Capturing a Killer Flu VIRUS |
The
deadliest flu strain in history has been resurrected. What can the 1918
VIRUS reveal about why it killed millions and where more like it may be
lurking?
On September 7, 1918,
at the height of World War I, a soldier at an army training camp
outside Boston came to sick call with a high fever. Doctors diagnosed
him with meningitis but changed their minds the next day when a dozen
more soldiers were hospitalized with respiratory symptoms. Thirty-six
new cases of this unknown illness appeared on the 16th. Incredibly, by
September 23rd, 12,604 cases had been reported in the camp of 45,000
soldiers. By the end of the outbreak, one third of the camp's
population would come down with this severe disease, and nearly 800 of
them would die. The soldiers who perished often developed a bluish skin
color and struggled horribly before succumbing to death by suffocation.
Many died less than 48 hours after their symptoms appeared, and at
autopsy their lungs were filled with fluid or blood.
Because this unusual
suite of symptoms did not fit: any known malady, a distinguished
pathologist of the era, William Henry Welch, speculated that "this must
be some new kind of infection or plague." Yet the disease was neither
plague nor even new. It was just influenza. Still, this particularly
virulent and infectious strain of the flu virus is thought to have
killed as many as 40 million people around the world between 1918 and
1919.
This most lethal flu
outbreak in modern history disappeared almost as quickly as it emerged,
and its cause was long believed lost to time. No one had preserved
samples of the pathogen for later study because influenza would not be
identified as a virus until the 1930s. But thanks to incredible
foresight by the U.S. Army Medical Museum, the persistence of a
pathologist named Johan Hultin, and advances in genetic analysis of old
tissue samples, we have been able to retrieve parts of the 1918 virus
and study their features. Now, more than 80 years after the horrible
natural disaster of 19181919, tissues recovered from a handful of
victims are answering fundamental questions both about the nature of
this pandemic strain and about the workings of influenza viruses in
general.
The effort is not
motivated merely by historical curiosity. Because influenza viruses
continually evolve, new influenza strains continually threaten human
populations. Pandemic human flu viruses have emerged twice since
1918--in 1957 and 1968. And flu strains that usually infect only
animals have also periodically caused disease in humans, as seen in the
recent outbreak of avian influenza in Asia. Our two principal goals are
determining what made the 1918 influenza so virulent, to guide
development of influenza treatments and preventive measures, and
establishing the origin of the pandemic virus, to better target
possible sources of future pandemic strains.
IN MANY RESPECTS, the 1918 influenza pandemic
was similar to others before it and since. Whenever a new flu strain
emerges with features that have never been encountered' by most
people's immune systems, widespread flu outbreaks are likely. But
certain unique characteristics of the 1918 pandemic have long remained
enigmatic.
For instance, it was exceptional in both its
breadth and depth. Outbreaks swept across Europe and North America,
spreading as far as the Alaskan wilderness and the most remote islands
of the Pacific. Ultimately, one third of the world's population may
have been infected. The disease was also unusually severe,' with death
rates of 2.5 to 5 percent--up to 50 times the mortality seen in other
influenza outbreaks.
By the fall of 1918 everyone in Europe was
calling the disease the "Spanish" influenza, probably because neutral
Spain did not impose the wartime censorship of news about the outbreak
prevalent in combatant countries. The name stuck, although the first
outbreaks, or spring wave, of the pandemic seemingly arose in and
around military camps in the U.S. in March 1918. The second, main wave
of the global pandemic occurred from September to November 1918, and in
many places yet another severe wave of influenza hit in early 1919.
Antibiotics had yet to be discovered, and most
of the people who died during the pandemic succumbed to pneumonia
caused by opportunistic bacteria that infected those already weakened
by the flu. But a subset of influenza victims died just days after the
onset of their symptoms from a more severe viral pneumonia-caused by
the flu itself--that left their lungs either massively hemorrhaged or
filled with fluid. Furthermore, most deaths occurred among young adults
between 15 and 35 years old, a group that rarely dies from influenza.
