H1N1 Flu -
Interview Date: November 2009
From the Special Topic of
In our Special Topics analysis of H1N1 flu, the work of
Dr. Peter Palese ranks at #9 by total cites, based on 71
papers cited 3,073 times. His record in
Essential Science IndicatorsSM from
Reuters includes 86 papers, the majority of
which are classified under Microbiology, cited a total of
4,255 times between January 1, 1999 and June 30, 2009. He
is also a Highly Cited Researcher in the field of
Dr. Palese is Professor and Chair of Microbiology,
Professor of Medicine, Infectious Diseases, and head of his
own laboratory at the Mount Sinai School of Medicine in New
York. Below, he talks with ScienceWatch.com
correspondent Gary Taubes about his highly cited
What was the line of research that led to
your highly cited 1999 Journal of Virology paper, "Rescue of
influenza A virus from recombinant DNA" (Fodor E, et al.,
73: 9679-82, November 1999)?
This is literally the result of more than 10 years of work. My lab was the
first one to develop a system that allows changing the genome of an
influenza virus. So why is that important? In order to study influenza
virus or other viruses, you would like to change a particular amino acid
and then look for whether that change, for example, makes the virus more or
less virulent. This system allows you to say something about the function
of this gene. It also allows you to change this gene to alter the
properties of that virus.
If you want to make a vaccine, this technology is very important. We
started trying to do that back around 1985; we only succeeded around 1990,
and that was for one particular gene. The 1999 Journal of Virology
paper was when we succeeded in doing that for all genes in the virus in one
What does it mean to "rescue" the virus?
Remember, the influenza virus is an RNA virus, meaning there is no DNA
involved in the replication cycle. RNA infects the cell, and more RNA is
made—there's never any viral DNA. Proteins are made from the RNA and
so more viruses are made and the cells are eventually killed. In order to
do this changing of a specific amino acid—say, the amino acid in
position 55—you have to go into DNA and make plasmids. Usually the
flow of genetic information in normal cells is DNA to RNA to protein.
In the case of this influenza virus, there's no DNA. So in order to make a
change in that amino acid at position 55, you have to go first into DNA and
then the DNA is transcribed into RNA. This is also called "reverse
genetics" for this reason. So you rescue the virus from the recombinant
DNA. Then the DNA is transcribed into RNA. At the time we had to use 12
different plasmids to do that. Now it can be done simpler and easier.
Was there one particular obstacle or challenge that
you had to overcome to pull this off?
"There's actually very little
similarity between the 1918 virus and the
Well, as I mentioned, we had to use the 12 different plasmids. At the time,
it wasn't easy to clone all this genomic material. We also didn't know
whether just by putting those plasmids into one cell we would achieve the
right level of regulation—maybe one plasmid would express more than
the others. That looked very difficult and we couldn't predict whether it
would work or not. It took us a long time to do it.
Was there any serendipity involved with getting it
No, this was just slogging along. Serendipity is always a good for us in
this business. But, in this case, it was a matter of trying all kinds of
conditions and making incremental steps forward. We started with one gene,
and then we went to two genes and so on. There was no "aha!" or "eureka!"
How many genes does an influenza virus
It has eight RNAs, but 11 genes. A few of these eight RNA segments, these
mini-chromosomes, code for more than one gene.
What have you've learned from this research about
Well, even before the 1999 paper—back in 1980, in fact—my lab
was the first to establish a genetic map of influenza viruses. Using a
different technology, we were able to identify which of these RNA segments,
which mini-chromosomes, code for which genes. We were able to establish a
genetic map, comparable to a human genetic map, but obviously much, much
smaller. So at that time we were able to say that mini-chromosome one has
these two genes, etc. That was important to know. Then we can ask what we
learned from this reverse genetics. So that 1999 paper really reported on
the ability to make an influenza virus in the laboratory.
One thing we were able to do with that is make the extinct 1918 pandemic
flu virus in the laboratory. In that case, the virus didn't exist anymore.
All we had was the sequence taken from samples found in people who died in
1918. The virus was gone but there were enough RNA fragments left intact so
that the sequence could be obtained by Jeff Taubenberger. We were then able
to use this reverse genetics technique to reconstruct the extinct pandemic
virus in collaboration with Terry Tumpey from the CDC. That really gave us
lot of information. It told us that, indeed, this 1918 virus was really the
most virulent, the most pathogenic, the mother of all influenza viruses.
