[APPLAUSE] Thank you for coming for
the second installment here of the College of
Science lecture series. It's a much more pleasant,
quiet, and comfortable place than McKale. I can guarantee you that. [LAUGHTER] I will do better, no, I
don't know about that. So I want to thank our
underwriters first-- the Arizona Daily Star,
Carondelet, Galileo Circle, Godat Design, Holualoa
Companies, Miraval Resort and Spa, Raytheon, Research
Corporation for Science Advancement, Tucson
Electric Power, and Ventana Medical Systems,
for making it possible for all of us to see this for free. [APPLAUSE] Today we're in for a treat
at exactly the right time. Michael Worobey studies viruses. Half of us seem to be
having a virus lately. So it's a perfect time to
listen about pandemics. Let me tell you a little
bit about Michael. He is an extraordinary
individual. And we're very lucky that
he is in this town with us. He's an evolutionary
biologist, Michael Worobey. He grew up in British Columbia. In 1997 he left Canada for
Oxford as a Rhodes Scholar, earning his doctorate there, and
staying on as a research fellow at St. John's College. He came here in 2003, and
is now Professor of Ecology and Evolutionary Biology. He's a Packard Fellow,
and a National Academy of Sciences Kavli Fellow. Dr. Worobey's
research integrates molecular and
computational methods with historical, archival,
and epidemiological approaches to investigate when, where,
how, and why pathogens, like HIV and influenza viruses,
emerge from animal reservoirs and cause pandemics. As you'll see from
this lecture, Mike is something of a
fanatical sleuth. He could be actually on TV. His research
involves field work, such as collecting samples from
wild chimpanzees in Africa, molecular biology, and
developing and applying new techniques for
recovering viral RNA and DNA from ancient
or degraded specimens, and molecular evolutionary
analysis of gene sequences. He's made several
seminal discoveries, establishing how and when
HIV jumped from chimpanzees, spread for decades in
Africa, and then emerged in North America and elsewhere. Mike was also one of the
leaders of an international team of researchers that pinpointed
the origin of the 2009 swine flu epidemic within
weeks of its discovery. When its 110, Mike takes off
from Tucson, so he's smart. And he takes off to the
west coast of Vancouver, where he's trying to
transform a pile of cedar logs into a cabin with the
help of his chainsaw. Mike. [APPLAUSE] Thanks, Joaquin. My clicker? So you can tell
from Joaquin's voice that he's the most
dedicated Dean of Science. He actually got
influenza in preparation for my talk tonight. Just to set the stage. I want to start tonight
with some numbers. So influenza doesn't just cause
pandemics, worldwide epidemics. It's also a seasonal virus. It gets established in
the human population. There are two lineages,
H1N1 and H3N2, that circulate every year. And here are some numbers. So every year 5% to 30% of
the population gets Infected. Most of us were probably
infected by the time we were five years old. And that first infection
kind of sets the stage for the rest of your life. Your immune system
remembers that first virus, and for the rest of your
life kind of responds to it every time you're reinfected. You get it for about a week
and then you clear the virus. And it's gone until the
next time you encounter it. So just regular old flu every
year accounts for, on average, 31 million outpatient
visits in the US. 200,000 people end
up in the hospital, for a total of 3.1
million hospitalized days. Total economic burden $87
billion-- that's medical cost, work lost, work time
lost, and so forth. And the bottom line
is it kills something like 30,000 people
in an average year. So this is a serious disease,
more than half a million worldwide usually each year. And if you tally those
up, every year in the US, people's lives are
cut short by a total of more than 600,000 years. Let's go back to 1918 now. [VIDEO PLAYBACK] So we're missing the audio
here but we're getting-- It was the worst
epidemic this country-- - There it is. - Has ever known. It killed more Americans
than all the wars this century combined. It was a phantom, and we
didn't know where it was. In a gradual remorseless way, it
kept moving closer and closer. But you never knew
from day to day who was going to be
next on the death list. There were so many people
dying that you ran out of things that you'd never
considered running out before-- caskets. Before it was over, it
almost broke America apart. I remember my mother
putting a white sheet, a white piece of
cloth over his face, and they closed the casket. [END PLAYBACK] So 1918 was different. There's never been
an epidemic as lethal as what happened
with flu in 1918. You can see it here on this
graph of mortality rates by year, from about
1900 up to the 1990s. It's not too hard to see 1918. Absolutely unprecedented,
not just for flu, but for any other pathogen
to kill so many people in such a short time. In the US, at a time
when the population was maybe a third of what it
is now, 675,000 people died, most of them within
about three months-- October, November, December. In that year, the culling
by the Spanish flu actually dropped the average
lifespan in the US by 12 years. Around the world, something
like 50 million people died. Estimates range even
as high as 100 million, and possibly for instance, 20
million just in India alone. So this was just
unlike anything we've ever seen before or since. And still about 100
years after it happened, we don't really know why. So what I do is
evolutionary genomics. So I take the genomes sequenced
from things like influenza virus, and when possible I line
them up against other genomes from the same
germs, and then try to read the history of
those germs from the DNA, essentially. This is a figure from the
paper that Joaquin alluded to. In 2009 when the swine
flu jumped into humans, we tried to figure out
where it came from, what species that jumped from,
and when it made the move. And I'll come back to that. But basically at
this stage, I just want to communicate how
rich the information is, now that we have full genomes. And for flu we have
tens of thousands of complete genomes
that are available. I used to read National
Geographic when I was young. And I can remember
looking at stories where you have an
archaeological dig, and little hints about things
that happened in the deep past. And thinking, you know,
that's really great, but this kind of wistful