Strikingly, people younger than 65 years accounted for more than 99
percent of all "excess" influenza deaths (those above normal annual
averages) in 1918-1919.
Efforts to understand the cause of the 1918
pandemic and its unusual features began almost as soon as it was over,
but the culprit virus itself remained hidden for nearly eight decades.
In 1951 scientists from the University of Iowa, including a graduate
student recently arrived from Sweden named Johan Hultin, went as far as
the Seward Peninsula of Alaska seeking the 1918 strain [see box on page
71]. In November 1918 flu spread through an Inuit fishing village now
called Brevig Mission in five days, killing 72 people--about 85 percent
of the adult population. Their bodies had since been buried in
permafrost, and the 1951 expedition members hoped to find the 1918
virus preserved in the victims' lungs. Unfortunately, all attempts to
culture live influenza virus from these specimens were unsuccessful.
In 1995 our group initiated an attempt to find
the 1918 virus using a different source of tissue: archival autopsy
specimens stored at the Armed Forces Institute of Pathology (AFIP). For
several years, we had been developing expertise in extracting fragile
viral genetic material from damaged or decayed tissue for diagnostic
purposes. In 1994, for instance, we were able to use our new techniques
to help an AFIP marine mammal pathologist investigate a mass dolphin
die-off that had been blamed on red tide. Although the available
dolphin tissue samples were badly decayed, we extracted enough pieces
of RNA from them to identify a new virus, similar to the one that
causes canine distemper, which proved to be the real cause of the
dolphin deaths. Soon we began to wonder if there were any older medical
mysteries we might solve with our institute's resources.
A descendant of the U.S. Army Medical Museum
founded in 1862, the AFIP has grown along with the medical specialty of
pathology and now has a collection of three million specimens. When we
realized that these included autopsy samples from 1918 flu victims, we
decided to go after the pandemic virus. Our initial study examined 78
tissue samples from victims of the deadly fall wave of 1918, focusing
on those with the severe lung damage characteristic of patients who
died rapidly. Because the influenza virus normally clears the lungs
just days after infection, we had the greatest chance of finding virus
remnants in these victims.
The standard practice of the era was to
preserve autopsy specimens in formaldehyde and then embed them in
paraffin, so fishing out tiny genetic fragments of the virus from these
80-year-old "fixed" tissues pushed the very limits of the techniques we
had developed. After an agonizing year of negative results, we found
the first influenza-positive sample in 1996, a lung specimen from a
soldier who died in September 1918 at Fort Jackson, S.C. We were able
to determine the sequence of nucleotides in small fragments Of five
influenza genes from this sample.
But to confirm that the sequences belonged to
the lethal 1918 virus, we kept looking for more positive cases and
identified another one in 1997. This soldier also died in September
1918, at Camp Upton, N.Y. Having a second sample allowed us to confirm
the gene sequences we had, but the tiny quantity of tissue remaining
from these autopsies made us worry that we would never be able to
generate a complete virus sequence.
A solution to our problem came from an
unexpected source in 1997: Johan Hultin, by then a 73-year-old retired
pathologist, had read about our initial results. He offered to return
to Brevig Mission to try another exhumation of 1918 flu victims
interred in permafrost. Forty-six years after his first attempt, with
permission from the Brevig Mission Council, he obtained frozen lung
biopsies of four flu victims. In one of these samples, from a woman of
unknown age, we found influenza RNA that provided the key to sequencing
the entire genome of the 1918 virus.
More recently, our group, in collaboration
with British colleagues, has also been surveying autopsy tissue samples
from 1918 influenza victims from the Royal London Hospital. We have
been able to analyze flu virus genes from two of these cases and have
found that they were nearly identical to the North American samples,
confirming the rapid worldwide spread of a uniform virus. But what can
the sequences tell us about the virulence and origin of the 1918
strain? Answering those questions requires a bit of background about
how influenza viruses function and cause disease in different hosts.
