Every one of us has picked up a coronavirus infection at some time. Some 5-10 per cent of all common colds are caused by them. In other species, they can be very destructive - many millions of chickens are destroyed each year because of coronavirus infections. And feline peritonitis virus is possibly the major cause of death from infectious disease in kittens in the UK. But in humans they were thought to be relatively benign - until recently.

In March 2003, a life-threatening form of pneumonia exploded onto the world stage. The disease was named severe acute respiratory syndrome (SARS), its cause an entirely new species of coronavirus. Professor Stuart Siddell of the University of Bristol suddenly found his research field had turned red hot.

Professor Siddell has spent almost his entire research career studying these viruses, intrigued by their unconscionably complex genomes and unique way of replicating in their hosts. The genome of coronaviruses, so called because their envelope is fringed with a 'crown' of proteins, consists of a single strand of RNA 30 000 bases long. Two-thirds of this - almost three times the entire polio genome - codes for proteins involved in replication. Curiously, while most viruses requisition a cell's own replication machinery on infection, coronaviruses bring theirs with them. It is not clear why they have opted for self-sufficiency, but it makes coronaviruses an interesting topic to study.

"Many might argue one should go for the simplest system; my argument is to go for a system at the edge of what is possible. The complexity is difficult to work with, but it also makes for a very rich experimental field."

In 1979, when he decided to study coronaviruses, few could even be cultured in the laboratory and recombinant DNA techniques were primitive. But Professor Siddell's instinct for the organism reaped rewards. Working for nearly 20 years in Wuerzburg, Germany, he rose from postdoc to professor. Then, in 2001, the opportunity to take up a chair at Bristol, coupled with a well-equipped laboratory and a Wellcome programme grant, brought him back to the UK.

His research interests are two-fold: to understand the basic molecular biology of the virus and its interaction with the host cell, and from this to identify specific steps in virus replication that can be targeted by antivirals and vaccines.

Coronaviruses are especially challenging to study, because of the difficulty of creating stable DNA copies (cDNA clones) of their genome. Professor Siddell and his team made a major breakthrough in 2001, when they found a way of maintaining infectious cDNA clones in vaccinia viruses. "Before that, material was cloned using bacteria, and the long complex genome proved very unstable. Now, with a robust experimental system, we have the ability to study the function of coronavirus genes in detail. Our hope is to get a far better understanding of not only this virus family but of the fundamental mechanisms that link viral infection and the host immune response."

Outbreak

The work was progressing slowly but surely when, in March 2003, the world changed. From November 2002, reports of an 'atypical pneumonia' had been coming from the Guangdong province of southern China. At the end of February, a World Health Organization (WHO) scientist passed on news of a hospital outbreak in Hanoi, Vietnam. A similar illness broke in Hong Kong. The WHO went on full alert on 12 March, and global panic ensued. The disease was SARS.

The WHO set up a massive effort to identify the organism and understand its spread. In all, 13 laboratories from ten countries went to work, among them the UK's Health Protection Agency (HPA). The HPA called Professor Siddell in to give expert advice: his was one of only two labs in the UK working with these viruses, and he could supply genetic material, as well as immunological reagents.

"It was a remarkable response by any standards," notes Professor Siddell. "In less than a few weeks the world had the organism, its RNA genome and diagnostic tests. But we were lucky - the infection broke out before establishing an uncontrollable base in rural China. And the WHO had a fully operational system developed for influenza pandemics, so the surveillance mechanisms were there. We may not always be so lucky."

Rumour has it that this new disease was also picked up so quickly because the world was on high alert against bioterrorism. In fact, it was nature that provided the first real test. "The epidemic has taught us that nature is a true bioterrorist. These things can come without warning, from anywhere - nature creates new pathogens and it is very difficult to predict what species will be important. People who do so are usually wrong. No one was prepared for a coronavirus to cause such severe illness."

Professor Siddell argues that it also highlights the importance of basic research. "SARS is a prime example of why we have to invest in basic research. Before this, coronaviruses were unfashionable, studying them attracted comparatively little funding. Now, they are on the world stage."

His own work will be given a new boost. "High-quality, long-term immunity and the development of effective antivirals will have to come from such fundamental research. What is being done now is rough and ready, enough for an emergency perhaps, but unlikely to be effective long-term."

He ends with a warning: "This will keep on happening in the future, as it has with HIV and now SARS. The governments and WHO were lucky this time; if it had got a good grip in the area around Guandong before being picked up, there could have been a major world problem. We have to remain vigilant. We need to understand how viruses evolve, recombine and cross the species barrier."

He sees the problems now as political, not scientific. "I think that we may have contained the SARS outbreak in countries like ours with a good health infrastructure, but in my view there will always be residual pockets of SARS, in China and the Far East, from which we will get periodic outbreaks that can cross the world. We cannot afford to become complacent."

External links

• Professor Stuart Siddell at the University of Bristol (Research interests)
• SARS: breaking the chains of transmission (WHO - 5 July 2003)
• Health Protection Agency in the UK

Further reading

Franks T J, et al. (2003) Lung pathology of severe acute respiratory syndrome (SARS): a study of eight autopsy cases from Singapore. Hum. Pathol. 34: 729

Holmes KV. (2003) SARS coronavirus: a new challenge for prevention and therapy. J. Clin. Invest. 111: 1605-9.

Anand K, et al. (2003) Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science. 300: 1763-7. Epub 13 May 2003.

Rota P A, et al. (2003) Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science. 300(5624): 1394-9. Epub 01 May 2003.