special receptors. Some are a poor fit for the specific hemagglutinin subtype that has been inhaled, so the virus keeps going. But some are just right. When the hemagglutinin finds the right receptor, the spiky protein plugs in, allowing the virus to fasten to the outside of the cell like a pirate ship preparing to board another vessel. The human cell seeks to stem the attack by engulfing the virus, then walling it off while trying to digest it with acid. But all the cell has done is speed its own demise. The acid triggers a remarkable transformation of the flu virus. The hemagglutinin turns itself inside out, baring a hidden weapon often likened to a molecular grappling hook. The virus uses this to pull itself even tighter against the cell. The membrane of the virus dissolves, and the viral genes stream into the core of the cell like marauding buccaneers.
A virus cannot reproduce on its own. But once inside the human cell, it finds everything it needs to do so. The viral genes hijack the cell’s own genetic machinery and deliver fresh commands. The innocent cell is soon churning out viral proteins, which are assembled into a brood of new viruses. Within hours, up to a million progeny are ready to explode forth and continue the mission.
But escaping the cell is not so easy. The same receptors on the cell’s surface that first attracted the virus now try to ensnare its offspring. So the neuraminidase steps in to cut them loose, leaving behind the lifeless wreckage of a human cell.
Most flu viruses fall into one of two types, either influenza A or influenza B. While the former can infect a wide array of species besides humans and cause severe illness, the latter tends to be found only in people and is less virulent. Influenza A viruses are further categorized by the proteins on their surface. The strain that struck Hong Kong in 1997 and continues to menace the world today is identified, for instance, by its H5-type hemagglutinin and its N1-type neuraminidase, hence influenza A (H5N1). Like all flu viruses, H5N1 originated in waterfowl, and that’s where most flu strains stay, circulating benignly among wild birds. But over the centuries, a few strains have succeeded in crossing the species barrier, either directly or via intermediate hosts like pigs, to infect people. Over time, these have evolved into the ordinary seasonal viruses that we usually associate with flu, losing much of their bite as humans develop immunity. The prosaic H1N1 strain that in recent years has kept millions of people in bed each winter, for example, is descended from a virus that first infected humans in the early twentieth century, sparking the catastrophic Spanish flu pandemic of 1918. The swine flu strain that erupted in early 2009 is also an H1N1 strain and it too can trace its lineage back to the Spanish flu. But swine flu, which scientists believe emerged only recently from pigs, has diverged so far from other H1 viruses over the years that vaccines against the seasonal H1N1 variant afford little protection against this new arrival.
So what distinguishes avian and human flu strains? Research suggests there may be several factors explaining why some viruses circulate primarily or exclusively in birds while others spread easily among people. Much of the suspicion centers on the receptors in the human respiratory tract. The hemagglutinin of human flu viruses fit better into one type of receptor common in the nose, sinuses, and upper reaches of the airway. Avian viruses, including H5N1, prefer a different type of receptor that is characteristic of birds but relatively rare in the upper airway of humans. Instead, this avian-type receptor is found deep in our lower respiratory system. Scientists surmise this is why H5N1 primarily strikes the lungs, as opposed to the throat and nasal cavity. This could also explain why the virus remains hard to catch, since these avian-type receptors are buried and relatively inaccessible. And when the deep lung does get infected, the virus has a long trip back up the windpipe before being coughed or sneezed into the air, making it hard to spread.
Yet all that separates the world today from an unprecedented calamity could be a slight retooling of the virus, some evolutionary tinkering with the hemagglutinin to make it a better fit for the receptors in the nose and throat, a change in another protein allowing the virus to better replicate in the temperatures of the upper airway, a few other genetic tweaks. Some researchers estimate it would take at most a dozen minor adjustments.
Scientists were aware of H5N1 even before it killed Hoi-ka in 1997. A version of the strain had initially been detected four decades earlier in chickens in Scotland. But no one thought it could jump the species barrier to people. It was strictly avian. That’s why its sudden appearance in the lab sample from Hong Kong was so startling. By making the leap, the virus had satisfied two of three conditions for a pandemic. It was novel—no one had been exposed, so no one had immunity—and it had proven it could infect people. Now it just had to show it could get around.
