BREAKTHROUGH

WHO Yoshihiro Kawaoka University of Wisconsin–Madison

FIELD Virology

ACHIEVEMENT Flu pandemic prevention research.

The virus sits in 2-milliliter vials inside a freezer kept at minus 80 degrees Celsius. At that temperature, in that deep of a deep freeze, the virus is preserved as if in amber, lying in wait. Under a microscope it looks something like a medieval battle weapon, a spherical object stabbed with dozens of little spikes, like the actual virus it was engineered to replicate: the 1918 strain of H1N1, otherwise known as the Spanish flu, a pandemic estimated to have killed more than 40 million people.

The freezer is locked and sealed inside a room made of concrete walls set within a lab surrounded by another set of walls—those outer walls made of 18 inches of concrete, every inch of it reinforced by steel rebar. A box within a box, as it's known in the research world. Entry is through a series of rooms starting with air-locked, submarine-type doors, and the place is rigged with extensive alarms—more than 500 of them in all, spread throughout the building and attached to various pieces of equipment, ready to alert safety personnel and the campus police who monitor the facility around the clock if someone who doesn't belong there tries to get in.

The freezers, the air-locked doors, the alarms—they must all operate perfectly, because perfection is the minimum requirement at the $12.5-million Influenza Research Institute. The facility sits on the outskirts of the University of Wisconsin-Madison, home of the Badgers, whose basketball team went to the Final Four this year. But the building seems a thousand miles from all that.

Assuming they pass the FBI background check necessary even for the administrative assistants who work there, employees entering the lab are required to remove all their street clothes, including undergarments. Once they put on dedicated scrubs, with shoe covers both inside and outside a pair of dedicated garden clogs, they access an anteroom outside the lab. To go into the laboratory, they need a different pair of clogs and shoe covers specific to that space, and must pull on a Tyvek jumpsuit, a hooded respirator outfitted with an air filter, and two pairs of disposable Tyvek gloves. Upon leaving, they take all that off in a specific order, then take a 5-minute shower with soap and water during which they are required to wash all orifices and blow their noses.

The suite that houses the virus is a BSL-3-Ag facility—essentially the most secure building of its kind in existence, give or take one or two features. (The building also houses research on the Ebola virus.) Not one particle of anything is allowed to escape.

The institute was built in 2008 largely to advance the efforts of one man, Yoshihiro Kawaoka, a professor of virology who several months ago published a study detailing his successful bid to build the virus—a strain of influenza that's almost identical to the Spanish flu—from contemporary flu genes. For the study he infected ferrets with the virus and mutated the strain to make it more easily transmissible through respiratory droplets—in other words, from sneezing mammal to sneezing mammal.

In another freezer in another part of the building sits an H5N1 virus that includes genes from the swine flu that killed nearly half a million people in 2009. Kawaoka published his work on that one in 2012. And in yet another deep-freeze storage unit resides another version of that 2009 pandemic strain—one that, according to a published report based on information leaked from a closed-door scientific meeting, is designed to elude human immunities as easily as water flows around rocks.

Why would he do that, even in an impermeable fortress such as that one? At first Kawaoka declined to explain why for this story. Eventually he agreed to meet for 1 hour, in a conference room near the front door of his lab, in the presence of his university department chair. Kawaoka and his minder seemed uncomfortable as the meeting began. The department head smiled with a little too much enthusiasm and seemed to have an itch under his white beard that he didn't want to scratch. Kawaoka rubbed his hands together and stared at a closed laptop as if it were a friend to whom he wanted to tell a secret. He looked as if he were waiting for the question he knew would be asked, the one everyone asks when they hear what he has done, the question even some of his colleagues at the highest levels of the scientific community have asked publicly.

Is Yoshihiro Kawaoka crazy?

Outside the concentric, secure rings of his research facility, and outside the comforts of Madison—the university, and officials in the state of Wisconsin itself, have been unwavering in their support of Kawaoka, to the point of constructing the $12.5 million building in order to fight off other suitors—that question has been debated by hordes of people with varying degrees of credibility.

His study of the H5N1 virus, because it detailed so precisely his methods for rebuilding the virus, was so controversial that a National Institutes of Health advisory panel recommended parts of the research be kept from the public when it was scheduled to appear in 2012 in the journal Nature.

