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Hi I'm back from my second lecture now. This is going to be
quite different from the first one you heard. First one was the
the science that goes on in my lab. This talk is why I do that
science and why we all have to be aware of what's going on
in this global village that we live in. It has become clear
that the global infectious disease threat is real and something we
have to worry about. Today infectious diseases are the leading
cause of death worldwide and the third leading cause of death
in the United States. Now the diseases that predominate
we all know about and have heard about. Of course they include
***/AIDS. They include acute lower respiratory infections,
diarrheal diseases, tuberculosis, malaria but since 1973,
at least 29 previously unknown diseases have emerged. Now
20 diseases have re-emerged in new places where they never
were before and are sitting in new ecosystems. And the question
of course is, "Why is this happening?" Where do new diseases
come from? Why are we facing such an escalation?
And in point of fact, this is due to the very dramatic changes in the
society and in the environment in which we live. There's been an
explosion population growth, spreading poverty, global warming,
and urban migration, and what we're finding is new pathogens in
new places and old pathogens in new places. And what do we mean by,
"How is this happening?" So if we have urban migration,
which means we're moving into our forests, a typical disease that
is now blooming all over the place is Lyme disease, carried by a tick.
And that was due to deforestation to make way for new homes.
And this causes a tick bite that's carrying this bacterial infection
is quite devastating. Another that we of course all know about is
***/AIDS that is growing and spreading in all urban populations.
Another interesting one is called Hantavirus. This virus was unknown.
It's new to us. And it appears in the American far West in
Utah and Arizona. It's carried by mice and rats. This is a very
nasty virus with a 60% kill rate. And we're still trying to understand it.
Another one that's coming out of the forests in Africa is
caused by a virus, and it's Ebola. And that is a very difficult virus
to deal with. Now we have also the different kinds of changes in our environment.
For example, Mad Cow disease, which you've all read about and
heard about, which is caused not by a bacterium, not by a virus,
but by a protein that changes conformation and goes into a
state that causes a very severe neurological brain defect.
And why did this somehow get out of the box? And if you remember
in England several years ago, there was just an outbreak
of Mad Cow disease, and it turned out to be due to the fact
that the production of the foodstuffs that we feed all of our
livestock was made differently. We were feeding them various kinds of
vegetable, mineral, and animal refuse and this time they would
include the nervous structure--the brains and the nerves. And that's
where these prions were. And then it wasn't until the mandate
came down to change the preparation of food for our livestock that
this epidemic was dropped down. And this had to be changed worldwide.
So this is another example of us trying to survive in large populations
and feed everybody by changing the way in which we carry
out what we do. The other thing that's happened is that
there's been a resurgence of very drug-resistant tuberculosis.
And in South Africa now, there are strains of the bacillus that
causes tuberculosis that are resistant to every known antibiotic
and it's a particularly virulent strain with a very high kill rate.
So the crowding, urban mixing of people and pathogens has given
us a bloom of bacteria that are resistant to antibiotics. Now
we also know that we have international travel everywhere.
It's increased. If we have a disease outbreak in Kuala Lumpur,
in a day, the person that gets on that airplane with an infectious
disease can be in Chicago in that same day. So that we are
rapidly moving all over this globe, and there's an incredibly rapid spread
of disease, reminding of us that no country is an island. And we now
live in a global village, which means that all the countries on this globe
have to now coordinate, collaborate, and help one another
to identify diseases and to disseminate things that will help
squash down an outbreak of some kind. Now, one other thing that
happens when this guy picks up a disease in Kuala Lumpur and
winds up in Chicago--now the people in Kuala Lumpur may have
been living with this disease for a little while and they've built up immunity.
But the people in Chicago have no immunity to this and so it's
a bigger problem. Now the part of this that's difficult is that we have
asymptomatic travel. You get on a plane and you feel fine but in fact
you're infected. And of the big problems with a possible influenza
epidemic is if you catch flu bug--influenza--you are asymptomatic
for at least two days. And during that period of time, you are
infectious. So you don't know what you're transferring. And that is
what leads you to pandemic. Now another problem of course is
the loss of control of our national borders. And we're really not very
good at carrying out our quarantine laws. It's difficult to do this.