feeling of, there must be so much that
we'll never know about. And genomics, and evolutionary
genomics in particular, is taking us back in time to
places where 15, 20 years ago, we thought we couldn't go. But when you have a
collection of genomes, that collected information can
tell really important stories. Every one of these
virus particles presents two main things to the
outside world, i.e. our immune system--
an H and an N. The H you can think
of like a key. That's the key for the
virus to get into the cell. And the N you can think
of like a little scalpel. When those new virions,
those new virus particles, are made in the cell,
after the genome, those eight segments takes over
the machinery inside the cell, and turns it into a factory
for making new flu viruses. The N protein on the
outside of the virus cuts a little hole, essentially,
for those near virus particles to escape. Those antibodies
that you saw, this is promotional material
from a drug company. They make antibodies
essentially as drugs. Our own body makes antibodies. And every time we're exposed
to a new germ like flu, it's like a little R&D project. Our immune system comes up
with essentially a drug, a molecule that binds
either to HA, the H, or to N, the scalpel. And it's just physical binding. It just gets in the way
of those viral proteins from doing what they
need to do for the virus to complete its life cycle. It's as simple as that. And those eight genome segments
contain the information not just for the H and the N,
but for all the other dozen or so proteins that allow
the flu to do its thing. And so here is a flu genome. This is the one
and only complete genome that you're likely to
see during this series of talks, because RNA viruses are
very sensible and thrifty. And they can do the whole thing
in about 10,000 nucleotides, OK? So that's one segment. And you can read the
A's, C's, G's and T's. That's the segment that
codes for the key, H. And that's the scalpel,
N. And that's it. That's all that the
flu needs to take over our giant bloated genome
and start turning the knobs and making it do what it
wants our genome to do, which is to create more
copies of the virus. And so you can think of the
battle between flu virus and the immune system
as a boxing match. And in one corner
you have the virus that brings to the table this
H protein, the key to get in, and the N protein, the
scalpel to cut out. But we come to the table
with something as well. After that initial exposure
when we're children, we make antibodies, sorry,
to both of those proteins. So that the next time we see
an influenza virus in our body, we bind those antibodies
to it, and if not kill it, slow it down. And that can make the difference
between pneumonia and death after you get flu, or a kind
of cough and a mild fever. So this kind of dynamic, where
you have the immune system kind of putting up this
barrier, and the flu attempting to get around it, sets up
what evolutionary biologists call Red Queen dynamics. And it's named
after the Red Queen from Through the
Looking Glass, who said "it takes all
the running you can do to keep in the same place." And you see this
a lot in nature. It's kind of an arms race. Our antibodies bind to the flu,
so once you get this year's flu strain, next year's
flu strain had better be a little bit
different in the H and the N, otherwise
it's not going to be able to pierce
your defenses. And that Red Queen arms
race kind of dynamic is why you need to get a
new flu vaccine every year. Unlike things like
measles, the flu evolves, so that your initial
immunity doesn't necessarily do the trick next time
you encounter the virus. So there's another small
element of the story that I want to
introduce you to here. It was discovered by this
guy, Tom Francis Jr., who actually trained Jonas Salk,
and developed the first flu vaccine that was used during
World War II, Pretty much the same technology that
we use today, actually. And he noticed something
really weird in the late 1940s. So in the late 1940s there was
a complete vaccine failure. The flu that was out
there had changed so much that the
previous vaccine just didn't do any good whatsoever. And so he was doing
experiments, and noticed that when he gave a vaccine
based on the new flu variant that had replaced
the old one to teenagers, instead of making antibodies
to the new variant as you would hope your
immune system would do, it actually boosted
up the old antibodies that it remembered
from-- that each person's immune system remembered from
their childhood infection. And he named that process
the original antigenic sin. So it's kind of like
the other original sin, that it kind of taints
you for life, potentially. And it's part of the story. We'll come back to it. But what that's
important for is the year to year dynamics of the
things like H1N1 and H3N2 that are the
seasonal strains now. It's less important
for this process which is the other big way
that influenza comes up with evolutionary novelty. Instead of just making minor
tweaks to the H or the N, every once in a
while, a new flu virus is created that mixes
and matches segments from two different viruses. So if you have a person
infected with H1N1, and as happens
from time to time, that person is
simultaneously infected with a bird virus that
normally doesn't infect humans, the virus that comes out that
person can be an H1N7, if you have one segment or more from
that bird virus jumping in. We call that re-assortment. And that's, as you might
imagine, a kind of game changer. Whatever immunity you had to N1
from your childhood infection or lifetime exposure,
it's useless. N7 is so different
antigenically, that your antibodies
to the previous version don't really help you. And that process,
this jumping in of complete genome
segments from nature, from non-human
reservoirs, is what ushers in what we
call pandemics, which are these worldwide big
epidemics that are occasioned by completely new
genetic diversity from the pool of various
subtypes of virus that exist in these animal
hosts, jumping into humans and starting to spread. And so when that happens,
let's say in 1957, after H1N1 circulated,
an H2N2 virus jumped into humans in 1957. At that point on an individual
level and a population level there was almost no
protection from age H2N2. And so you have a big year, a
couple million people dying, instead of half a million. In 1918 you had
the same process. You had some new stuff coming
in, but 50 million people died. So this is the kind of layered