In June Kawaoka and his team published the results of the 1918-like virus study in the journal Cell Host & Microbe, and on the day of publication, before most people had had a chance to read the results, The Guardian ran a story under the headline "Scientists Condemn 'Crazy, Dangerous' Creation of Deadly Airborne Flu Virus." The article referred to the virus as "life-threatening" and quoted Lord May, former chief scientific adviser to the British government, as saying Kawaoka's work was "absolutely crazy." Simon Wain-Hobson, of the esteemed Institut Pasteur in France, told the newspaper, "It's madness."

The scientists who object believe Kawaoka's work violates the Nuremberg Code's rules for research with biological agents, and argue that engineering nonnatural biological pathogens creates the potential for a laboratory accident that would release them and in turn cause a calamity. They believe the risk of the research represents such a danger that it must be stopped.

In July The Independent ran a piece based on a report from a closed-door meeting contending that Kawaoka had engineered a new influenza virus, one that would "render the human immune system defenseless" were it to escape from his lab in Madison. A day later Gizmodo tweeted a link to a recap of the article, with this heading: "Scientist creates new flu virus that can kill all of humanity."

Tweets such as that one, linked to a damning article, combined to make Kawaoka's work on viruses to go viral. Before long, tweets and blog posts and all other forms of electronic outrage spread far and wide through communities who have as much scientific knowledge as chickens do. One tweeter opined that Kawaoka "should be locked in a padded cell." He occasionally receives threats in his email, that if he doesn't stop his work, et cetera. He forwards these to the FBI and tries not to think about them. He tries to think only about work.

There is, after all, no logical end point to what he does. All around us there is influenza, everywhere, in many forms. Waterfowl carry the virus, ducks especially, and more often than not they do not present symptoms, even though they shed the virus at a nearly constant rate, mostly through their intestinal tracts, which is to say when an infected duck shits in a pond, it shits influenza into the pond. Because waterfowl exist wherever there is water, they not only spread the flu every where but they facilitate the mutation of milder forms of flu into dangerous iterations.

Here is one way this might occur: Say an H5N3-infected blue-winged teal, which has the rather apt scientific name Anas discors, heads down the Mississippi Flyway from Madison to Arkansas and lands in a pond to rest and defecate in the pond. Then a pig wallows at the shore and becomes infected with H5N3 and comes down with some preliminary symptoms—runny nose, cough, mild fever. Soon after, a mallard infected with H1N1 arrives on the Mississippi Flyway from central Missouri and lands on and defecates in the same pond, and the unfortunate H5N3-infected pig returns and now becomes infected with the Missouri duck's strain of flu. If a number of conditions come together at that moment inside that pig, the rare event may occur when two forms of virus combine into one—a new virus for which no mammal has developed immunity. If this novel strain of influenza can be transmitted through the air from creature to creature, that's when people start using the word pandemic.

Scientists around the world are pursuing various strategies for dealing with this sort of scenario—with beating back a pandemic should one break out, or preventing one in the first place. But influenza has always been present on earth, even though the virus itself was not isolated until 1902. The flu needs only cells to flourish. A protein in the flu known as hemagglutinin forms a head-like structure that attaches to a cell and essentially breaks through the walls. The virus then infects the cell, uses the cell's machinery to make copies of itself, and kills it. Often the infection remains in the upper respiratory system, which is the kind of influenza we call the seasonal flu, but on rare occasions, owing to the virus's ability to mutate, it will find a way to defeat the defenses holding it back. Consequently, this new, mutated strain will become more virulent and move from the upper respiratory system to multiple organs and have a strong chance of killing its host and spreading rapidly to other hosts.

Influenza infects many animal species naturally—chickens, pigs, horses, and dogs, in addition to waterfowl. In commercial chicken farming, for example, influenza can wipe out millions of birds at a time and in turn cost economies millions, so for financial stability alone, the flu must be controlled. Since many of the same strains of influenza that appear in animals also infect humans, and some are transmissible between species, veterinary researchers are the front line of defense against the disease.