And we are going to return to this later in my talk because in many diseases--
effective quarantine laws are the only thing that we're going to
use to protect ourselves. Now every one of these issues is something
that is being worked on and understood by many countries
coordinated by the World Health Organization. The final issue that
is almost making where we live now a perfect storm is that
while we have increased globalization, while we have increased
population, while we have increased urbanization, and the migration of
pathogens into new ecological niches, we have the rise of
antibiotic-resistant pathogens. So let me tell you what an
antibiotic is. An antibiotic is a small compound either made
in a laboratory or made by some living creature and when
this compound is made, what it does is kill the pathogen.
It kills the bacterial pathogen. Perhaps I should just remind you
of the difference between a bacterial pathogen and a viral
pathogen. A virus is not a living cell. A virus just has a protein
coat and the genetic material sits inside this coat. And it
cannot make more of itself. The only way it can make more of itself
is if it infects a host cell--one of our cells, one of the cells that are
of a rat, or a monkey, or some other animal. And then it gets in there
co-opts the machinery of that cell and makes many more of itself.
That's a virus. A bacterial cell is this little tiny living cell that can grow
and divide and respond to its environment and figure out if it's
a pathogen how to get into a host cell and make you very ill.
So that's a bacterial cell. Antibiotics are specific for bacterial cells,
not viral infections. And what has happened is that we have had
a history of various kinds of antibiotics, which were first discovered
in 1946 with penicillin. Then soon after that, we had strep and staph
infections that would be very sensitive to penicillin. Today, 80%
of all strains of staph--staphylococcus--are resistant to penicillin.
This was quite a shock to us. In 1950 we had more antibiotics that
would infect multiple bugs--streptomycin, chloramphenicol,
tetracycline. Then in 1953 there was a Shigella outbreak in Japan
and it resulted in the appearance of a strain of dysentery bacillus
that was resistant not just to one antibiotic but to many. And that
was a red flag. And people started becoming somewhat concerned.
Up now to 1982, when we had the last new class of antibiotics--the quinolones--
resistance is rising, really, in a frightening manner. Cipro, to which
we were eating like candy when there was an anthrax scare in
the United States, has caused enormous resistance to that particular drug.
In 1998, vancomycin, which is considered by many an antibiotic of
last resort for staph infections and other kinds of pathogens,
we are now seeing the emergence of resistance to Vancomycin as well.
Now what happens when something becomes resistant to an antibiotic
is that it turns out that these bugs are very, very smart and what they
have learned how to do is if they see a drug coming towards
it, like arithrimycin, it figures out how to spit it out. Or if the
antibiotic manages to get into the bug, the bacteria have figured out
a way of chemically modifying that antibiotic so that it's no longer
working. And they also have figured out how to change the target
of that antibiotic in that particular cell so it doesn't work any longer.
So these bugs are very smart and we're in a war with them and
the bugs are winning. And what we need is to understand how to make
new and better antibiotics. If I just look at staph infections in the
United States, in 1957 100% sensitive to penicillin. 1982-- fewer
than 10% of all staph cases could be cured by penicillin.
1993-- only vancomycin survived as an effective antibiotic. And today, as I
told you, there are strains that are resistant to everything. So
one of the questions is, "Why is antibiotic resistance growing so rapidly?"
And in fact, what we're seeing is that antibiotics are put into animal
feed, into aerosols for fruits and vegetables. Of the 50 million
pounds of antibiotics produced annually in the U.S., 40% go into
livestock. So how does this resistance arise? Let's say you
have 10 to the ninth (10^9) bacterial cells all resistant to a particular antibiotic.
One of those 10^9 cells has a mutation that makes it resistant.