history of the virus from now, when we have H1N1 and H3N2
circulating, back in time. If you were born before '57,
your childhood infection, your first exposure was to H1N1. That set the stage for
the rest of your life. [VIDEO PLAYBACK] No one was safe. In Washington, Victor
Vaughn was working late trying to make sense
of the hellish chaos. He uncovered an unnerving fact. Usually influenza
kills only the weak, the very young, and very old. But this time it had
a different target. People in the very prime
of life from 21 to 29 were the most vulnerable of all. This infection, like war, kills
the young, vigorous, robust adults. The husky male either made
a speedy and rather abrupt recovery, or was likely to die. The situation was upside
down and backwards. A disease that's supposed
to be a mild disease is killing people. The people it's killing
are the strongest members, the most robust
members of our society. [END PLAYBACK] OK so the plot thickens. Not only was 1918 unusual in the
large number of people dying, but the wrong people were dying. Flu's supposed to kill very old
people and very young infants. But in 1918, you had this
extra peak in mortality in 20 to 40 year olds,
and really focused in on people about 25 to 29,
who normally almost never die from flu compared to the
rest of the age groups. And so there are several
kind of mysteries, but there are also
clues that we need to address here if
we want to figure out what happened in 1918. So first is that young people,
young adults, were dying. And that's unusual. The second is while
young adults were dying, the very age that normally
does most of the dying in a flu epidemic, the most elderly, they
actually died in fewer numbers than they did
during seasonal flu. So if you just compare
the mortality among, say, 85 year olds in 1918, in
the midst of the worst pandemic, the worst epidemic of
disease that humanity has ever faced, the most
vulnerable people actually died at lower levels than
they had in the five years before from whatever
flu strain existed then. Very strange. Another key thing, when
you watch documentaries about the flu, the 1918
flu, or hear about it, you often hear scary
stories of people turning blue, feeling fine, and
dropping dead a couple of hours later. Those cases happened
occasionally. But the vast majority of people
who died from flu, including those young people
in 1918, died of secondary bacterial pneumonia. Which is the way flu
has always killed, and it's the way it kills now. So I have a picture up
here of a garbage can. And it is a garbage
can, not a trash can, because it's Canadian. [LAUGHTER] And this garbage can
is one like the one that killed my 93-year-old
grandfather a few years ago. So a few years ago he
fell in his kitchen. He busted a rib on
the garbage can. And several weeks later,
after contracting pneumonia and getting congestive
heart failure, he died. And you can think of flu,
in 1918 and otherwise, like that garbage can, or
like a shot to the ribs. It lands you on your
back for a few weeks. It creates inflammation,
fluid buildup in your lungs where you need them clear
for oxygen, for gas exchange. And pneumonia is
really, really deadly. It always has been,
and it still is. And that's what
killed people in 1918. The other clue is that
it was an H1N1 virus. And so how do we know that? We know that because people like
Jeff Taubenberger and his team have actually gone back to
tissue samples from 1918. So here we have wax-embedded
autopsy tissue samples taken from a victim
of the Spanish flu. And Jeff Taubenberger
and his team take slices of that
material, and they amplify up that genome that we saw before. So we know exactly, genetically,
what this thing looked like. In fact, the one complete
genome that we have from 1918 comes from here. So this is a place called
Brevig Mission, which is a little village in Alaska. And in 1918, the
Spanish flu pretty much wiped out the whole village. And a lot of people
ended up in mass graves. And this guy here, [? Johan ?]
[? Holten, ?] is a virologist, who for years had been saying we
might be able to get virus out of those graves. If they were buried
in permafrost, you might have good
preservation of material. He tried in the '50s, at a time
before genomics and amplifying gene sequences. What he needed to
do then was actually get a live virus-- couldn't
do it, not possible. Everything's kind of
dead and fragmented. So he went back in the
'90s on a solitary trip. I thought this was funny. So he carried just one tool,
a pair of garden clippers borrowed from his wife,
without permission. And let me just go back. There they are. [LAUGHTER] OK? So from this mass grave, via
Mrs. [? Holten's ?] garden clippers, to the big screen. That's not just a flu genome. That is the Spanish flu
genome from that victim from that mass grave in Alaska. Those A's, C's, G's
and T's are the virus that killed that person
and so many others in 1918. And I can remember when the
first full gene came out in 1998. And it was very exciting
because finally we had insight into why this
thing killed so many people, and killed young people. We had the full gene of the H
protein, this most important gene of all. And it was published. And it was kind of like
hmm, there's nothing here. There's no smoking gun. There's nothing you can
see in the actual genome sequence that really
tells us anything about why it was so nasty. And it turns out you need
more than just one genome. You need to put it into
context of other ones. So those are the clues. But we're left with
really big questions. Did this virus jump
in from a bird? Did it come from swine influenza
and human influenza swapping genes? Some people interpret
the data in that way. When did it happen? We don't really know when
this virus came together. And we don't know where. We don't even know which
hemisphere this occurred in. There's good agreement
on a couple of points. One, we have no idea
why young people died in such high numbers. And two, the Spanish
flu wasn't from Spain. [LAUGHTER] So Spain was one of the only
countries in Western Europe that didn't have press
censorship during World War I. So in the summer when things
started heating up with the flu pandemic, they were
publishing stories. And so everyone
associated it with Spain. OK so back to what I do. So I look at genome sequences
of this sort and compare them. And I'll just take you
through this 2009 example to warm you up for 1918. OK so the main tool here is
called a phylogenetic tree, or an evolutionary tree. This is the first
