Recreating the Spanish Flu
October 9, 2003
Influenza as a bioweapon does not sound like a particularly grave threat. Annual outbreaks kill many people, particularly the elderly; but a case of the flu is generally percieved as an uncomfortable nuisance rather than a grave threat. But flu viruses can be devastating. In 1918 and 1919, the so-called "Spanish flu" killed an estimated 20-40 million people worldwide and, since then, the highly changeable flu virus has resurfaced in a variety of particularly virulent forms.
The strain of influenza virus that caused the 1918 global epidemic ("pandemic") was exceptionally aggressive. It showed a high capacity to cause severe disease and a propensity to kill fit young adults rather than the elderly. The mortality rate among the infected was over 2.5%, as compared to less than 0.1% in other influenza epidemics (Taubenberger et al. 1997). This high mortality rate, especially amongst the younger, lowered the average life expectancy in the USA by almost 10 years (Tumpey et al. 2002). Creation of this particularly dangerous influenza strain, as it is currently pursued by a US research team, may thus pose a serious biowarfare threat.
A recent commentary in the Journal of the Royal Society of Medicine (Madjid et al. 2003) noted that influenza is readily transmissible by aerosol and that a small number of viruses can cause a full-blown infection. The authors continued: "the possibility for genetic engineering and aerosol transmission [of influenza] suggests an enormous potential for bioterrorism" The possible hostile abuse of influenza virus is seen as a very real threat by public health officials in the USA. Just two weeks ago, $15 million was granted by the US National Institutes of Health to Stanford University to study how to guard against the flu virus "if it were to be unleashed as an agent of bioterrorism".
US scientists led by a Pentagon pathologist recently began to genetically reconstruct this specifically dangerous 1918 influenza strain. In one experiment a partially reconstructed 1918 virus killed mice, while virus constructs with genes from a contemporary flu virus had hardly any effect.
Attempts to recover the Spanish flu virus date to the 1950s, when scientists unsuccessfully tried to revive the virus from victims buried in the permafrost of Alaska. In the mid 1990s, Dr Jeffrey Taubenberger from the US Armed Forces Institute of Pathology started to screen preserved tissue samples from 1918 influenza victims. It appears that this work was not triggered by a search for flu treatments, or the search for a new biowarfare agent, but by a rather simple motivation: Taubenberger and his team were just able to do it. In previous experiments they had developed a new technique to analyse DNA in old, preserved tissues and for now looking for new applications: "The 1918 flu was by far and away the most interesting thing we could think of" explained Taubenberger the reason why he started to unravel the secrets of one of most deadliest viruses known to humankind.
A sample of lung tissue from a 21-year-old soldier who died in 1918 at Fort Jackson in South Carolina, yielded what the Army researchers were looking for: intact pieces of viral RNA that could be analysed and sequenced. In a first publication in 1997, nine short fragments of Spanish flu viral RNA were revealed (Taubenberger et al. 1997). Due to the rough tissue preparation procedure in 1918, no living virus or complete viral RNA sequences were recovered.
Genetic techniques helped to isolate more Spanish flu RNA from a variety of sources. By 2002, four of the eight viral RNA segments had been completely sequenced, including the two segments that are considered to be of greatest importance for the virulence of the virus: the genes for hemagglutinin (HA) and neuraminidase (NA). In the forthcoming issue of the scientific journal Emerging Infectious Diseases, another article on the Spanish flu DNA sequence will be published (Reid et al. 2003).
The project did not stop at sequencing the genome of the deadly 1918 strain. The Armed Forces Institute of Pathology teamed up with a microbiologist from the Mount Sinai School of Medicine in New York. Together, they started to reconstruct the Spanish flu. In a first attempt, they combined gene fragments from a standard laboratory influenza strain with one 1918 gene. They infected mice with this chimera, and it turned out that the 1918 gene made the virus less dangerous for mice (Basler et al. 2001).
In a second experiment, published in October 2002 (Tumpey et al. 2002), the scientists were successful in creating a virus with two 1918 genes. This virus was much more deadly to mice than other constructs containing genes from contemporary influenza virus. This experiment is only one step away from taking the 1918 demon entirely out of the bottle and bringing the Spanish flu back to life.
The scientists were aware of the dangers of their creation. The experiments were conducted under high biosafety conditions at a laboratory of the US Department of Agriculture in Athens, Georgia. Possible hostile use of their work was an issue considered by the scientists:"the available molecular techniques could be used for the purpose of bioterrorism" (Tumpey et al. 2002:13849).
