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9. Frontiers of Biomedical Engineering: Biomolecular Engineering: Engineering of Immunity
Poziom:
Temat: Nauka i technologia
Professor Mark
Saltzman:
Okay, this week we're going to
continue in our discussion about
the immune system.
But talk about sort of
engineering the immune system,
how to produce immunity in
individuals.
And we're going to do that by
talking about some examples,
some historical examples,
in the sort of technology and
vaccine development.
And what I hope to do over
the course of this lecture and
the lecture on Thursday,
is complete what's described on
this outline slide here.
First, using a couple of
examples that have turned out to
be very important,
one is the example of smallpox,
and the second is the example
of polio.
Talk about how vaccines were
developed in these particular
situations, and how the
development of the biology is
coupled with delivering this
through populations,
and how these sort of
intricately woven together.
It's not enough to understand
the biology of how to create a
vaccine, if you can't make
enough of the vaccine or deliver
it to people in ways that it's
useful.
And so we'll talk about how
that happened in the--using the
examples of smallpox and polio.
And that will bring us to a
general discussion of sort of
the tools that are available now
for vaccine development,
which we'll talk about on
Thursday.
I don't have to say too
much about why vaccines are
important.
You know about this,
and this is a slide that I
showed you.
The graph is something I showed
you on the first day of class,
that over the last hundred
years in particular,
but what's shown on this slide
is over the last 300 years.
Life expectancy for humans has
increased dramatically.
And one of the reasons that's
most responsible for that is
that humans aren't dying at as
young an age from infectious
diseases as they did three or
four hundred years ago.
And there are many reasons for
this, our success in eliminating
infectious diseases as causes in
the developed world.
And you know what those reasons
are.
One is that doctors started
washing their hands in between
when they saw patients.
That had a remarkable effect on
reducing transmission of
infectious diseases,
in doctor's offices and
hospitals.
Another is that we learned a
lot of things about engineering
of public systems,
like water supplies.
Separating our water supply
from sewage and learning how to
do wastewater treatment was a
really important part of
reducing infectious diseases.
But vaccines,
and particularly in the last
hundred years,
vaccines have been one of the
most important elements in our
progress.
And so what this slide just
reminds you of how much progress
we've made.
Also, shows you something about
the challenge of it,
because we are susceptible to
attack from lots of different
kinds of microorganisms.
So, not just a spectrum of
viruses, but there's viruses and
bacteria and parasites and other
microorganisms that can cause
disease.
And so this slide just
illustrates that in a simple
way, the range of different
kinds of organisms that your
immune system is trying
to--whoops!
[laughs]
Wait a minute,
I've lost control of--I'm
not--Oh, there it is.
It's not showing up on the
screen for some reason.
That, this shows the range of
morphologies of microorganisms
that your immune system has to
potentially encounter,
from complex organisms like the
syphilis pathogen here,
a virus, this is a
false-colored image of a virus,
very tiny, not shown to scale
here;
and bacteria like
salmonella and
staphylococcus.
So these organisms like this
are abundant in the world around
us and our immune system
prevents us from getting sick
most of the time.
So what is a vaccine?
A vaccine is a prepared,
it's a preparation,
that's prepared in some way.
We're going to talk about how
they're prepared,
but it's a preparation that is
intended to stimulate your
immune system.
So, what that really means,
you know, from last week's
lecture, is that the vaccine
stimulates these particular
cells in your immune system to
give you immunity.
We're usually talking about
adaptive immunity here.
So, either stimulates the
production of--and
differentiation of B-cells,
to produce a specific antibody
that can neutralize the virus,
or stimulates the production of
cytotoxic T-cells that can kill
infected cells within your body.
But in any event,
the vaccine is intended to
stimulate the immune system to
produce an effector
response--either antibodies or
specific cells--that can combat
spread of the microorganism
through your body.
Usually it's done by taking
all or part of the infectious
agent, and showing them to your
immune system in some way.
And so we talked very briefly
last time about this business of
antigen presentation,
how your immune system--one of
the things that it does
especially well,
is recognize what's part of you
and what's not part of you.
It can separate between what's
part of yourself and what's
foreign, and it does that by
presenting,
by recognizing antigens that
are presented in the context of
the major histocompatibility
complex,
MHC.
So a vaccine is designed in
order to engage that biology,
in order to provide antigens
that will stimulate specifically
your immune system.
Usually it involves pieces of
the infectious agent itself,
to cause that engagement.
So, that's what a vaccine is,
and vaccination is the process
of taking that vaccine that
you've developed and giving it
to people,
either individual people or
groups of people,
or as we'll talk about today,
people all over the world.
And so that's a very different
thing, right?
Designing something that works
in a particular individual,
and designing something that
can be used in people all over
the world,
involve different sorts of
accomplishments.
Well, we've all had some
experience with vaccines.