Kawaoka is a veterinary researcher. He has been fascinated with such things since he was a college kid in Japan who wanted to know the inner workings of animals—the muscles, the bones, the blood, the cells—and majored in veterinary medicine. After graduate school and many experiments and papers, he had become an accomplished research veterinarian with a rising reputation in his field. Then he came to the United States to work at the world-renowned St. Jude Children's Research Hospital in Memphis, Tennessee, where he stayed for 14 years, until he had the good fortune, he says, to join the faculty of the University of Wisconsin-Madison, where he's been a professor in the School of Veterinary Medicine since 1997. Kawaoka also holds a professorship at the University of Tokyo, where he spends between two and three months a year, and he regularly gives presentations of his research all over the world. In 2006 he won the Robert Koch Award, which, in the world of microbiology, is akin to the Nobel. Everyone in the field knows of him and of his work, and the demands upon him, from both the scientific community and the scientific press, are relentless. Kawaoka says he has worked all day, seven days a week, since his last vacation, which was so long ago he no longer recalls what year it was.

He's 58 years old, but he somehow looks not a day older than 35—lean, no bags under the eyes—and he smiles a lot and has a warm laugh. He's been married for a long time and has a 33-year-old son who lives on the West Coast. His commute is a 15-minute drive in a Toyota, during which he likes to listen to female jazz vocalists. When he parks in front of his lab each morning, before he gathers his briefcase and heads in, he sometimes pauses to note the fine weather or to watch birds flying overhead. He may think more thoughts than the average person during the course of his day, but he keeps most of them to himself.

As the interview progresses, Kawaoka begins to lean into the conversation, to become more animated. He has an appealing self-deprecating streak. If you ask him if it's miraculous that he can engineer new viruses, he throws up his hands and chuckles and says, "Well, my sister couldn't do it." Any scientist with the proper training, he says, can pursue the same research. Despite the long hours, despite the controversies, he says he loves his work, and the main reason is that it's fun. And what's fun, he says, is learning new things. Relentless inquiry, for him, is the greatest joy in the world. He shrugs as if to say, what else could you want out of life? Instead, he says, "When my work is no longer fun, I will quit."

Which still doesn't get to the heart of the question about re-creating the 1918 flu: Why?





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Here is one thing most of the general public doesn't understand: There is no way to defeat the flu. Kawaoka shakes his head. It can never be eradicated from the earth.

What if you kill all the ducks?

He lets out a laugh at the thought of that. He extends his arms to the universe and says, "There are too many of them!"

One realistic way to stop the flu from at some point turning into a pandemic, in Kawaoka's opinion, would be to stop the transmission of influenza from birds and other animals to humans, and in order to do that, he believes he must continue with his specific type of work, which is called gain-of-function research. Remember how the flu can mutate in nature—the unfortunate pig? Kawaoka imitates this phenomenon in his lab. He manipulates viruses—or mutates them—to study them. By doing that, he says we can learn how to react when a new virus occurs by mutation in nature—a virus such as the Spanish flu. If we know how a mutation works—if we have observed it and cataloged its behavior—then we can assess whether existing countermeasures such as vaccines and antiviral drugs are effective in combating it. If we know that they are, then we can create a stockpile. Through this process, his research aims to save lives.

So far, ferrets and mice constitute the only casualties of Kawaoka's research (ferrets are considered to be the best animal for virus testing because they react to the flu in much the same way humans do). To test the virulence of a given mutated flu, Kawaoka infects those species, but the animals do not pass from this world in vain. Kawaoka's controversial studies have shown that the lab-generated mutations are treatable with the antiviral drug oseltamivir, otherwise known as Tamiflu, which suggests that the dangerous viruses in his lab are not as dangerous as they sound.

Indeed, it turns out that after a virulent new flu spreads, after all the misery it may cause, humans develop resistance to it. The 2009 swine flu? That now circulates as a seasonal malady, and if the 1918 virus were to return, even in Kawaoka's re-created form, we would have nearly complete immunity to it. You could probably spread that form of the flu on toast with no ill effect. This is difficult to believe, given the angst over his work, but when pressed Kawaoka becomes more animated than at any point in the interview, shaking his head like a dog shaking off water. Even the supposed wipe-out-the-world virus—from the article in the Independent—was completely misunderstood, which resulted in a story that was "thoroughly inac curate," says the university's biosafety manager, Rebecca Moritz.

You may wonder why he doesn't simply say as much when he's under seige. But if he uses that defense—See? It's harmless!—rather than making a case for the work's importance, he would have no way to argue for research with viruses that truly are hazardous.