EACH OF THE THREE novel influenza strains that
caused pandemics in the past 100 years belonged to the type A group of
flu viruses. Flu comes in three main forms, designated A, B and C. The
latter two infect only humans and have never caused pandemics. Type A
influenza viruses, on the other hand, have been found to infect a wide
variety of animals, including poultry, swine, horses, humans and other
mammals. Aquatic birds, such as ducks, serve as the natural "reservoir"
for all the known subtypes of influenza A, meaning that the virus
infects the bird's gut without causing symptoms. But these wild avian
strains can mutate over time or exchange genetic material with other
influenza strains, producing novel viruses that are able to spread
among mammals and domestic poultry.
The life cycle and genomic structure of
influenza A virus allow it to evolve and exchange genes easily. The
virus's genetic material consists of eight separate RNA segments
encased in a lipid membrane studded with proteins [see top illustration
on opposite page]. To reproduce, the virus binds to and then enters a
living cell, where it commandeers cellular machinery, inducing it to
manufacture new viral proteins and additional copies of viral RNA.
These pieces then assemble themselves into new viruses that escape the
host cell, proceeding to infect other cell. No proofreading mechanism
ensures that the RNA copies are accurate, so mistakes leading to new
mutations are common. What is more, should two different influenza
virus strains infect the same cell, their RNA segments can mix freely
there, producing progeny viruses that contain a combination of genes
from both the original viruses. This "reassortment" of viral genes is
an important mechanism for generating diverse new strains.
Different circulating influenza A viruses are
identified by referring to two signature proteins on their surfaces.
One is hemagglutinin (HA), which has at least 15 known variants, or
subtypes. Another is neuraminidase (NA), which has nine subtypes.
Exposure to these proteins produces distinctive antibodies in a host,
thus the 1918 strain was the first to be named, "HINI," based on
antibodies found in the bloodstream of pandemic survivors. Indeed, less
virulent descendants of H1N1 were the predominant circulating flu
strains until 1957, when an H2N2 virus emerged, causing a pandemic.
Since 1968, the H3N2 subtype, which provoked the pandemic that year,
has predominated.
The HA and NA protein subtypes present on a
given influenza A virus are more than just identifiers; they are
essential for viral reproduction and are primary targets of an infected
host's immune system. The HA molecule initiates infection by binding to
receptors on the surface of certain host cells. These tend to be
respiratory lining cells in mammals and intestinal lining cells in
birds. The NA protein enables new virus copies to escape the host cell
so they can go on to infect other cells.
After a host's first exposure to an HA
subtype, antibodies will block receptor binding in the future and are
thus very effective at preventing reinfection with the same strain. Yet
flu viruses with HA subtypes that are new to humans periodically
appear, most likely through reassortment with the extensive pool of
influenza viruses infecting wild birds. Normally, influenza HAs that
are adapted to avian hosts bind poorly to the cell surface receptors
prevalent in the human respiratory tract, so an avian virus's HA
binding affinity must be somewhat modified before the virus can
replicate and spread efficiently in humans. Until recently, existing
evidence suggested that a wholly avian influenza virus probably could
not directly infect humans, but 18 people were infected with an avian
H5N1 influenza virus in Hong Kong in 1997, and six died.
Outbreaks of an even more pathogenic version
of that H5N1 strain became widespread in Asian poultry in 2003 and
2004, and more than 30 people infected with this virus have died in
Vietnam and Thailand.
The virulence of an influenza virus once it
infects a host is determined by a complex set of factors, including how
readily the virus enters different tissues, how quickly it replicates,
and the violence of the host's immune response to the intruder. Thus,
understanding exactly what made the 1918 pandemic influenza strain so
infectious and so virulent could yield great insight into what makes
any influenza strain more or less of a threat.