phylogenetic tree ever, in Darwin's notebook from 1937. And what a
phylogenetic tree does is describes a process of
common ancestors splitting into independent lineages. And whether this
is a species that gets separated
into geographically isolated populations, and enough
time passes, and enough DNA mutations occur independently,
or whether you're looking at descendants
of a single female, my wife is in the audience
and we have two daughters. So 10,000 years
from now, you might find some people
trace back to Hazel, and some people
trace back to Iris. Whatever happened in
terms of DNA mutations along each of those
lineages was independent. And that forms the
branches on the tree. So it's a fundamental
tool in biology. So fundamental, you
might want to get it tattooed on your body. It's a very fresh
looking tattoo. [LAUGHTER] When you do an images
search of this, you get about a dozen
different tattoos of people who
independently thought, I'm going to be the only
person in the world who has this tattoo. [LAUGHTER] OK so here's a tree. Here's a real schematic
phylogenetic tree, where if you looked at a
bunch of human DNA sequences, they would trace back
to a common ancestor about 100,000 years ago. If you compared them
to chimpanzee DNA, there's many more
changes in each lineage before you get back to
the common ancestor, say five million years ago. So now let's switch
to 2009 swine flu. So the new flu that jumped
into humans in 2009, we found traced back to an ancestor
not too many months, maybe four months, before
the first case was noticed. But if you compare the human
virus to the closest pig viruses, and every one
of the eight segments was a pig segment, so this
thing jumped directly from pigs. You have to go back
to about 10 years ago. And what that means is that
the actual constellation of genome segments that
formed that 2009 virus, formed many years before
it jumped into humans, and spread cryptically in pigs. And our surveillance of
pigs is obviously so bad that no one knew about it
until it jumped into humans. OK so how do you
get those dates? This is kind of one of the main
things I do in my research. And with viruses they evolve so
quickly, that you can actually see evolution
happen in real time. And you can liken
it to a saguaro. And there are, I know, quite
a few Canadians in the crowd. So just imagine a Douglas
fir tree and you'll be OK. [LAUGHTER] If you just go out
into your front yard and look at your
cactus, it's really hard to guess how old it is if you
don't have anything to go on. But if you had say, a picture
from 1999, and then another one from 2009, now just with 10
years window of observation, you can start to get an idea
of how fast the thing grows. And maybe you would
extrapolate back and say, it's about 100 years old. So what we do with
viruses is the same. We sample them at different
time points, calibrate what we call a molecular
clock, and then you use that to-- this is
Salvador Dali's painting called Bayesian phylogenetics
and relaxed molecular clocks. [LAUGHTER] So if you do that
with influenza, what I noticed about a year
and a-- so this project really kind of got rolling
a year and a half ago. One night I had a whole bunch
of these evolutionary trees out on my kitchen table. And I was actually using
my daughter's plastic ruler to just measure the
kind of-- the distance from the base of the
cactus to the tip, and compare that to the date. The same thing with the cactus,
except with these actual trees. And what really came out
was that the virus evolves, the clock ticks at a
very different rate, in viruses infecting say,
pigs, on the one hand, or humans on the other,
or horses, or birds. And you can't just
average across them. If you average across
them, things go wrong. So I started collaborating
with a couple of other people, [? Gwangju ?] [? Hahn, ?]
who is my graduate student. [? Gwangju, ?] are you
in the audience here? There he is,
excellent PhD student. And so [? Gwangju ?] and I
started gathering together all of the genome sequences
of flu, more than 100,000 of these genome segments. And then teamed up with this
guy here, Andrew Rambaut, who I worked with in Oxford. He's one of the best
all around biologists, and an incredible
computer program. And we came up with a method
that just kind of makes that simple correction
of allowing the clock to tick at different rates. And he's a very good biologist,
especially considering he's only 18 inches tall. He's just- [LAUGHTER] - Absolutely amazing. The truth is I,
of course, didn't email him asking for a picture. I just did a Google
Images search. When you Google
images, Andrew Rambaut, you get phylogenetic trees, and
two very low quality photos, including this one. So those are my
main collaborators. I also want to thank Tom
Watts, who's my lab manager, and has a hand in
everything I do. And also my wife. So while I've been
doing this project, I've been kind of
immersed, living between about 1872 and 1918. And thinking about 50
million dead people, and particularly for
the last six months. My main goal normally in life
is to make my wife laugh. And I haven't been
doing that too much over the course of this project. But with this tool in
hand, what we found, was basically
everything that had been done in the
last 10 or 15 years on evolutionary trees
of flu, including stuff that we had done, was wrong. And this is just a kind of
figurative representation. But everything that you
do without correcting for the different
clock rates is kind of like looking through
a fun house mirror. When you make the correction,
everything snaps into place. And I know what you're
thinking, that it doesn't look any better now than
it did in the previous slide. But I'll take you through it. It's not as bad as it looks. OK, so here's this
Brevig Mission. This is the flu sequence
from one genome segment from that 1918 patient. And you see, that's 1918 there. And it's nested in a
little part of the family tree along with human
viruses and pig viruses. And just a few
years before 1918, it jumped from a bird,
boom, right there. And it jumped from
a bird that lived in the Western hemisphere. So this whole big
family tree kind of splits into two main lineages. One-- all these black lineages
are from bird viruses. One from the Western
hemisphere, another from the eastern
hemisphere, and they trace back to a virus
at this point here, that existed a few
years after 1872, OK? So we're getting somewhere
now, at least for this segment. This thing seems to have jumped