How does it feel to be the target of harsh criticism, some of it obviously ill-informed, as he was this summer? Some of Kawaoka's brightness peels away, and he slumps forward. Then he looks up.

"It makes me sad," Kawaoka says.

He explains. It's not because the attacks hurt his feelings or make him feel threatened. He says he just wishes his critics understood that he is doing his research in order to try to help protect humanity, not to wipe it out. This is partly where he finds the fortitude to press on—the hope that one of his discoveries could save untold lives. He never contemplates giving up on the complicated, sometimes dangerous, and essential work of understanding what could happen in nature and trying to get ahead of it.

He acknowledges that his work is risky, that there is no such thing as zero risk, but if the forecast calls for a 10 percent chance of rain, we don't carry an umbrella. True, the stakes are much higher with hazardous viruses, and he understands the fear with his work: What if he engineers a virus for which existing medications don't work? That is a risk, in his opinion, worth taking. Kawaoka, who is now also conducting studies on the Ebola virus, insists he practices great caution and agrees with the safety regulations for his lab—even though, he says, the people working there are more likely to get the flu from their children than at work. "You are at much more risk of catching the flu," he says, "if you go to the park and feed the ducks."

On the day he says this, the weather in Madison is as perfect as a person could imagine: sunny, small cumulus clouds dotting a blue sky, low humidity, temperatures drifting toward the high 70s, and a gentle breeze. Just down the road, in the Teal Pond Wetlands at the university's arboretum, ducks and geese land in the marshes or take wing and travel along the flyway that extends from the Mississippi River to lakes Monona and Mendota, the two large lakes in Madison, and to the isthmus in between where 43,000 students study, work, live, and play.

On the campus's Memorial Union Terrace, a few hundred people—undergrads, families with children, some professor types—have gathered to relax in the famous steel sunburst chairs and take in the view of Lake Mendota. They drink beer and eat bratwurst and seem uniformly content. Sailboats dot the water. Closer to shore, a few students try paddleboarding. Just now this seems like one of the loveliest places in the world.

Next to the pier, there is a sign in the water: FOR SWIMMER HEALTH, DO NOT FEED THE DUCKS. Four juvenile mallards swim in frenzied circles nearby, scrabbling for a bratwurst bun some idiot has chucked into the water. The ducks jostle and quack and snap till the bun becomes what looks like white stars in a greenish-blue firmament, then all traces of it vanish and the mallards settle down. One hops onto the pier and defecates on it.

A couple of teenage girls in swimsuits approach the pier in bare feet, laughing and talking about paddleboarding, and they scare off the mallard. One of the girls steps on the fresh duck poop, but she doesn't notice. She's going to hop on a paddleboard for the afternoon. Four miles away, in a place she'll probably never know or see, a freezer hums steadily in the dim light, protecting the work of a scientist who cares only about keeping her safe.

Reconstructing a Killer

An oversimplified look at how Kawaokare-created the 1918 Spanish flu. —Kevin Dupzyk

STEP 1: Reverse Engineer the Nearly 100-Year-Old Virus.

For each gene of the 1918 virus, Kawaoka found a modern version—from various bird viruses—that produced a near-identical protein. Then he assembled their gene sequences, resulting in a patchwork strain genetically similar to the one from 1918, whose genome was reconstructed in 2005.

STEP 2: Make Sure It Works.

Namely, that it causes an infection. The manufactured virus didn't get ferrets as sick as the real 1918 flu did, but it provoked more severe symptoms than a seasonal virus used as a control.

STEP 3: Find Out What Allows the Virus to Spread.

A pandemic only happens when a virus is highly communicable. He put infected ferrets in cages next to healthy ones, but his engineered flu didn't spread. He swapped gene sequences from the 1918 flu into his strain until he determined which were key to spreading infection.

STEP 4: Mutate the Crucial Genes.

In nature a scientist obviously isn't manually swapping gene sequences. Kawaoka needed to see how his engineered virus would behave if it had known mutations thought to be necessary for bird viruses to spread in mammals. He created different combinations of these mutations and infected ferrets again.

STEP 5: Repeat as Needed.

One set of ferrets showed symptoms more similar to those of the real 1918 flu. It turned out the virus had gained additional mutations. He repeated the ferret experiment. Again the virus mutated. In all he attained 10 mutations. Next step: Watch to see if a similar virus appears in nature.





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Sasha Nialla

Victoria Will

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