WITH THE 1918 RNA we have retrieved, we have
used the virus's own genes as recipes for manufacturing its component
parts--essentially re-creating pieces of the killer virus itself. The
first of these we were eager to examine was the hemagglutinin protein,
to look for features that might explain the exceptional virulence of
the 1918 strain.
We could see, for example, that the part of
the 1918 HA that binds with a host cell is nearly identical to the
binding site of a wholly avian influenza HA [see illustration on page
69]. In two of the 1.918 isolates, this receptor-binding site differs
from an avian form by only one amino acid building block. In the other
three isolates, a second amino acid is also altered. These seemingly
subtle mutations may represent the minimal change necessary to allow an
avian-type HA to bind to mammalian-type receptors.
But while gaining a new binding affinity is a
critical step that allows a virus to infect a new type of host, it does
not necessarily explain why the 1918 strain was so lethal. We turned to
the gene sequences themselves, looking for features that could be
directly related to virulence, including: two known mutations in other
flu viruses. One involves the HA gene: to become active in a cell, the
HA protein must be cleaved into two pieces by a gut-specific
protein-cutting enzyme, or protease, supplied by the host. Some avian
H5 and H7 subtype viruses acquire a gene mutation that adds one or more
basic amino acids to the cleavage site, allowing HA to be activated by
ubiquitous proteases. In chickens and other birds, infection by such a
virus causes disease in multiple organs and even the central nervous
system, with a very high mortality rate. This mutation has been
observed in the H5N1 viruses currently circulating in Asia. We did not,
however, find it in the 1918 virus.
The other mutation with a significant effect
on virulence has been seen in the NA gene of two influenza virus
strains that infect mice. Again, mutations at a single amino acid
appear to allow the virus to replicate in many different body tissues,
and these flu strains are typically lethal in laboratory mice. But we
did not see this mutation in the NA of the 1918 virus either.
Because analysis of the 1918 virus's genes was
not revealing any characteristics that would explain its extreme
virulence, we initiated a collaborative effort with several other
institutions to re-create parts of the 1918 virus itself so we could
observe their effects in living tissues.
A new technique called plasmid-based reverse
genetics allows us to copy 1918 viral genes and then combine them with
the genes of an existing influenza strain, producing a hybrid virus.
Thus, we can take an influenza strain adapted to mice, for example, and
give it different combinations of 1918 viral genes. Then, by infecting
a live animal or a human tissue culture with this engineered virus, we
can see which components of the pandemic strain might have been key to
its pathogenicity.
For instance, the 1918 virus's distinctive
ability to produce rapid and extensive damage to both upper and lower
respiratory tissues suggests that it replicated to high numbers and
spread quickly from cell to cell. The viral protein NS1 is known to
prevent production of type I interferon (IFN)--an "early warning"
system that cells use to initiate an immune response against a viral
infection. When we tested recombinant viruses in a tissue culture of
human lung cells, we found that a virus with the 1918 NS1 gene was
indeed more effective at blocking the host's type I IFN system.
To date, we have produced recombinant
influenza viruses containing between one and five of the 1918 genes.
Interestingly, we found that any of the recombinant viruses possessing
both the 1918 HA and NA genes were lethal in mice, causing severe lung
damage similar to that seen in some of the pandemic fatalities. When we
analyzed these lung tissues, we found signatures of gene activation
involved in common inflammatory responses. But we also found higher
than normal activation of genes associated with the immune system's
offensive soldiers, T cells and macrophages, as well as genes related
to tissue injury, oxidative damage, and apoptosis, or cell suicide.
More recently, Yoshihiro Kawaoka of the
University of Wisconsin-Madison reported similar experiments with 1918
flu genes in mice, with similar results. But when he tested the HA and
NA genes separately, he found that only the 1918 HA produced the
intensive immune response, suggesting that for reasons as yet unclear,
this protein may have played a key role in the 1918 strain's virulence.