from a bird not too many years before 1918, and probably
from the Western hemisphere. Also check out that horse
lineage while I get a drink. So this was a big surprise. This horse lineage, known from
just a handful of sequences, first isolated by a
woman in Prague in 1956. And it probably went
extinct in the '70s. So no one cares about. No one even includes it
in analyses normally. But we were doing a
comprehensive analysis, and we included it. And it turned out to be a
kind of key to the story. We'll get back to
it in a second. Now let me take you from that
one genome sequence to six. So now we've got six of the
genome sequences, everything except that key G and
N. And all six of them have this, basically the same
story-- the human virus jumping from birds shortly before 1918. Boom, boom, boom,
boom, boom, boom. Western hemisphere,
Western hemisphere. So what this looks
like is a single event. A single virus brought all
of these avian influenza genome segments into
the Spanish flu genome a few years before 1918. Let's now zoom in
on one of them. So here's our 1918 sequence. There's the related human ones
that circulated up to 1957. Most of you in the
crowd tonight would have been exposed to that. But that 1918 virus jumped
from a bird really close to 1918, and probably
from Canada or the US. All of the closely related
viruses are from North America. So now we're
getting even closer. Six of those genome
segments seem to have jumped in
from North America. And if you look at
the species here, the conventional wisdom is that
flu jumps from wild waterfowl. That's the basic
conventional wisdom about the reservoir of flu. That's the natural
home of flu viruses. And every once in a while an
accident, an unnatural event happens, and one of those
genes jumps into humans. Well it could have
been a turkey, could have been a chicken. And starts to look a little
bit more like the situation now, with H5N1, which is this
virus that infects poultry worldwide. And about which there's a
tremendous amount of concern that it might make the jump. OK let's now go back
to the horses, OK? Same pattern, horse
horse horse horse horse. So at node one here,
what you're looking at is the ancestor of that big bird
lineage that gave rise to most of the Spanish flu genome. And a horse lineage,
and at node 1 there's just two possibilities. Either that was a virus that was
in a bird and jumped to a horse at that point. Or it was in a horse,
and jumped into a bird. So now the story is going
to get even more strange. And believe me, when I
was doing this research, and started making inferences
about what happened and when it happened,
I actually didn't know about the great
epizootic of 1872. And if actually, if
you wouldn't mind, can you raise your
hand if you've heard about the great
epizootic of 1872? Larry Venable's showing off, OK. So he's heard me give this
talk before, I'm pretty sure. OK, I didn't know
about it either. An epizootic is just an
epidemic in an animal. It's a different name, OK. But in 1872, starting
in Toronto in the fall, you had essentially
Spanish flu for horses. You had a devastating
outbreak of influenza in horses that swept from
Toronto in all directions. By 1873 in March,
it was out this way. And so the US cavalry
and the Apaches were actually
fighting each other on foot for several weeks. Because all their horses and
mules were either sick or dead. And this was actually a
historically extremely important event. This is at a time
when horsepower came from horses and mules. And each one of these cities,
like Boston, for instance, for several weeks, all
the horses and mules were sick or dead. And it's kind of like
a science fiction movie where all of the cars, trains,
and the electrical grid get knocked out for three weeks. It was pandemonium. It was-- half of Boston, the
oldest part of Boston burnt down, because they were
trying to drag the fire engines with teams of young
men instead of horses. And it wasn't just a
historical curiosity, OK? This horse flu outbreak is
connected to the bird flu outbreak that we see in that
evolutionary tree historically. So just about a year
ago, the same guy that generated the 1918
genome of the virus was doing some
historical research with David Morens,
who's a historian. And they found this weird thing. In 1872 simultaneously with this
horse flu outbreak, in city, after city, after
city, there's reports of what, for all the
world, looks like highly pathogenic avian influenza. Except it's five, six
years before that disease was scientifically
recognized in Europe. So this is a real
headline from the New York Herald in November of 1872. "Swelled Heads on the
Thanksgiving Gobblers & Henfluenza Devastating
the Chicken Coops." Very strange. OK this match between the
evolutionary tree telling the story of a potential horse
to bird jump of these virus segments, and the history. And it's really hard to
dismiss the coincidence. And what it looks
like is instead of the conventional
view of birds being at the center of the genetic
diversity of the virus, that before the birds
had it, horses had it. And they gave it to the birds. And so the majority of the
genome of that 1918 virus started in horses, jumped
probably, and almost certainly into domesticated
birds, possibly then into wild birds in the
Western hemisphere, North America, and then
finally into us. And again, this is not abstract. So after I saw Joaquin this
evening and shook his hand, and he told me he
was feeling sick, after rushing to the
bathroom and washing my hand, I thought well
maybe he's got flu. Chances are, some of us in the
audience tonight have H3N2. That's the seasonal flu
that's going around. Well five of its
eight genome segments trace back to the 1918 virus. And six of its eight
genome segments trace back to that
horse in Toronto. OK, the next part has absolutely
nothing to do with influenza. But while I was digging around
about the history surrounding the 1918 virus, and I was really
interested in troop movements and horse movements
from North America to the Western Front in
1918, I stumbled across this. And figured I got to
share this with you guys. So apparently, there
were lots of plans that never came to fruition
for Germany to invade Canada. So Canada was fighting as
part of the British empire in World War I for several years
before the US entered the war. The US was still neutral. And one genius imagined
through rose tinted glasses that there were
probably 100,000 secret German military reservists
