutralize cellular defense mechanisms. In particular, the assembly of vaccinia has been extensively studied by electron microscopy of infected cells and, more recently, by tomography of infectious vaccinia virus particles. Building on this knowledge, our research aims at elucidating the molecular details of poxvirus assembly using X-ray crystallography.
Teaching in Biochemistry, Molecular Biology and Virology at the undergraduate and post-graduate level.
- Molecular Biology unit in the Biomedical Science course (coordinator)
- Biochemistry Honours course (lecturer)
- Molecular Virology (lecturer)
- Medicine (BMedSc); Nutrition (NUT); Radiology courses (RAD1011) (lecturer)
Mentor – Talented Students Program (also known as the Scholars Program)