These ongoing experiments are providing a
window to the past, helping scientists understand the unusual
characteristics of the 1918 pandemic. Similarly, these techniques will
be used to study what types of changes to the current H5N1 avian
influenza strain might give that extremely lethal virus the potential
to become pandemic in humans [see box on opposite page]. An equally
compelling question is how such virulent strains emerge in the first
place, so our group has also been analyzing the 1918 virus's genes for
clues about where it might have originated.
THE BEST APPROACH to analyzing the
relationships among influenza viruses is phylogenetics, whereby
hypothetical family trees are constructed using viral gene sequences
and knowledge of how often genes typically mutate. Because the genome
of an influenza virus consists of eight discrete RNA segments that can
move independently by reassortment, these evolutionary studies must be
performed separately for each gene segment.
We have completed analyses of five of the 1918
virus's eight RNA segments, and so far our comparisons of the 1918 flu
genes with those of numerous human, swine and avian influenza viruses
always place the 1918 virus within the human and swine families,
outside the avian virus group [see box on next page]. The 1918 viral
genes do have some avian features, however, so it is probable that the
virus originally emerged from an avian reservoir sometime before 1918.
Clearly by 1918, though, the virus had acquired enough adaptations to
mammals to function as a human pandemic virus. The question is, where?
When we analyzed the 1918 hemagglutinin gene,
we found that the sequence has many more differences from avian
sequences than do the 1957 H2 and 1968 H3 subtypes. Thus, we concluded,
either the 1918 HA gene spent some length of time in an intermediate
host where it accumulated many changes from the original avian
sequence, or the gene came directly from an avian virus, but one that
was markedly different from known avian H1 sequences.
To investigate the latter possibility that
avian H1 genes might have changed substantially in the eight decades
since the 1918 pandemic, we collaborated with scientists from the
Smithsonian Institution's Museum of Natural History and Ohio State
University. After examining many preserved birds from the era, our
group isolated an avian subtype H1 influenza strain from a Brant goose
collected in 1917 and stored in ethanol in the Smithsonian's bird
collections. As it turned out, the 1917 avian H1 sequence was closely
related to modern avian North American H1 strains, suggesting that
avian H1 sequences have changed little over the past 80 years.
Extensive sequencing of additional wild bird H1 strains may yet
identify a strain more similar to the 1918 HA, but it may be that no
avian H1 will be found resembling the 1918 strain because, in fact, the
HA did not reassort directly from a bird strain.
In that case, it must have had some
intermediate host. Pigs are a widely suggested possibility because they
are known to be susceptible to both human and avian viruses. Indeed,
simultaneous outbreaks of influenza were seen in humans and swine
during the 1918 pandemic, but we believe that the direction of
transmission was most probably from humans to pigs. There are numerous
examples of human influenza A virus strains infecting swine since 1918,
but swine influenza strains have been isolated only sporadically from
humans. Nevertheless, to explore the possibility that the 1918 HA may
have started as an avian form that gradually adapted to mammalian hosts
in swine, we looked at a current example of how avian viruses evolve in
pigs--an avian HIN1 influenza lineage that has become established in
European swine over the past 25 years. We found that even 20 years of
evolution in swine has not resulted in the number of changes from avian
sequences exhibited by the 1918 pandemic strain.
When we applied these types of analyses to
four other 1918 virus genes, we came to the same conclusion: the virus
that sparked the 1918 pandemic could well have been an avian strain
that was evolutionarily isolated from the typical wild waterfowl
influenza gene pool for some time--one that, like the SARS coronavirus,
emerged into circulation among humans from an as yet unknown animal
host.
OUR ANALYSES of five RNA segments from the
1918 virus have shed some light on its origin and strongly suggest that
the pandemic virus was the common ancestor of both subsequent human and
swine HIN1 lineages, rather than having emerged from swine. To date,
analyzing the viral genes has offered no definitive clue to the
exceptional virulence of the 1918 virus strain. But experiments with
engineered viruses containing 1918 genes indicate that certain of the
1918 viral proteins could promote rapid virus replication and provoke
an intensely destructive host immune response.