All the others will be killed by that antibiotic, but that one
will happily grow and divide and then you have a bloom of an
antibiotic-resistant pathogen. By feeding antibiotics in huge quantities
to all of our livestock, we are increasing the chances of that one
guy to develop antibiotic resistance. Another reason that things--
this resistance--is growing so rapidly is that there are growing numbers
of immunocompromised people. And this is really partly due to
the wonders of medicine and also to new infectious diseases.
Chemotherapy patients have very, very low immunity. They're infected
by many different bacteria and they grow and divide and develop
resistance. Transplant patients, AIDS patients, even just aging populations--
if you're over 65, your immune system is going to hell in a handbasket.
And so you have to really realize that you are particular sensitive to
bacterial infections and again you become a reservoir for increased
antibiotic resistance. There's also the excessive use of antibiotics,
over-prescription and then unregulated over-the-counter sales. So these
are all very serious problems. Of course, as I told you before,
international travel has us all over the place. And so if you get
a multi-drug-resistant strain of streptomycin in Spain, you wind up
with it in South Africa in four days if somebody is traveling rapidly.
So we have complete and rapid dissemination. Now what I'm
going to turn to is the story of where new bugs come from.
Where do new pathogens come from? And the story I'm going to tell you
is one of E. coli 0157. It's a new and pervasive pathogen. It's a food
contaminant that is now the leading cause of kidney failure
in children. Now the first time I told this story was in a very
unusual scenario. It was during Bill Clinton's administration.
And he became very worried about genetic engineering--
in other words, what we can do in the lab now in building new
groups of genes and perhaps altering a pathogen or altering some other
normal process. And he was worried. He wanted to know how
worried we should be about malevolent forces actually creating
new pathogens. And he wanted to understand what was happening.
And I was part of a group of six people who were invited to speak
with President Clinton and his whole cabinet. And the story I
told them really was that genetic engineering, yes we can do
in the lab, but the bugs and the various kinds of critters in the
natural world are much better genetic engineers than we are and
the example is E. coli 0157. Now, this is a picture of a virus
and I'm going to show you and tell you how this figured in
to the genetic engineering that was carried out by E. coli 0157.
So where did it come from? E. coli 0157 was first isolated
from a 50-year-old woman in California, who came down with
severe gastric distress and bloody diarrhea. She survived but
she was quite ill. Then in 1980, 14 children were admitted to a Toronto
hospital with the same symptoms. Of these, two children died
and the rest were left with severe kidney damage. Again
the bug, the bacterium, isolated from one of these kids
was the same as that found in that 50-year-old woman and
upon analysis, the very surprising development was that this
E. coli cell, which is a bug that grows in all of our gastric system
and is quite harmless, had picked up a gene--a particular gene--
from another bug, a pathogen called Shigella that coded for a toxin.
So now we had taken an E. coli cell and put in a gene that made it
a pathogen. That is genetic engineering. In 1981, in White City,
California 12 people eating at a local hamburger place became
ill with the same symptoms. 1982 in Michigan--again a local hamburger
place--E. coli 0157 was found in its meat patties. 1993--Jack-in-the-box
restaurants in the Northwest--hundreds became ill. Four kids died.
And this continues on and on. It was found in 1996 in contaminated
apple juice and lettuce. And that turned out because the E. coli cell
picked up not only your gene for the toxin but a gene that makes
it resistant to acid. So it could grow in an acidic environment,
which normal E. coli does not. 1997--there was again a huge
recall of contaminated hamburger meat. And in 2007, just a couple
months ago, contaminated spinach was found. And that came
from the runoff from livestock, which were not too far away.
So it turns out that now, there are 25 to 30 outbreaks per year
in the United States alone of E. coli 0157 contamination
and 5% of our dairy cows carry this pathogen. So how did this
happen? How do we think that this occurred? So what I'm showing you
here is a bacterial virus. Remember I told you that a virus
has a protein head, and that's shown here. That's the head.
This is its tail, and there's DNA in this head. And this over here
shows you what the virus looks like. This over hear shows you a
diagram of this virus. Looks like a moon lander, doesn't it?
And what this moon lander does is it lands on a bacterial cell
and it injects the DNA, the genetic material, right into the
bacterial cell that it hits. And this is how we believe this happened.