living in the US. And that if he
planned an invasion, they would probably be joined
by maybe a quarter million German Americans. And just throw in
300,000 Irish Americans-- [LAUGHTER] - They've got to hate
the British enough to invade Canada. [LAUGHTER] And this is the relatively
sane part of the story. So the plan was this--
to maintain secrecy, the army of 650,000
would dress as cowboys. [LAUGHTER] So this also served as
excellent comedy relief while I was doing this project. It kind of cleared my head. And this is not just some
crazy thing off the internet. I found out two days ago
when I was writing this talk that the paper was written by
a guy I took a course from, Simon Fraser University,
on World War Ii history. So this is real. I know that guy. And it was taken
seriously enough that the foreign office actually
had the lawyers look at it. And they said, you
know, this is OK. You need some way
for them to know who's part of the secret plot. And dressing as cowboys
seemed the obvious thing. No one's going to
suspect 650,000 cowboys with German accents. [LAUGHTER] And so this was not,
this never happened, but not because it was insane. But because the
German foreign office was worried that the invasion
might bother the United States, who was still neutral. OK. So this was basically
just to clear our palate before the final part
of the talk here. So back to flu. We've got a virus, most
of its segments in 1918 have jumped in from a bird flu. The end of these two
important proteins on the surface of
the virus, the end looks a lot like
those other six, looks like a bird
virus that jumped in. But the H is a different story. So this H protein,
its genetic diversity, if you compare it to
all the other ones, is way older than all
the other segments. And it's a very
simple interpretation. It's the same thing that
happened in 1957 and 1968. That an already
existing virus in humans with an H1 that probably jumped
in in about 1900, combined with an avian virus a
few years before 1918. And that formed the genome. OK so that's the story,
that's the basic. Those are the facts. And now how do we link those
to what happened in 1918? Well it turns out that
evolutionary trees are not the only way that
you can look back in time at what was
happening with influenza. And before there
was 1918, there was 1889, and before that
1847, and before that 1830, periodic pandemics, when we
think new influenza H and N genome segments
entered the population and became new human viruses. If you look at people
born just after 1900, there's a big spike
in the anti-bodies of those people to H1. And that's not what you would
expect if H1 came in 1918. If it came in in
1918, you would think that babies born in 1916, -17,
-18 would have that spike. So now we've got some
triangulation going on. The gene sequences
are telling us H1 probably jumped in in 1900. The antibodies in people's
blood is telling us people born during this
time probably had H1. And you can go back further. So this pink line here
is HeN8 antibodies in people born during
the 1889 pandemic. Very, very clear signal that
the virus in 1889 was H3N8. That's not my discovery. That was already known
and quite widely accepted. But check this out-- N8
didn't disappear in 1900 when I think H1 jumped in. It stuck around. And this was actually the best
part of this whole project. I had worked out the
kind of main parts of it. But I couldn't, I still
couldn't figure out why, in 1918, you would have
this switch where 20 to 40 year olds would suddenly be doing
much worse with this new virus. And 88 year olds were suddenly
doing much better with H1N1. It affected them less
than the previous virus. And so I thought to
myself, you know, the 1889 virus
was probably H3N8. And so I wonder if the N8 was
actually passed like a baton, as often happens with flu,
from 1889 to 1900 virus, and then to the
1900 to 1918 virus. And I thought OK, I'm going
to have to write a grant. And I'm going to have to learn
how to do all this stuff that I don't normally do. And then I thought,
oh wait a minute. This is not how we
work as scientists. And thought I'll look through
the scientific literature. And within about five
minutes, I found a paper from March of 1973, a
month before I was born. And in the abstract
of the paper it said that it really seems
like the N8 portion, the N8 antigens, persisted in a virus
after 1900 until about 1915 or 1916. And that was like, OK, this
is actually coming together. And if you-- I'm just going to
skip through that-- if you put it all together,
now you can start to fill in the
layered immunity that would have existed in the
population alive in 1918. Other people had
already speculated that those old people did
well because their childhood infection was H1N1. If that was the case,
once they were re-infected 80 years later
with another H1N1, their body retained that
memory and was pumping out good H1N1 antibodies. 1900 may have been an H1N8
which would mean the cohort born between 1900 and 1918 would
have had some protection. They would have had prior
exposure to H1 so the 1918 virus wasn't completely new. It's this little wedge
here, these people who were primed as
infants and children by the 1889 virus,
which was probably H3N8. They were probably the worst
off in terms of their childhood immunity. They probably had very little
protection to the 1918 virus, probably kind of
similar to a baby who'd never had any
influenza before, have no antibodies at all. Their H3N8 were useless
against H1 and N1. And that's what
it looks like when you're in a boxing
match against a virus, and you have no antibodies. It's like having two arms tied
behind your back, and boom. I also notice that
Sonny Liston's foot looks very long in this photo. That's like the
German cowboys, has nothing to do with anything. OK so if you just
take this model, and you say what's the
sort of average cohort protection of people of
different age groups? Well 88 year olds, we
think maybe they had H1N1, and so they had good protection
in 1918 against H1N1. These guys here sort
of had intermediate. They had some protection
from H1, not from N8. And various reasons I'm
not going to go into, these ones also may have
had sort of half protection. But it's this one
, this cohort here, the babies of the 1889 pandemic,
that were the worst off according to this model. And if you just
compare that to who died more than seasonal flu, and
less than seasonal flu in 1918, it looks pretty similar. Thank you, Ken [? Gaudet. ?]