In future work, we hope that the 1918 pandemic
virus strain can be placed in the context of influenza viruses that
immediately preceded and followed it. The direct precursor of the
pandemic virus, the first or spring wave virus strain, lacked the
autumn wave's exceptional virulence and seemed to spread less easily.
At present, we are seeking influenza RNA samples from victims of the
spring wave to identify any genetic differences between the two strains
that might help elucidate why the autumn wave was more severe.
Similarly, finding pre-1918 human influenza RNA samples would clarify
which gene segments in the 1918 virus were completely novel to humans.
The unusual mortality among young people during the 1918 pandemic might
be explained if the virus shared features with earlier circulating
strains to which older people had some immunity. And finding samples of
H1N1 from the 1920s and later would help us understand the 1918 virus's
subsequent evolution into less virulent forms.
We must remember that the mechanisms by which
pandemic flu strains originate are not yet fully understood. Because
the 1957 and 1968 pandemic strains had avian-like HA proteins, it seems
most likely that they originated in the direct reassortment of avian
and human virus strains. The actual circumstances of those reassortment
events have never been identified, however, so no one knows how long it
took for the novel strains to develop into human pandemics.
The 1918 pandemic strain is even more
puzzling, because its gene sequences are consistent neither with direct
reassortment from a known avian strain nor with adaptation of an avian
strain in swine. If the 1918 virus should prove to have acquired novel
genes through a different mechanism than subsequent pandemic strains,
this could have important public health implications. An alternative
origin might even have contributed to the 1918 strain's exceptional
virulence. Sequencing of many more avian influenza viruses and research
into alternative intermediate hosts other than swine, such as poultry,
wild birds or horses, may provide more clues to the 19i8 pandemic's
source. Until the origins of such strains are better understood,
detection and prevention efforts may overlook the beginning of the next
pandemic.
Influenza is a small and simple virus-just a
hollow lipid ball studded with a few proteins and bearing only eight
gene segments. But that is all it needs to induce the cells of living
hosts to make more viruses. One especially important protein on
influenza's surface, hemagglutinin [HA], allows the virus to enter
cells. Its shape determines which hosts a flu virus strain can infect.
Another protein, neuraminidase [NA], cuts newly formed viruses loose
from an infected cell, influencing how efficiently the virus can
spread. Slight changes in these and other flu proteins can help the
virus infect new kinds of hosts and evade immune attack. The
alterations can arise through mistakes that occur while viral genes are
being copied. Or they can be acquired in trade when the genes of two
different flu viruses infecting the same cell intermingle.
Seeking clues to the origin of the 1918
virus's hemagglutinin [HA], the authors analyzed gene sequences for the
Hi-subtype of HA from a variety of flu strains and constructed a
phylogeny showing their evolutionary relationships. Samples of the 1918
strain [S. Carolina, New York, Brevig] fell within the family of
human-adapted flu viruses. The 1918 H1 gene's distance from the known
avian family could indicate that it originated in an avian flu strain
but spent time evolving in an unidentified host before emerging in
1918. Supporting this conclusion, a contemporary avian strain found in
a preserved Brant goose [Alaska 1917] was evolutionarily distant from
the 1918 strain and more similar to modern bird flus.
Devil's Flu: The World's Deadliest Influenza Epidemic and the Scientific Hunt for the Virus That Caused It. Pete Davies. Henry Holt and Co., 2000.
America's Forgotten Pandemic: The Influenza of 1918. Second edition. Alfred W. Crosby. Cambridge University Press, 2003,
The Origin of the 1918 Pandemic Influenza Virus: A Continuing Enigma. Ann H. Reid and Jeffery K. Taubenberger in Journal of General Virology, Vol. 84, Part 9, pages 2285-2292; September 2003.