Okay. In this diagram I show you a Shigella bacterial cell. The blue
circle indicates the chromosome--the single chromosome.
And the little moon lander up there indicates the virus.
So the virus injects its DNA, and that's that little circle in the
center of the head, into the cell. Once that DNA gets into the
cell, it codes for things that chop up that blue chromosome.
You chop up that blue chromosome and the little piece
that contains that Shigella gene, then gets put into the head
of a new virus. And so this new bacterial virus contains
its own DNA and a little bit of that Shigella DNA. And that little bit
contains the gene that causes a toxin. Now what happens is
that that same virus hits an E. coli cell. And we believe this
happened during an epidemic of dysentery in Central America
when both E. coli and Shigella were mixed. And this virus injected
its DNA into the harmless E. coli. And this piece of DNA got
incorporated into the DNA of this E. coli, creating E. coli 0157.
That, folks, is genetic engineering. That happens naturally.
So now let me tell you a second story. And the second story
deals with why it's so difficult when we're first faced with something
that we haven't seen before in a given country to decide whether this
is a natural outbreak. Is it a malevolent deed? Where is it coming
from? And this is an interesting story. Now West Nile virus
causes an encephalitis-type disease. But it had never been found
in the Western hemisphere. And this is several years ago now.
And the way it started was that birds in the Bronx zoo started to die.
And they had an encephalitis-type infection. And a vet in the Bronx zoo
sent her tissue samples to the CDC--Center for Disease Control--
and they were pretty overwhelmed because the CDC never has
enough money to do everything they have to do and they sort of
said, "Yeah, we'll get to this. Birds are dying." Well, at the same time
there was an increasing number of human patients in New York City,
which were exhibiting and dying from an encephalitis-type disease.
People thought it was the mosquito-born St. Louis encephalitis virus.
They didn't really know. Then the chief of Emergency Management
in New York City managed to co-opt the entire supply of "Off."
"Off" is something that kills mosquitoes and flying bugs, and he
just sprayed "Off" all over the city and he stopped the epidemic
cold. Meanwhile, the lady vet at the Bronx Zoo was still trying
desperately to find out why her birds were dying. Waiting to hear
something from the CDC, and the weeks were going on and she
happened to go to a wedding on the West Coast and sitting
next to her at this wedding was a virologist. And not particularly
interested in dancing, they started talking about this odd thing
that was happening to her birds at the zoo. And he said, "Look,
why don't you send me some of her tissues, and I'll try to figure out what
you've got." And that's what happened. He very rapidly identified
this as West Nile Virus. Now everyone's initial reaction was,
"This couldn't be. We don't have West Nile Virus in the Western
hemisphere!" But at about that time, in Fort Collins, the CDC had
in fact identified this as well as West Nile Virus. It just took too long.
And this was our first experience with trying to rapidly identify
something new. Now, interestingly, concurrently while all of this
was going on, an Iraqi defector had reported that Saddam Hussein
was developing a strain of West Nile Virus as a biological warfare
agent and was preparing to release it. This was never confirmed.
Was this a BW event? We don't know. Did this come into the United
States on a 747 that a mosquito happened to crawl into? We don't
know. We don't know the answer, but what's important--what one
has to remember--is anything we do to identify a new outbreak
will be relevant no matter what the source is--malevolent or natural.
The problem is to understand what we've got and to rapidly
understand how we can analyze these things and identify the
agents. Now, this is changing. And this is changing particularly because
of what we found with SARs. Now that's happened fairly recently.
SARs is Severe Acute Respiratory Syndrome. It's caused by a
corona virus, which is an RNA virus. It's similar to the viruses that
cause the common cold. It has a very high potential for natural evolution
so it can change itself a lot. Now with SARs--it's an interesting story
because this is an infection that first started predominantly in
Hong Kong and Beijing and Guangdong Province in China. But
very rapidly appeared in Toronto. And what happened there
is that we had a highly infectious agent that exemplifies this
global village we live in. There was a scientific meeting in Hong Kong.
