From our Summer 2000 issue. See all out past issues here.

One spring morning in 1918, Albert Gitchell didn’treport for duty. Gitchell, an army cook at Camp Funston, Kansas, had a fever, sore throat, muscle aches, and the chills. He was diagnosed with the flu and sent to his quarters for bed rest. By noon that day 107 of his comrades fell ill. Within two days, the number climbed to 522. Victims collapsed with crippling headaches, their skin ranging from blue to purple to black. Bodies piled up three and four deep on morgue floors. The living coughed violently, fought projectile nosebleeds and organ failure, and within three to five days of infection, most drowned as their lungs filled with bloody fluid.

The so-called Spanish flu pandemic swept from continent to continent, leaving a trail more lethal than the world had seen since the sixteenth century. In less than a year, influenza claimed an estimated 30 million lives—about 22 million more than World War I—and vanished as quickly as it arose.

The twentieth century saw three influenza pandemics: After the Spanish flu, the Asian flu of 1957 killed almost 70,000 in the United States alone; the Hong Kong flu of 1968 killed 36,000. Pandemics come in waves, usually one every 20 years, and according to the Centers for Disease Control and Prevention, the United States can expect one to strike at any time, and leave more than 200,000 dead.

Julius Youngner perches on the edge of his reclining office chair, his back to a window overlooking the rainy streets of Pittsburgh. Trim white hair frames a face flush with frustration as he pounds his fists on his desk. Youngner’s voice, which quickly gives away a childhood spent in New York City, is an unusual mixture of soft and smooth with Manhattan wit and edge. Unless he’s speaking about his research.

“I feel very passionate about this,” he says, his voice suddenly thick with New York aggression. “You want to know why passionate? I’ll tell you why passionate. You ever heard of influenza pandemics? 1918? Killed about 30 million? Or Asia? Hong Kong? That’s why passionate.” Then he leans back in his chair and lets out a slow, deep breath through his nose as he folds his arms behind his neck and calms himself.

Youngner, 79, is a distinguished service professor in the School of Medicine’s Department of Molecular Genetics and Biochemistry. He and his colleagues are using a vaccine they’re pretty sure could stop the next influenza pandemic dead in its tracks. Now they’re holding their breath until they can further develop it.

To understand Youngner’s passion, it’s essential to understand three facts about influenza. First, it comes in different forms: influenza A, B, and C. Youngner doesn’t worry himself with B and C, because they’re not the ones tied to pandemics. That’s a job left solely to influenza A.

Second, each flu virus has spiky proteins on its surface which latch onto the cells lining a host’s respiratory tract—this is how the virus infects. These proteins, hemagglutinin (H) and neuraminidase (N), are the way viruses are identified, and a key to flu pandemics. The strains of flu now in the human population—like the H3N2, which spreads through schools and offices sending people home for a few days or weeks at most—are not completely foreign to our immune systems. We’ve been exposed to these strains for years, so our bodies know how to handle them. But if the surface proteins change, we have no defense.

Third, influenza viruses carry their genetic material on eight segments of single stranded RNA—this means that, instead of having one chromosome with many genes on it, flu has eight little chromosomes, each with genes encoding only 10 gene products. But, because each influenza A strain has a similar eight-segment genome, if two different strains infect the same cell at the same time, they can shuffle genes around, change their HN configurations, and create an influenza strain our bodies have never seen. Sometimes these changes inactivate the virus; sometimes they have no effect at all. But sometimes, they start pandemics and kill millions of people.

Influenza viruses can change through genetic recombination of two known strains or by the introduction of a completely new strain from another species. For example, an influenza strain originating from chickens was detected recently in Hong Kong but was stopped before it could spread.

From the day Private Gitchell turned up sick, it only took about six months for the death toll of the Spanish flu to reach 30 million. Today, once a new influenza strain emerges, it takes probably six months to make a new vaccine. But Youngner and Patricia Dowling, research associate professor of molecular genetics and biochemistry, think they’ve found a way to protect against any strain of influenza A—even those not yet in existence.

Dowling and Youngner are studying a human flu vaccine that has already been proven safe and effective; they propose using it as a powerful antiviral.