Global Host Immune Response:
Pathogenesis and Transcriptional Profiling of Type A Influenza Viruses
Expressing the Hemagglutinin and Neuraminidase Genes from the 1918
Pandemic Virus. J. C. Kash, C. F. Basler, A. Garcia-Sastre,
V. Carter, R. Billharz, D. E. Swayne, R. M. Przygodzki, J. K.
Taubenberger, M. G. Katze and T. M. Tumpey in Journal of Virology, Vol.
78, No. 17, pages 9499-9511; September 2004.
DIAGRAM: INFLUENZA VIRUS The two major surface
proteins, HA and NA, protrude from a lipid bilayer. Inside, eight
separate RNA segments specify additional proteins that determine all
aspects of the virus's function.
DIAGRAM: INFECTION AND REPLICATION A flue
virus's HA protein binds to sialic acid on the surface of a host
organism's cell, allowing the virus to slip inside, where it releases
its RNA, which enters the cell's nucleus. There the viral RNA is copied
and its genetic instructions are "read," prompting cellular machinery
to produce new viral proteins. The new viral RNA and proteins then
assemble into viruses that bud from the cell membrane. At first, their
surfaces are coated with sialic acid. To prevent viruses from binding
to one another's hemagglutinin proteins and to the host cell surface,
neuraminidase clips the sialic acid, freeing the viruses to infect
other cells.
DIAGRAM: REASSORTMENT New flu strains can
result when two different viruses infect the same cell. Copies of their
RNA can mix and produce progeny with combination of genes from both
parent viruses. In this manner, a bird or animal flue strain can gain
genes conferring the ability to spread more easily among humans.
DIAGRAM: HEMAGGLUTININ [HA] of the 1918 flu
strain was re-created from its gene sequence by the authors'
collaborators so they could examine the part that binds to a host
cell's sialic acid and allows the virus to enter the cell. HA binding
sites usually are shaped differently enough to bar cross-species
infection. For instance, the human-adapted H3-type HA has a wide cavity
in the middle of its binding site [left], whereas the avian HS cavity
[center] is narrow. The 1918 Hl-type HA {right] more closely resembles
the avian form, with only a few minor differences in the sequence of
its amino acid building blocks. One of these alterations [above right]
slightly widens the central cavity, apparently just enough to have
allowed a flu virus with this avian-type HA to infect hundreds of
millions of humans in 1918-1919.
DIAGRAM
PHOTO (BLACK & WHITE): INFLUENZA VICTIMS
lie at U.S. Army Camp Hospital No. 45, Aix-les-Bains, France, in 1918.
Flu killed 43,000 American servicemen mobilized for World War I,
representing nearly 40 percent of U.S. military casualties.
PHOTO (BLACK & WHITE): RED CROSS NURSES in
St. Louis carry a flu patient in 1918. Health workers, police and a
panicked public donned face masks for protection as the virus swept the
country. Nearly a third of all Americans were infected during the
pandemic, and 675,000 of them died.
~~~~~~~~ By Jeffery K. Taubenberger; Ann H. Reid and Thomas G. Fanning
JEFFERY K. TAUBENBERGER ANN H. REID and THOMAS
G. FANNING work together at the Armed Forces Institute of Pathology in
Rockville, Md. In 1993 Taubenberger, a molecular pathologist, helped to
create a laboratory there devoted to molecular diagnostics--identifying
diseases by their genetic signatures rather than by the microscopic
appearance of patients' tissue samples. Early work by Reid, a molecular
biologist, led the group to devise the techniques for extracting DNA
and RNA from damaged or decayed tissue that allowed them to retrieve
bits and pieces of 1918 flu virus genes from archived autopsy
specimens. Fanning, a geneticist with expertise in the evolution of
genomes, helped to analyze the genes' relationships to other animal and
human flu viruses. The authors wish to note that the opinions expressed
in this article are their own and do not represent the views of the
Department of Defense or the AFIIP.
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