Someone got sick. They wound up in Toronto and it was all
over the place. But SARs is an example in which we were much better
at identifying the agent rapidly by sequencing. We were also
able to realize that the only thing that would be effective
was quarantine. And this is interesting because in fact
Singapore was very effective in quarantine. They said, "This is
what we have to do to stop this." Whereas Hong Kong and Toronto
were not. Ultimately it stopped. The dealing with this was very effective.
And actually there were very few deaths if you look at it in a global way.
But the effect on the economy was enormous. And so this tells
us that even a minor outbreak is going to have severe economic
implications globally. And what it did do though was help the World
Health Organization build a network of reporting, of understanding, of
diagnosing outbreaks of diseases everywhere in the world. So
that we would know how to respond and deal rapidly with them.
Now what I'm going to do is end this talk with a discussion of something
that's facing us all right now. And that's Asian bird flu H5N1.
This causes influenza. Influenza is with us all the time, various
different kinds of strains. This is a particularly frightening
one. However, there is no strong evidence as yet of human-
to-human transmission. Right now, this is a disease of birds--
local fowl, poultry, wild birds. Our concern is that H5N1, which
mutates rapidly, will ultimately go from person to person.
Now, let me tell you a little bit about this virus because it's relevant.
Each virus has a single strand of RNA containing 8 genes.
Each gene encodes a single protein. This very high mutagenicity
rate, in other words changing the kind of protein that's made
from each gene, can happen by reassorting the genes by
single-base mutations. And it just changes rapidly. That's
why we get flu shots every year. And basically at this time
we know that the transmission of H5N1 goes from ducks to
either wild birds or to some cats, tigers, lions, leopards, house pets
with a fairly easy transmission. However, from wild birds to humans
does occur. It's not easy. You need very personal contact.
And humans to humans--there's not strong evidence of that yet.
Our concern is that it might happen. And so what is H5N1 mean
anyway? "H "stands for hemaglutinin and that is a protein that sits
on top of that cage that the RNA sits into. The function of
that hemaglutinin is to allow the virus to bind to the host cell
and allow entry of the RNA to do its bad stuff. "N" stands for
neuraminidase. Neuraminidase is another kind of protein
that's also sitting on the surface of the cell and it allows
newly formed viruses to escape and infect other cells. We have
two anti-virals out there now. One is called Tamiflu.
The other is Relenza. And the neuraminidase is the target for both
of these. And in fact, the best way to use something like Tamiflu
is if you've not been infected yet, it will give you 80% protection
for awhile. If you've been infected, it will drop the viral load so that
you're not as contagious. You'll still get sick but you won't
be as sick. Now if we look at the history of flu viruses, the most serious
flu pandemic occurred in 1918 and that influenza was H1N1.
It killed 40 million people worldwide and H1N1 means a particular
derivative of the hemaglutinin and the neuraminidase. 1957
flu was H2N2--killed about 2 million people. 1968--H3N2 killed about
a million. I know that one very well because I caught that one.
And let me tell you--a real flu infection is no fun. Their current
Asian bird flu is H5N1 as I've said. Scary thing about this guy
is that right now it has a 50% kill rate, which is enormous.
And humans have no immunity against H5, whereas we have some
against H1, H2, and H3, which has been around for awhile.
So what needs to be done? How are we going to deal with this?
Let me just tell you first that using something like Tamiflu
is best done in my opinion not by sprinkling Tamiflu amongst
the 30 million people in the world but rather using it where there's
a hot spot. Now that we have an entire network of reporting
coming all over the world, keeping their eyes out for hot spots
of sudden break outs of H5N1, possibly being passed from human to
human, then our Tamiflu has to get there immediately. And then
what you do, is you cordon off the area, quarantine, treat with
Tamiflu, and start vaccines. Now clearly the vaccine we have now
is to the H5N1 that only goes between birds and possibly cats.