Old people, good protection, low mortality. 25 to 29 year olds,
kind of naked, no help from their
antibodies, two arms tied behind their
back, high death rates. And it seems unlikely that it's
a coincidence that World War I packed 20 to 30 year
olds into high densities in army camps, troopships,
trains, the front lines. If this model is
correct, what that was was essentially taking
kind of dry tinder and packing it into very
compact physical locations. And if that's the case, then
probably the emergence of H1N1 was both a cause
and a consequence. World War I may have been
an ecological disaster in terms of allowing an
H1N1 virus to emerge. And once it did, it was
most likely to infect people who had no protection. OK so what does this mean? First thing is this,
which I tell my daughters on a daily basis. If that is what happened in
1918 it's kind of reassuring. It means we can
actually have a handle on the likelihood of a 1918-like
pandemic happening again. And it's not very likely. The next slide here shows
a big difference from 1918. That's about half
a percent mortality per year due to infectious
disease in 1918, now, negligible. So there's just not
as much pneumonia secondary bacterial infections
and all of the other things that actually deliver
the coup de grace when you're infected with flu
as there was back then. And we have things that
we can do about it. We have vaccines against a whole
bunch of bacterial pathogens, vaccines against
flu, and antibiotics, modern medical interventions. If everything else was equal to
1918, and you put that virus, and you had that layered
immunity, everything else except modern medicine,
it's very unlikely that things would
unfold in anything like what they did in 1918. At the same time, it
makes you kind of-- and this is something
that was raised by Joaquin during my practice
talk-- kind of makes you think about the
benefit that we have in this current age,
when we have antibiotics to streptococcus pneumoniae
which kills so many people, and so forth. And so I've got
juxtaposed do not panic with antibiotic
resistant diseases pose apocalyptic threat. But actually this is
a resource that you don't want to squander on things
that you don't need antibiotics for. You want your
antibiotics to work to prevent you from dying
from things like this if they ever happen. OK so this perspective
also gives us a handle on where things are
going to go from this time forward in terms
of new pandemics. Will H5N1 jump into humans? We don't know. But if it does, it would seem
that the people born in 1968, who their childhood infection
was an H3N2, different, those individuals who are
now about 40 years old, might be a kind of
beachhead cohort like the 25 to 29 year
olds were in 1918. So looking ahead you
might want to think about targeting
vaccines to those people if a H5N1 pandemic took hold. And you might be able to slow it
down, or maybe even prevent it. H5N1 has been in the news
quite a bit lately, this highly pathogenic avian virus. It's not clear whether it can
ever be transmitted from human to human. And there are scientists who
are working with ferrets, which are the best mammalian
model, that whatever happens in ferrets seems
to happen in humans. And you'll be happy to know
that they have developed mammal transmissible H5N1. Seasonal flu, OK so
there's H3N2 and H1N1. H3N2 is the severe virus. It's the one that's
circulating this year. It kills about 25,000
people in an average year over the age of 65,
H1N1 maybe 1,000. So it's-- H1N1 is extremely
mild in the elderly. Why is that? No one knows. Well if you were
born before, got to be careful here who I
include in the elderly cohort. [LAUGHTER] If you're 65 or older,
if you wouldn't mind raise both your hands. [LAUGHTER] Very brave. OK so that's-- keep them
up if you don't mind, and then look around. I'm not 65 or older. That's our herd immunity to
H1N1 if indeed this childhood infection is really important. And if you were born-- if you
are that age, look around now. Because that's the
childhood immunity to H3N2. So this might be,
actually, really important, not just for pandemics, but
for seasonal flu as well. And I should also
just very briefly say that looking ahead
several decades, eventually today's 40
year olds will be 65. And at that point,
there will be a lot of H3N2 childhood antibodies. And the prediction
would be that H3N2 would stop being so severe. And H1N1, if it's still
around, would be more severe. OK wind things up here. The timing of those genomic
analyses of maybe 1915. A few years before
1918, maybe this virus actually already existed and
was cryptically circulating. This is interesting because
other people had rediscovered a couple of old papers
from the Lancet that were published before the
1918 pandemic occurred. Both of them talking
about purulent bronchitis. So both of them were from
army camps, one in ETOP in France, which was
the main receiving hospital from the
Western front, and one in Aldershot in England. And both of these
in 1916 and '17 witnessed what, in retrospect,
looked a lot like Spanish flu. Really high mortality
in young people, a lot of the
heliotrope cyanosis, this ashen blue pallor. And at least this group
here speculated a year later that that indeed
was an early Herald wave of the 1918 virus. Adolph Abrahams was
the doctor on this one. He was the brother of Harold
Abrahams, the sprinter that you might remember
from Chariots of Fire. This one here was the
first of these two papers to be published. And there's a guy named
John Oxford in England who's been speculating for
years that maybe these were early Herald waves. And in a lot of his
papers he kind of said, you know, we don't have
sample-- we don't have access to these samples because a few
weeks after World War I ended, those hospitals in ETOP were
demobilized, like, immediately. And so one night, again