And we were able to identify which gene was most important for the 1918
virus; what was really different from other influenza viruses since that
That virus really was the most virulent of all
influenza viruses? It wasn't just that there was little immunity and
that soldiers returning from the war managed to incubate it and spread
it far and wide?
I have maybe 5,000 different influenza viruses in my freezers, and that
1918 virus is clearly the most virulent human influenza virus that we have.
This was not only one out of a century, but one out of a millennium
probably. There are examples of people living in Iowa, having enough to
eat, being in un-crowded conditions, not in a boat, not in a military
installation, and they died within 24 hours after getting sick. So yes, the
troops moving in boats from Europe to the States and back again were
incubators, and clearly living in the trenches or in barracks wasn't
healthful, with 15 people living right on top of each other, but the virus
also caused a lot of damage, a lot of morbidity and mortality in areas
where these conditions were not found.
Considering what's going on in the world today with
the H1N1 pandemic, I have to ask how does this new pandemic virus
compare or relate to the 1918 virus?
There's actually very little similarity between the 1918 virus and the
present one. Certainly the present swine influenza virus is an H1N1 virus,
meaning it has a hemagglutinin and a neuraminidase—that's what the
'H' and 'N' stand for—and both are subtype one. And 1918 also belongs
to that group of subtype of H1N1. It has to, since the 1918 virus went into
the pig population and has basically circulated there for the last 91
years. The new virus is a direct descendant from the 1918 virus; however,
91 years lie in between. But the new virus, the novel H1N1 2009 virus, is
very mellow; it is much attenuated compared to 1918 virus. So there are
very few parallels other than that it's an H1N1, and interestingly enough
this virus also appears to infect more young people.
Do we know why that is?
"...this 1918 virus was really the
most virulent, the most pathogenic, the
mother of all influenza
It just happens that older people have been more often exposed to H1N1
viruses. People over 50 have seen many more of these infections than
younger people. So it is not so much that the virus targets specifically
the young ones. It is a fairly mild virus and it happens that the older
populations are better protected because they have experienced infections
with this virus. Therefore, they are more immune and they are partially
protected against H1N1 viruses. So this manifests itself as a shift of
morbidity and mortality toward younger people. In contrast, regular
seasonal influenza affects more older people.
However, the total number of fatalities per infected individuals is much,
much lower than it was in 1918—probably lower by a factor of 1,000.
And in 1918, the higher incidence in young people (as compared to the older
segment of the population) was probably for the same reason. There had been
an earlier virus in 1889, which partially protected the older population.
What research are you pursuing now in your
We are interested in understanding and studying in great detail what this
novel H1N1 virus is doing. We have an interesting transmission model, in
which we measure how well different influenza viruses transmit from one
animal to another. We're using guinea pigs. It allows us to say which gene
of a particular influenza virus is responsible for (good) transmission. We
can identify and pinpoint what it is in the virus that makes it very well
transmissible. This is important because, for example, the H5N1 virus, the
avian influenza virus, does not transmit well and therefore hasn't been a
Are you involved in the effort to create a
universal flu vaccine that will work for all strains?
This is certainly a very important research agenda and many groups want to
do that; to develop a vaccine that may be protective for more than a couple
of seasons. That's clearly a direction many of us are taking, my lab
If the 1918 virus were to come back, would it be as
deadly as it was 91 years ago?
No. And the reason is we all have experienced, some more than others,
infections with H1N1 viruses. So there would be partial immunity in the
entire population—what we call herd immunity. That's point number
one. The second is that we have drugs like Tamiflu that are effective
against influenza viruses. Thirdly, and more importantly, we have vaccines
now that we can use. So we can make vaccines in a very brief period of
time. There wouldn't be any technical challenges. It's an H1N1 virus and we
know how to make H1N1 vaccines.
And fourth, we have antibiotics, so we can treat all the bacterial
infections that tend to follow the initial influenza infection and
exacerbate the patient's situation. If there's another secondary bacterial
infection, we can take care of it with antibiotic treatment. So far all
these reasons, if that 1918 virus were to reappear it would be much less of
an issue than it was in 1918. It wouldn't even be
Peter Palese, Ph.D.
Mount Sinai School of Medicine
New York, NY, USA
KEYWORDS: INFLUENZA A VIRUS, RECOMBINANT DNA, RNA VIRUS, AMINO
ACIDS, PLASMIDS, REVERSE GENETICS, GENETIC MAP, MINI-CHROMOSOMES, 1918
PANDEMIC FLU VIRUS, HEMAGGLUTININ, NEURAMINIDASE, NOVEL H1N1,
TRANSMISSION MODEL, VACCINE.