There is no sound scientific reason to conduct these experiments. The most recent experiments (Tumpey et al. 2002) allegedly seeked to test the efficacy of existing antiviral drugs on the 1918 construct – but there is little need for antiviral drugs against the 1918 strain if the 1918 strain would not have been sequenced and recreated in the first place. It is true that biodefense research – and any kind of civilian medical research – is always a race with its counterpart, the evolution of naturally occuring infectious agents or the development of biowarfare agents. But in this race it should be avoided to create the threats that are allegedly the motivation for the research. A vicious circle is created: "The technologies are in place with reverse genetics to generate any influenza virus we wish ... studies are envisaged using genes of the 1918 Spanish Influenza virus." These arguments were recently brought forward to justify another maximum biosafety laboratory for biological defense work in Texas. Without Taubenberger’s pioneering work, the money for the lab experiments might have been saved and better invested in combatting naturally occuring diseases such as tuberculosis, malaria, or HIV.
Other papers argued that the experiments may help to elucidate the mechanisms of influenza evolution and virulence (Taubenberger et al. 1997, Basler et al. 2001), but this argument is also deeply flawed. Since 1918, a many different influenza viruses with different virulence and pathogenicity properties have been isolated and characterised by researchers around the world - a more than abundant source for generations of scientists to study influenza evolution and virulence. A resuscitation of the Spanish flu is neither necessary nor warranted from a public health point of view.
There may be many reasons for the individual scientists to work on this project, not least the scientific prestige - the"Spanish flu" subject matter practically guaranteed a series of publications in prestigious journals. From an arms control perspective it appears to be particularly sensitive if a military research institution embarks on a project that aims at constructing more dangerous pathogens - if Jeffery Taubenberger worked in a Chinese, Russian or Iranian laboratory, his work might well be seen as the "smoking gun" of a biowarfare program.
Basler CF, Reid AH, Dybing JK, Janczewski TA, Fanning TG, Zheng HY, Salvatore M, Perdue ML, Swayne DE, García-Sastre A, Palese P, Taubenberger JK (2001) Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. PNAS 98:2746-2751
Madjid M, Lillibridge S, Mirhaji P, Casscells W (2003) Influenza as a bioweapon. J Roy Soc Med 96:345-346
Reid AH, Janczewski TA, Raina M. Lourens RM, Elliot AJ, Rod S, CL Berry, JS Oxford, JK Taubenberger (2003) 1918 Influenza pandemic caused by highly conserved viruses with two receptor-binding variants. Emerg Infect Dis [serial online] October 2003, available from: http://www.cdc.gov/ncidod/EID/vol9no10/02-0789.htm
Reid A, Fanning TG, Janczewski TA, McCall S, Taubenberger JK (2002) Characterization of the 1918 "Spanish" Influenza Virus Matrix Gene Segment. J Virol 76:10717-10723
Taubenberger JK, Reid AH, Krafft AE, Bijwaard KE, Fanning TG (1997) Initial genetic characterization of the 1918 ‘Spanish’ influenza virus. Science 275:1793-1796
Tumpey TM, Garcia-Sastre A, Mikulasova A, Taubenberger JK, Swayne DE, Palese P, Basler CF (2002) Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus. PNAS 99:13849-13854
 Stanford University News Release 17 September 2003, online at http://mednews.stanford.edu/news_releases_html/2003/septrelease/bioterror%20flu.htm
 Spanish flu keeps its secrets. Nature science update at www.nature.com/nsu/990304/990304-5.html
 Profile: Jeffery Taubenberger at www.microbeworld.org/htm/aboutmicro/what_m_do/profiles/taubenberger.htm
 AFIP scientists discover clues to 1918 Spanish flu, www.dcmilitary.com/army/stripe/archives/mar28/str_flu032897.html
 The so called "nonstructural" gene (NS)
 It should be noted that for this experiments, a standard influenza strain was used that was specifically adapted to mice and that was lethal to mice. The scientists reasoned that the 1918 gene probably weakened the lethality for the mice as it stemmed from a human-adapted strain.
 This time, the 1918 genes for hemagglutinin (HA), neuraminidase (NA) and matrix (M) were used, single and in combination. Only the combination of the 1918 HA and NA genes caused a dramatic increase in lethality if compared to constructs containing genes from a more recent human influenza virus. The scientists concluded: "These data suggest that the 1918 HA and NA genes might possess intrinsic high-virulence properties." (Tumpey et al. 2002:13853)
 Letter (4 February 2003) from Robert G. Webster, Professor of Virology at St. Jude Children's Research Hospital to Stanley Lemon, Dean, School of Medicine, University of Texas Medical Branch (UTMB) at Galveston, in support of the UTMB application to contruct a National Biocontainment Laboratory. Released to the Sunshine Project under the Texas Public Information Act
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