What we will ultimately need--if this happens--if it mutates to
human-to-human is that we then have to get a new vaccine
that will be against that particular variant. And a lot of work
is going on right now by many small companies and many
large pharmaceutical houses to be ready to make this as quickly as
possible. Now one thing that is important to realize is that
vaccines are made in eggs. I mean zillions of eggs. If you go to one of these
vaccine production places, it's astonishing. It's like a football field
of eggs. And virus gets injected into these eggs and then a high titer
of more viruses made that's impaired. You kill it. You then make
the vaccine. The reason that we use eggs is that you get a very high
titer. One thing that I can't stress too strongly is that in fact
you can't get flu from a flu shot. It's dead. But you certainly can
get immunity. But people seem to think that vaccines are an
absolute panacea. It's not true. Flu vaccines are 70-90% effective
in young healthy people and only 40-60% effective in people over
65. So that the flu alone is not going to save us. But there are
many things that we can do to help ourselves. One of the things
we have to do is that we have to stockpile face masks--the kind
you buy in the hardware store for painters--syringes, medical
supplies, food, and water. Currently we do not have in the United States
enough ventilators if we were to have a pandemic. So it's extremely
important that we learn how to deal with large amounts of people
becoming ill. So what if we do get a pandemic? What does a
country do? And what I'm going to do is end with sort of an
economic part and that is in ordinary times economic logic does
not dictate pandemic preparedness. We all keep low inventories.
We don't want redundancy in reserves. We have lots of offshore
drug production because it's cheaper. We don't guarantee the
purchase of flu drug as we do with other kinds of weapons.
In fact we have just in-time delivery with no surge capacity.
Now what does this mean if you have a pandemic? The supply
chain is very thin. Every hospital contains only 30 days of drugs.
We have, in a pandemic, workers becoming ill. Drug company
workers, the production of new vaccines and new drugs will become
less. And in fact, we'll have borders closed and embargos. They
can't get in. Truck drivers get sick. Things can't be delivered.
We then have to say, "Alright, what do we need to do to deal
with this?" We need scaled-up manufacturing and stockpiling of
vaccines and anti-viral drugs, as well as antibiotics because
many people die of flu infection by a secondary bacterial infection.
So we need antibiotics. There's a pneumococcal vaccine that is
something people should all have that helps. We need better
surveillance and epidemiology on a global scale, very accurate
reporting of case clusters. We need actual procedures for drug
delivery and most important, we need quarantine laws. Not only
here in the United States but everywhere in the world. And
our population has to understand what these population laws,
what these quarantine laws, are before we're faced with the
absolute disaster of a pandemic. And you have to know what
you're supposed to do in a quarantine, where you'll get your medicines,
who will see you. And this can't be done just at a national level.
It has to be done in cities and towns where groups of people
can work together. That's probably the strongest thing. Now
let me just end by turning this back to what are the things that needs
to be done with this emerging infectious diseases with the way
in which our world has changed and the basic science that's
going on. So we have now a real need to increase basic research
to understand these viral and bacterial pathogens. We have to
identify genes essential for the pathogen's survival. We have to
sequence and compare bacterial and viral genomes. We have to
identify virulence factors and resistance genes and understand
how they work. And as I said in my previous lecture, by understanding
how the bacterial cell carries out all of its functions to let them grow
and divide, we have identified new targets and designed new
antibiotics. That's just one lab. And this has to happen in many
many more. The second thing that we have to do is design
and stockpile new vaccine strategies and in fact make combination
antibiotics where you have a particular drug that kills the bug
but in that same pill or shot you've got a compound that prevents
the resistance from being expressed. And then finally for epidemic
control, we have to develop techniques for very fast--hours, not
days, not like what happened with West Nile or even the slowness
of SARs, which was much better--to identify causative agents.
To do this, we have to exploit viral and bacterial DNA sequence-
based technologies. We need, as I keep saying, an increased
network of surveillance and reporting protocols and finally
return to the historical use of quarantine. If we all work together
and if we realize that we are not just independent islands
and separate countries, we work together as a global village
and help us combat these things. So with that, I'd like to thank
you very much.