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Deadly 1918 Epidemic Linked to Bird Flu, Scientists
Say
By GINA KOLATA
Published: October 5, 2005
Two teams of federal and university scientists announced
today that they had resurrected the 1918 influenza virus,
the cause of one of history's most deadly epidemics, and had
found that unlike the viruses that caused more recent flu
pandemics of 1957 and 1968, the 1918 virus was actually a
bird flu that jumped directly to humans.
The work, being published in the journals Nature and
Science, involved getting the complete genetic sequence of
the 1918 virus, using techniques of molecular biology to
synthesize it, and then using it to infect mice and human
lung cells in a specially equipped, secure lab at the
Centers for Disease Control and Prevention in Atlanta.
The findings, the scientists say, reveal a small number
of genetic changes that may explain why the virus was so
lethal. The work also confirms the legitimacy of worries
about the bird flu viruses that are now emerging in
Asia.
The new studies find that today's bird flu viruses share
some of the crucial genetic changes that occurred in the
1918 flu. The scientists suspect that with the 1918 flu,
changes in just 25 to 30 out of about 4,400 amino acids in
the viral proteins turned the virus into a killer. The bird
flus, known as H5N1 viruses, have a few, but not all of
those changes.
In a joint statement, Dr. Anthony Fauci, director of the
National Institute of Allergy and Infectious Diseases, and
Dr. Julie Gerberding, director of the Center for Disease
Control and Prevention, said, "The new studies could have an
immediate impact by helping scientist focus on detecting
changes in the evolving H5N1 virus that might make
widespread transmission among humans more likely."
The work also reveals that the 1918 virus is very
different from ordinary human flu viruses. It infects cells
deep in the lungs of mice, and infects lung cells, like the
cells lining air sacs, that normally would be impervious to
flu. And while other human flu viruses do not kill mice,
this one, like today's bird flus, does.
But Dr. Jeffery Taubenberger, chief of molecular
pathology department at the Armed Forces Institute of
Pathology, notes that the bird flus have not yet spread from
human to human. He hopes the 1918 virus will reveal what
genetic changes can allow that to happen, helping scientists
prevent a new pandemic before it starts.
Scientists said the new work was immensely
important, leading the way to identifying dangerous viruses
before it is too late and to finding ways to disable
them.
"This is huge, huge, huge," said John Oxford, a professor
of virology at St. Bartholmew's and the Royal London
Hospital, who was not part of the research team. "It's a
huge breakthrough to be able to put a searchlight on a virus
that killed 50 million people. I can't think of anything
bigger that's happened in virology for many years."
The 1918 flu showed how terrible that disease could be.
It had been "like a dark angel hovering over us," Dr. Oxford
said. The virus spread and killed with terrifying speed,
preferentially striking the young and the healthy. Alfred C.
Crosby, author of "America's Forgotten Pandemic: The
Influenza of 1918," wrote that it "killed more humans than
any other disease in a similar duration in the history of
the world."
But the research, and its publication, also raised
concerns about whether scientists should publish the genetic
sequence of the 1918 virus. And should they actually
resurrect a killer that vanished from the earth nearly a
century ago?
"It is something we take seriously," said Dr. Fauci of
the National Institute of Allergy and Infectious Diseases,
which helped pay for the work. The work was extensively
reviewed, he added, and the National Scientific Advisory
Board for Biosecurity was asked to decide whether the
results should be made public. The board "voted unanimously
that the benefits outweighed the risk that it would be used
in a nefarious manner," Dr. Fauci said.
Others are not sanguine.
Richard H. Ebright, a molecular biologist at Rutgers
University, said he had concerns about the reconstruction of
the virus and about publication of procedures to reconstruct
the virus. "There is a risk verging on inevitability, of
accidental release of the virus; there is also a risk of
deliberate release of the virus," he said, adding that the
1918 flu virus "is perhaps the most effective bioweapons
agent ever known."
But Dr. D. A. Henderson, a resident scholar at the Center
for Biosecurity at the University of Pittsburgh and a
leading expert on bioterrorism, said he agreed with the
decision to reconstruct the virus and publish its genetic
sequence.