In the course of his viral research, Youngner found a mutant strain of influenza A that prevents any normal A strain from growing when they’re both in the same cell. He and Dowling called this phenomenon “dominance.” They published papers showing which gene was responsible for dominance, proposed a live influenza vaccine that contained a mutant to inactivate any live influenza A strain it encountered, and landed a grant from NIH for a small safety trial in humans. The results of the trial: no problem.

To probe whether their dominant mutant would be effective against any strain of influenza A, Youngner and his team used cultured cells to test it against every HN combination they could get their hands on—13 in all. In each case, as long as both the dominant virus and the virulent virus were strains of influenza A, the effect was the same: inactivation. According to Youngner, the implications of this finding could be monumental. If a new flu strain came along, this novel vaccine/antiviral—an attenuated live virus acting as a dominant mutant—could be injected after exposure to halt a pandemic before it took off.

“It wouldn’t make any difference if it were H7N7 or anything else. You could stop it,” he says. But as he talks, he shakes his head. After Youngner’s small trial in humans, his lab’s progress has slowed considerably. It seems Youngner and Dowling’s work goes against widely held beliefs (which Youngner calls dogma) that a vaccine is only used for prevention, not treatment, and that you don’t mix flu viruses because you never know what sort of shuffled virus will come out of the mix. The paralyzing fear: by combining a live virus and a mutant, Youngner may create sort of a “super vaccine,” that could lead to a super virus.

Yet he and his colleagues have completed preliminary studies to show that their idea is safe, and that they do know what kind of virus will come out of the mix—an attenuated one. In fact, virologists around the country, even if they aren’t entirely sold on the proposed vaccine, say they would like to see Youngner and Dowling take the next step. With so much at stake, that day won’t come soon enough for Youngner. The clock is ticking.

Youngner, it seems, is always on the edge or in the middle of the “next big thing.” He has witnessed the birth and growth of the field of virology, and with it, more excitement than he could have imagined. It all started with World War II.

With a doctorate and eight weeks of basic training behind him, 23-yearold Private Youngner found himself in a company of 100 men at Camp Barkley, Texas. One day, 99 shipped out. Youngner was the only man left. He asked what was wrong with him, why he couldn’t go. No one, not even the sergeant, knew the answer.

For two days Youngner scrounged for meals and slept in an empty barracks, until finally, a jeep drove up. The driver hopped out, said, “Get your stuff,” and Youngner soon found himself on a northbound train. His orders— which he couldn’t open until he was en route— simply said he was on special assignment, that the military police were not to bother him, and he was to get off at Knoxville, Tennessee, where he should open a second envelope. That envelope contained only a phone number. At 2:00 in the morning, the young private picked up a pay phone in Knoxville and dialed.

“Hello,” a voice said flatly.

“Uh, this is Private Youngner. . .”

“Where are you?”

“At the train station.”

“Good. There’s a bench behind you. Wait, somebody will be there to get you.”

So Youngner dragged his barracks bag to the bench, where he used it as a pillow, and quickly fell asleep, only to be awakened by a man hovering over him in a leather jacket.

“You Youngner?”

“Yeah.”

“Come with me.”

The two men got into a car and drove into the hills.

“Where are we going?” asked Youngner when he couldn’t contain it anymore.

“Oak Ridge.”

“What’s in Oak Ridge?”

“Don’t ask any questions.”

The next morning, he awoke in a room with about 30 other men, all as confused as he was. Later that day, they were told they were part of the Manhattan Project.

Youngner ended up spending two years in Rochester, New York, studying the effects of uranium salts and determining safe levels of inhalation. Within a few years, he found himself in Pittsburgh, working on another high profile project with the now legendary Jonas Salk.

In 1949, when Youngner arrived in Pittsburgh, Enders, Weller, and Robbins had just proven that polio could grow in cell culture, but Salk and his team were still growing it in monkeys. Youngner knew that until the team grew large quantities of the virus in cell culture, they would never have enough to make a vaccine. He ended up developing trypsinization, a technique for culturing animal cells on a large scale, which exponentially increased the amount of virus they could grow in the lab.