One day before Hoi-ka died in May 1997, Hong Kong’s public-health laboratory at Queen Mary Hospital had received a specimen of fluid from his windpipe. The sample was one of more than eighty collected every day from patients at the city’s hospitals and clinics. They were all sent to the lab, a small but hectic facility on the seventh floor of the clinical pathology building, erected on a hillside overlooking the western approaches to Victoria Harbor. The waters below were crowded with freighters emerging out of the mists of the South China Sea. Inside, the staff busily tested the samples, sorting them for flu, hepatitis, HIV, and other viruses, categorizing them by subtype when appropriate.
The technicians suspected that Hoi-ka was suffering from influenza and placed his specimen in a cell culture designed to grow the virus. When they looked at it a little later under a microscope, sure enough, it was flu. But what sort? Using an antibody test, they determined it was a kind of influenza A. They assumed it was one of two run-of-the-mill subtypes, either H3N2 or H1N1. The lab had chemical reagents to identify each of these seasonal strains. Yet every time they ran the test, they came up empty. They were stumped.
Dr. Wilina Lim was the adept yet unassuming chief of the virology lab. She spoke in quick, clipped sentences and had a no-nonsense manner that won her the respect of colleagues. Lim was sure the boy’s sample had to be seasonal flu. Since she never expected it to be something utterly new, she wasn’t particularly worried. Lim concluded that one of the ordinary strains must have evolved ever so slightly, which would explain why her lab’s reagents no longer picked it up. Still unaware that the boy had died, Lim decided to divvy up the specimen and ship these samples out for further analysis in specialized flu labs overseas, including the CDC in Atlanta and Mill Hill in London. She also sent a sample to a veteran Dutch virologist named Jan de Jong, who worked at an institute outside Utrecht in the Netherlands. Though they had never met, Lim and de Jong shared a fascination with odd and offbeat viruses and over the years had compared notes from time to time.
More than two months passed. Lim never heard back. Then, on a Friday in early August, she got a call from de Jong. He was coming to Hong Kong, arriving in two days, and would like to see her. He didn’t say why. Lim assumed he was just passing through. She said she’d be pleased to finally meet him. She reserved him a room at the Ramada Hotel in Tsim Sha Tsui, a teeming quarter of narrow streets jammed with shops hawking clothes, shoes, and electronics, where the air was pungent with the smells of tropical cooking and the night skies blazed with neon.
First thing Monday morning, she picked him up. They set off for Queen Mary Hospital. De Jong wanted to see her lab. Lim was behind the wheel of her Nissan, seated on the right like all drivers in Hong Kong, de Jong to her left.
After five minutes, as they approached the harbor tunnel, de Jong looked over and asked, “Do you have any idea what virus you sent me?”
“No, I don’t know,” she responded. She was betting it was some idiosyncratic version of the common H3 strain.
“It’s an H5.”
“What?” she asked. “H5?”
Lim was bewildered. She had never come across an H5 strain. She wondered to herself, “Where did this H5 come from?”
De Jong didn’t say much more about the test results during the ride, but privately he had a suspicion. It could be contamination or some confusion in classifying samples. That was why he wanted to inspect her lab, why he had come all the way to Hong Kong. But once they arrived at the hospital, he quickly saw her operation was well run.
A few hours later, Lim called Margaret Chan, the health department director. The scientists at the CDC in Atlanta, which had independently reached the same results, had yet to inform Hong Kong of their findings. So Lim’s news came as a shock.
“Are you sure?” Chan pressed. “H5N1? I have never heard of H5N1 infecting people.”
“That’s why I’m calling you,” Lim explained.
“Please educate me,” Chan told her.
Chan’s expertise was not infectious diseases. Her early medical interest had been pediatrics, followed later
