Why did you recreate the virus?
The reason that the 1918 pandemic was so deadly was not known and was a topic of considerable interest and speculation. Many ideas were suggested to explain the high mortality during the pandemic, the unusually rapid course of the disease in many victims and the very unusual incidence of high mortality in young adults. For example, it was suggested that the poor living conditions may have played a role in the incidence and severity of disease in soldiers in the first World War. Others suggested it was a unique property of the virus itself that was responsible. Even after Dr. Jeffrey Taubenberger published the sequences of all of the influenza genes, there was no clear answer to this question because none of the genes contained features that have been shown to be important in causing severe disease with other influenza viruses in either animals or humans. So the only way to answer the question was to reconstruct the virus and examine its properties in animal models of influenza disease.
Did it give you any new insights on viruses that exist nowadays (like bird flu?)
Our results suggest that one of the reasons the 1918 influenza was so severe was that infection is causing an over-stimulated immune response that actually contributes to the damage observed in the lungs of experimental animals rather than protecting the animal and assisting in clearance of the virus. The same effect may have also played a role in the very similar extensive lung damage frequently seen in people that died during the pandemic.
A similar over-stimulation of the immune response, referred to as hypercytokinemia, has also been observed in people that have died from severe disease caused by the highly pathogenic avian influenza (HPAI) H5N1 virus (or bird flu). We do not yet know why the 1918 virus caused this response but it is an indication that the ability to cause hypercytokinemia may be a shared property of very virulent viruses.
It is also important to understand that all influenza viruses ultimately originated from viruses that circulated in birds. The 1918 pandemic virus is likely a completely avian virus that became adapted to humans. Pandemics in 1957 and 1968 were caused by new influenza viruses that were generated by mixing the human viruses that were circulating at that time with avian viruses so that the new viruses now contained some avian virus genes. It is very possible that viruses with properties that are similar to the virus that became the 1918 pandemic virus are present in birds and could emerge as a new virus in humans-this may even be true of the H5N1 bird flu virus. So better understanding of why some viruses can cause such severe disease and some do not is always very valuable.
What were the reactions from bio-ethicists groups? Is the recreated virus seen as a real threat to mankind according to these groups? And what do you think yourself?
I am not specifically aware of any of the comments that were made by bio-ethicist groups and most comments that I know of were expressed by concerning individuals, such as the correspondence published in Nature, 432:549 (2004) in response to our first study using one gene from the 1918 virus. We were the second group to reconstruct the virus, the first being a collaborative study done at the Centers for Disease Control in Atlanta, USA. Both projects have been covered in letters to the journals and editorials that weighed the risks and benefits. It has been suggested that there is a considerable, and not justified, risk associated with making and using the virus in some articles but in general most of the scientific community, that has commented, supports this work. There are comments from other individuals and organizations, such as the Sunshine Project, but aside from the letters to the journals I mentioned, I have not read too many of the comments from other organizations.
Our work with the virus is all done in the highest level of biocontainment (Biosafety level 4) available in a secure facility that is equipped to handle and store highly pathogenic agents. All personnel are well trained and access to the virus is restricted to only those scientists that have clearance and training to work with it. We have made every effort to protect ourselves and the public and I am confident that the facility, security and highly trained personnel ensure that all of our work is done in the safest manner that is possible. Our goal in this research is better understand highly pathogenic viruses and apply this knowledge to enhancing public health so doing our work safely is our first priority.
It is understood that the 1918 virus is a human pathogen and I think that it is certain that the 1918 virus would infect humans and very likely could cause serious disease. But, the circumstances that exist now are very different than in 1918 and it is unlikely the virus poses as great a risk as it did in 1918. First, influenza viruses that are descended from the 1918 virus continue to infect people today and these exposures would provide some immunity against the 1918 virus, as would the influenza vaccine that is widely distributed in many countries. Second, many deaths in 1918 were the result of secondary bacterial infection but we now have antibiotics to effectively limit this problem. Third, we understand the nature of infectious diseases now and can very rapidly detect and diagnose them, which is critical in rapidly establishing quarantine to limit spread of the virus and initiating effective treatment for infected individuals. And finally, we have antiviral drugs for influenza that are effective against the 1918 virus.
Is the spanish flu virus viable outside the laboratorium?
The Spanish flu virus is a fully viable live virus and requires no unique laboratory conditions for it to grow.
Is there a patent on the spanish flu virus you recreated?
As far as I am aware, there is no patent on any aspect of the 1918 virus, and certainly not on the virus we made. Our virus is based entirely on gene sequences that were published and archived in a database (Genbank) that is accessible to the public.
Was the virus made from existing parts of DNA, or was the genome sequenced and afterwards created synthetically?
Dr. Taubenberger obtained the nucleotide sequence of all genes of the 1918 influenza virus from preserved lung tissues of victims of the 1918 pandemic. In these tissues the viral genes (which are RNA) existed as very small pieces of the original genes. The nucleotide sequences of these pieces were determined and from these small sequences from each gene it was possible to figure out the nucleotide sequences of the whole genes-like putting a puzzle of many small overlapping pieces back together into one long piece. This process provides a nucleotide sequence on paper but does not physically put the genes themselves back together.
For reconstruction of the virus, each of the genes were made synthetically from DNA based on the known nucleotide sequence. This DNA is then put into an appropriate vector, which is a DNA structure that allows the genes to be manipulated and eventually converted into the RNA form of the genes that is found in viruses.
Are you working on any other viruses or synthetic biological systems?
We do work with other influenza viruses that are generated from DNA-encoded copies of their RNA genes, as was done for the 1918 virus. In general though these genes are not synthetic like the 1918 genes but were produced by directly copying the existing viral genes themselves using specific enzymes and techniques. We do this because there are no effective methods to manipulate RNA itself. But if we first convert it into DNA we can manipulate the DNA very efficiently. And then the DNA must be converted back into RNA to produce a virus again. The process of producing a virus from DNA copies of the genes is called reverse genetics and has become a very important research tool.