According to Raymond Cypess, president and CEO of the American Type Culture Collection, the largest repository for cell and tissue cultures in the world, trypsinization changed the face of tissue culture investigation.

“Well,” says Youngner with characteristic humility, “it was just a technical advance.”

Indeed, his technical advance quickly became standard procedure in labs around the country.

Once he helped develop the means for producing polio on a large scale, Youngner moved on to inactivate the virus—leaving it crippled enough so it couldn’t cause disease, but active enough to provoke the necessary immune response in patients. He developed tests for quantifying polio and determining its viability; and after six years in the laboratory, the polio vaccine went into what would become a world-famous field trial. Soon, Salk’s voice boomed from television screens and radios around the world, announcing that the vaccine was safe and effective. In the media flurry, Youngner and his colleagues were not publicly acknowledged for their contributions—a point, Youngner will admit, that rankles him. Of course, he’s glad he was able to make the contribution he did. And it’s easy to see that this virologist’s life’s work has not been inspired by headlines. Instead he’s inspired to take on the polios and influenzas of the world. What haunts Youngner is the likelihood of another Spanish flu lurking somewhere around the corner; its tauntings are simply too loud for him to ignore.

He went on to make critical advances in many areas beyond polio: Youngner was the first to demonstrate that nonviral agents could trigger interferon induction, which led to the idea that interferon could have important functions beyond its use as an antiviral. He discovered that some viruses inhibit interferon in cells, which eventually led him to important contributions in the field of persistent viral infections. His advances have helped millions, but they are little known outside a comparatively small circle of peers and contemporaries.

“There are a lot of good scientists in the United States, but Juli goes above that. He’s one of our stars,” says Cypess. “Unfortunately, he’s also one of our most underrated scientists. But he has never sought publicity.”

Youngner chairs the Ethics Committee for the American Society for Microbiology—the biggest biological society in the world, with more than 40,000 members. And in the early ’90s, he was asked to serve on a research integrity adjudicationpanel at the Department of Health and Human Services. He served on a panel for a scientific misconduct trial—the infamous Baltimore Case, in which Thereza Imanishi-Kari was accused of falsifying research data, and Nobel-prize winning researcher David Baltimore risked his own career to defend his colleague. (After several contentious and visible years of investigation, Imanishi-Kari and Baltimore were exonerated, but not left unscathed.)

“Scientists should be obligated to take part in these things. They can’t just say, ‘No, I don’t want to get involved.’ By definition, because of the work they do, they are involved. And I’m not the kind of person who can ignore that. So, I told my wife, ‘I don’t know how long I’m going to be away.’ I went to DC for the trial, and did what I had to do.” He spent two years serving on the panel.

This call to value scientific integrity may well be part of the Youngner genome.

Julius Youngner’s son Stuart is a prominent bioethicist and psychiatry scholar who now heads the Center for Biomedical Ethics at Case Western Reserve School of Medicine in Cleveland.

There’s a very important lesson I learned from Juli,” says Gail Wertz, a former PhD student of Youngner’s and now a professor of microbiology at the University of Alabama. “Listen to the data, listen to the facts, and don’t be saddled with preconceptions. Because preconceptions are inhibitory to science, to developing new concepts, to finding out new information.”

Youngner has been listening to the data for some time now and is ready to make his next move. In his office, looking out at a raindrenched campus, he rubs his forehead, trying to contain his emotion.

“Today,” he whispers, “there’s nothing for an influenza pandemic. If one hits, there’s nothing we can do except start making a vaccine, and by then it’s too late.”

With Dowling, Youngner has gathered data for years through work in humans, ferrets, and now horses. Their equine vaccine, FluAvert, recently hit the veterinary market with a huge splash. The results coming in from all directions have convinced Youngner and Dowling their vaccine is safe and effective—perhaps even more so than they originally thought. Of course, they are quick to point out, they need to undertake more investigations before it can be licensed for human use.

“The thing about flu is, you never know when a new virus is going to come along,” says Dowling.

“And, like any new approach to science, our idea might not work.

“But it would be so important if it does.”