HONG KONG--Yi Guan has plenty of experience at ground zero of an epidemic. In spring 2003, the virologist at Hong Kong University (HKU) isolated the SARS virus from masked palm civets in a wild animal market in China's Guangdong Province. When the virus flared up again in late 2003, his team's recommendation to slaughter all captive civets in the area may have been the key to stopping SARS in its tracks: The virus has not reemerged since.
Although SARS is his claim to fame, Guan has spent most of his career studying influenza after earning a Ph.D. in swine flu under eminent flu expert Robert Webster of St. Jude Children's Research Hospital in Memphis, Tennessee. He is currently collaborating with Webster's group.
Guan has been highly critical of what he sees as WHO's slow response to the H1N1 emergency. He took a break from marathon hours in the lab and 3 a.m. conference calls with U.S. colleagues to speak with ScienceInsider.
Q: Where did WHO go wrong?
Y.G.: Friday night [24 April], I was in Bombay airport, waiting for a flight back to Hong Kong. They [WHO and CDC] already knew the situation in Mexico. Mexico said they had human-to-human transmission, and MMWR [Morbidity and Mortality Weekly Report] reported three cases in America--these cases were community cases. Already it was an outbreak in the U.S., although it wasn't severe, it didn't kill people. I was still optimistic we could contain H1N1. Then nothing happened all weekend.
Q: So WHO should have raised the alert level sooner?
Y.G.: Yes! WHO should have gone to level 4 or even level 5 on Friday. We missed the golden period to contain the virus. Several hours could be another couple hundred cases. Every second was valuable at that time. We made a huge mistake. From then on, it was countdown to the pandemic.
Q: Why have there been dozens of deaths in Mexico but mostly mild cases in other countries?
Y.G.: We still do not have the clues why this virus seems to be milder outside Mexico.
At the initial stage of reassortment [genetic mixing with other viruses], most influenza viruses have low fitness. Their genomes are composed of eight gene segments. The reassortment event forms a new family with eight members. You can say they can have a family conflict. This kind of conflict makes reassorted viruses' behavior very weird.
Q: Is it surprising how quickly H1N1 adapted?
Y.G.: All viruses, after interspecies transmission, will evolve fast. But why this H1N1 could become successful at efficient human-to-human transmission is still unknown. We have a knowledge gap about how influenza A viruses build up their pandemicity in humans. As swine H1N1 has being circulating in pigs since 1918, it has accumulated [many] differences from human H1N1 virus. So, for human beings, it looks like a novel subtype, as most human individuals lack immunity to this swinelike H1N1. This is one of the most important conditions for pandemic emergence. Whether the novel virus will develop into a more virulent strain--just like the Spanish flu did in the fall of 1918 to kill more people--we still don't have any idea.
Q: It depends on further mutations?
Y.G.: It depends on mutations and whether the virus further reassorts with other viruses--like H5N1. That could be a super nightmare for the whole world.
Q: You're talking about the Armageddon virus?
Y.G.: The chance is very, very low that these two viruses will mix together, but we cannot rule out the possibility. Now, H5N1 is in more than 60 countries. It's a panzootic, present everywhere except North America.
Q: If the nightmare comes true?
Y.G.: If that happens, I will retire immediately and lock myself in the P3 lab. H5N1 kills half the people it infects. Even if you inject yourself with a vaccine, it may be too late. Maybe in just a couple hours it takes your life.
Q: What have you learned from your work on H1N1 so far?
Y.G.: We almost figured out how H1N1 virus was generated--its evolutionary pathway. The virus has all the genetic markers that allow us to trace how and where it comes from. We have a huge tree [a family tree of influenza variants], a long history. My former supervisor here at HKU, Ken Shortridge, started flu surveillance in 1976. At each point where influenza virus changes, we made a record.
Q: Any truth to the speculation [in Chinese media] that the virus originated in China?
Y.G.: Actually, in this case, we cannot blame China. What's interesting, the virus reassorted four or five times.
Q: Is it surprising that you can have so much reassortment and still have a viable organism?
Y.G.: Yes, that's right! Basically, we figured out where the virus originated, and we are writing a paper. But where and how this jumped into humans--that needs to be worked out in the U.S.
Q: What are some other major knowledge gaps?
Y.G.: Every year we meet many reassorted viruses, we don't know which can jump to humans. Which one could become a pandemic? Nobody knows. We lack the knowledge to distinguish which virus has pandemic potential. This is a big limitation.
Many of us influenza researchers, we blame ourselves; if we have this knowledge, then we can get rid of pandemics in human beings. Life becomes very meaningful if you do something like that. SARS has been averted for 6 years. But I've been working 20 years on flu. I still don't know which variant will cause a pandemic. I feel frustrated by this. In my lifetime, I won't be able to solve this. Hopefully, my students will.
Q: Are you surprised there hasn't been a SARS outbreak since 2003?
Y.G.: The ecosystem was disrupted. No more large amounts of wild animals in the market, just next to your door. It was like a big mixing vessel. Like a PCR [polymerase chain reaction] machine. Put the virus in and amplify it. That's why my group has worked so hard to study the H5N1 ecosystem. We sample around 50,000 to 60,000 birds per year, about 200 per day. Like a factory. It's very mechanical work, very dangerous work.
Q: Somebody has to do it.
Y.G.: Yes! How else can you compare an outbreak with peaceful times? This information will be vital to understand H1N1.
You can find our full coverage of swine flu--including breaking news and analysis of the latest developments—here .