in the midst of this, some time after the
650,000 cowboys, I thought well, I wonder
if there might be samples. And so I thought OK, I'm going
to go through the author list. And I'm going to
target the pathologist. Because he'll be the one
that would have kept samples, if there are any. And so I started just
using the magic of Google. And I started searching
to see if I could find what happened to this guy. He survived the war. He went on to live
for quite a long time. I found that he had
two sons, one of whom survived to adulthood, and
his name was Charles Hammond. At about this point,
it's 2:00 in the morning. And my wife came out and
said go to bed, you wacko. It's 2:00 o'clock
in the morning, and why are you doing this? But I pressed on, and found
an obituary of this guy's son. And that obituary was
written by the husband of his granddaughter. And through a bit more
internet sleuth work that bordered on cyber stalking-- [LAUGHTER] - I found what I thought
was his e-mail address. And so 2:30 or 3:00
in the morning now, I send him an email. And say, you know
first off, forgive me if you're not the person
who I thought you were. And this is going
to sound crazy. But I'd really like
to find these samples. They'd be, amazingly,
they'd be kind of like the holy
grail for influenza, 1918 influenza research. Are you the right guy? Do you have any information? And the next morning
I got up and sat down and read my e-mail. And there was an e-mail
saying I am that guy. What a pleasure
to hear from you. And I think I have the samples
that you're looking for. So two boxes of slides were
preserved from this guy. They were his
teaching collection. And in those two
boxes of slides, there are at least a
handful of samples. March 18th, 19177, this
is from that study. The family sent me
a picture of him. So now we're stepping
back to 1917. This is the guy that
made that sample. And the bottom line, I went
to London a while back. They took me out to dinner. They're absolutely delightful,
very generous people. And they said, you know, he
would want you to look at this. And so even though these are
kind of family treasures, that's what we're going to do. And so we're trying
to figure out ways of sampling these slides
without destroying them. And the beat goes on. We'll see what we get out-- we
don't have any information yet. But I think with that, I will
thank you for your attention. [APPLAUSE] Oh, one more. Well you know that
the lecture next week is going to be another Michael,
and boy are you in trouble. So there's a few questions
that maybe Michael Worobey can answer? Michael. Yeah, Rich. So on that one slide showing
the strains circulating through humans, through time,
at the end you had the H3N2 and you had that H1N1. And it said H1N1 lab escape? Yeah, so I thought someone
might ask about that. So in 1957, the
Spanish flu like H1N1 went extinct when H2N2 emerged. In 1968, H3N2 kicked out H2N2. But in 1977, there was
a kind of mini pandemic, and H1N1 reemerged. And bottom line is if you
look at the molecular clocks, it was frozen in time,
not even since 1957, but it was 1950 H1N1 strain. And it's virtually certain that
it was an accidental escape, probably from an experimental
strain from China or Russia. And so yes. The worst pathogen
in human history was accidentally re-released
and not too many people know about it until you guys. [LAUGHTER] Yeah? Hi, I had a quick
question about, as far as immunization today. So vaccinations, I hear, I
could be completely wrong, but they only protect us from
about five different strands of flu virus. So I was wondering exactly
how the scientists determine which strands to protect us
from, and how really effective they are for us. And is it really worth
us taking the shots? Yeah, so first answer is
yeah, it is worth taking them. Second is that there are
two different variants, H3N2 and H1N1. And there's also another
variant called influenza B. So the normal vaccine has all
three of those components. And it's kind of glass
half empty or half full. It protects maybe
somewhere around 50%. And that's bad compared
to other vaccines. It's good if it prevents you
or someone you love from dying. There is one issue though. It does seem to have the worst
efficacy in the elderly, which is the age that you would want
it to have the best efficacy. And I'm hoping that
part of the story is that childhood infection with
what we call heterosubtypic, so the wrong subtype, might
actually be interfering with the efficacy. And we might be able to ramp
it up in those older people. There's one somewhere, yeah. Hi, so you mentioned earlier how
with the bird flu researchers, they're using ferrets
as a model organism. Why is, like, what's so
special about ferrets? Just because I would
never think of that. Yeah they just happen to have
lungs that act a lot like ours. Mice are also used. Pigs are also used. But ferrets, they
can be infected either through the nose
or through the blood. And whatever happens
in them seems to be the clearest analog
to what happens in humans. And so that's why they're used. Okay, the last one. Can the virus completely destroy
the host cells they're in? Or does the H and the
N just open the cell for the virus to pass in? It actually can leave the
host cell intact for a time, keep it alive. But once it is taken over,
it's no good as a host cell any more. If it does stay alive, it's
only staying alive to pump out new virus particles. Michael, thank you for
an extraordinary talk. My pleasure.
Good post! I just want to include a notice that the primary similarity between influenza and nCoV is the fact that they are both respiratory viruses - biologically they act very different.
This was amazing!
I used to work in Dean Ruiz's office back in 2006. Great guy. I am sure he wouldn't remember me, I was a receptionist for a short time.