"This work is of the greatest importance," he said, "and
it is very important that it be published."
The story of the resurrection of the 1918 flu began in
1995, when Dr. Taubenberger had an idea. He knew about the
1918 flu and the horrors of that pandemic. Medical
authorities at the time found it hard even to describe the
devastation. At Fort Devens, wrote one doctor, Victor
Vaughan, they saw young soldiers' "bodies stacked like
cordwood," dead from the flu. The epidemic, he added,
"visited the remotest corners, taking toll of the most
robust, sparing neither soldier nor civilian, and flaunting
its red flag in the face of science."
It had seemed hopeless, though, to discover what that
virus looked like. Viruses had not been discovered in 1918
and so no one had isolated and saved the one causing that
flu. But Dr. Taubenberger recalled that his institute had a
warehouse of autopsy tissue, established by President
Abraham Lincoln, who had ordered that every time a military
doctor examined a patient and took a tissue sample, a sample
must also be sent to and stored at the pathology institute.
Dr. Taubenberger wondered if he could find lung tissue from
soldiers who died of the 1918 flu and, if so, if he could
extract the virus.
He found tissue from two soldiers, snips of lung
soaked in formalin and encased in little blocks of wax. And
in that tissue was the virus, broken and degraded, just a
few molecules of virus, but there.
One of the patients was Roscoe Vaughan, who got the flu
when he was 21 years old and training at Camp Jackson, S.C.
On Sept. 19, 1918, he reported to sick call. He died on
Sept. 26, unable to breathe, the air sacs in his lungs
filled with fluid. The other patient was James Down, age 30,
who died on the same day at Camp Upton, in New York. The
snippets of their lung tissue had remained untouched for
nearly 80 years.
Then Dr. Taubenberger got a third sample, from a
woman who had died in Alaska when the flu swept through her
village, killing 72 adults, leaving just 5. The dead were
buried in a mass grave in the permafrost, and a retired
pathologist, Johann Hultin, hearing of Dr. Taubenberger's
quest, traveled from his home in San Francisco to the
gravesite in Alaska at his own expense, dug up the grave
with the villager's permission, extracted the woman's still
frozen lung tissue, and sent it to Dr. Taubenberger.
Dr. Taubenberger and his colleagues spent nearly a decade
carefully extracting and piecing together the viral genes,
like putting together a jigsaw puzzle. Along the way, they
published findings that they and others used to try to
understand the 1918 flu, but until now they had only
published the sequences of five of the eight genes. The last
three, which make up half the virus's length, are published
in their paper, in Nature.
In August, Terrence M. Tumpey of the Centers for Disease
Control and his colleagues used that information to
reconstruct the 1918 virus and ask what would happen if they
infected mice and if they infected tissue from human lungs.
And, they asked, would the virus remain as lethal if they
switched some of its genes with genes from today's influenza
viruses?
The scientists took great precautions, the director of
the C.D.C., Julie Gerberding, said at a news conference,
using special labs that were designed to protect the
researchers and prevent the spread of the viruses. "We have
erred on the side of caution at every step of the process,"
Dr. Gerberding said.
And now, the scientists say, they are starting to unmask
that virus's secrets.
In gene-swapping experiments, for example, they put
the hemagglutinin gene from the 1918 virus for one from a
more recent human virus. Suddenly, the reconstructed virus
could no longer replicate in the lungs of mice and no longer
killed the animals. It also could not attach itself to human
lung cells in the lab. Yet the 1918 virus' hemagglutinin
protein differs in just two critical amino acids from the
protein of a typical avian flu virus.
"Now we've shown experimentally that those two changes
are crucial for human adaptation," Dr. Taubenberger said. So
far, he added, they have not been seen in the Asian bird
flus.
The ultimate goal, he says, is to make a checklist
of changes to look for in the bird viruses.
"Now you have all these viruses going around and we don't
know, Is it going to adapt to humans? Is it going to cause a
pandemic? We don't understand the rules," Dr. Taubenberger
said. "There is a lot of science to go."
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