You can't go to school in this
country, and in many countries,
until you've had your
prescribed set of vaccinations.
And so they're already very
safe, very effective vaccines
available for many infectious
diseases.
There's a partial list that's
shown here, starting the top of
the list with smallpox,
and that's what we're going to
spend most of the time talking
about today.
There are vaccines for rabies,
for typhoid,
diphtheria.
Most recently,
or more recently,
there was a vaccine for
varicella, which you know is
chickenpox that was developed in
the last ten years.
Now, so there's probably a
number of people in this room,
so when I first started
teaching this class 20 years
ago,
everybody in the room had had
chickenpox.
Right, now are there people
here that have not had
chickenpox, right?
Because you had the vaccine,
presumably, and so you didn't
get the disease.
And so this is a substantial
change in the interaction of a
microorganism with a population,
right?
A lot of didn't get sick from
it now, and we got sick from it
before.
You also know that there's some
vaccines that are not yet
available, for diseases that we
would very much like to prevent.
HIV infection and AIDS is the
one that comes first to mind,
and is responsible for this
slide,
I think this is data from a few
years ago, 700,000 deaths per
year.
That number is undoubtedly
higher than now.
AIDS is a tremendous problem,
deaths from HIV infection and
AIDS a tremendous problem in
Africa and other parts of the
world.
But there are other
diseases that are numerically
even more important.
The whole category of diarrheal
diseases, caused by viruses
called enteroviruses,
where they, it infects your
gut.
Your gut's unable to function
in the normal way,
and so you get severe diarrhea.
You can become dehydrated and
die just as a result of the loss
of water there,
because of your body's natural
response to the infection.
And that causes five to ten
million deaths per year.
And children are particularly
susceptible to these.
Children get diseases from a
class of viruses called
rotaviruses,
for which we have no vaccine,
and- and so no way to protect
them.
Malaria causes a million deaths
per year, and schistosomiasis,
which is a parasitic disease,
is unfortunately a common cause
of death in the world.
And so these are situations
where we would very much like to
produce a vaccine,
but we can't yet,
and the question is 'Why?
Why is it difficult in some
cases to produce a vaccine when
we've been successful in so many
others?
And so one of the points I want
to make here,
on this slide,
is that this is a very
disease-specific thing.
Learning how to turn on your
immune system to protect you
from a specific pathogen turns
out to be very particular to
that pathogen.
That shouldn't be too
surprising given what we talked
about last week,
that your immune system,
the adaptive immune system in
particular, responds to
individual antigens differently.
Just to think about what's
most important in the U.S.,
of the top five reported
infections in the U.S.,
and this is again from a few
years ago, but I'm fairly sure
that the numbers haven't
changed,
three of the top five
infectious diseases,
or the infectious diseases most
commonly reported in the U.S.,
are sexually transmitted
diseases: Chlamydia,
gonorrhea and HIV infection.
None of these do we have
vaccines for,
and it's turned out that
sexually transmitted diseases
for a variety of reasons,
we'll come back to later,
are particularly difficult to
develop vaccines for.
We'll talk about why that's
been the case as we go through.
And this just is another
list, I mainly wanted you to
have it in your notes of
diseases that are important
around the world,
for which there are very active
programs to develop either
vaccines or more effective
vaccines.
You know that there is a
vaccine for hepatitis B,
for example,
which is on this list.
And you've all been vaccinated,
I would guess,
for hepatitis B.
It's the one where you have to
get three shots over a period of
six months, and so you have to
remember to go back,
you get a first ba--you get a
first shot, you have to remember
to go back after a month and get
a second shot,
you have to go back after six
months and get a third shot.
Then they test you to make sure
that you have adequate
protection, and some people need
an additional shot after that.
And so that's an effective
vaccines.
But it's only an effective
vaccine in the context where you
have people who can go to the
doctor's office,
or to an urgent care,
some kind of medical facility,
three times,
reliably,
at a specified period of time.
And that's not possible in all
parts of the world,
not everybody has that
opportunity to interact with
medical professionals that
often.
And so there's a lot of
interest, not just in developing
vaccines for diseases that we
don't have vaccines for,
but for delivering vaccines
that are more effective.
For example,
what if you could make a
hepatitis vaccine that was good
in one shot instead of three
shots?
Or vaccines that could be
transported more easily--the
hepatitis vaccine that we get is
not stable unless it's
refrigerated.
It's in solution,
it's refrigerated,
and it's very difficult to
transport refrigerated vaccines
to all the remote parts of the
world where you would like to
transport them.
And so that very practical
consideration turns out to be
important in how we use vaccines
in real populations.
So if you could make a
hepatitis B vaccine that didn't
require a shot or that didn't
require refrigeration,
that would be a tremendous
advance in spreading that
vaccine through the world.
So, that's another example of
the difference between a vaccine
that works, and a vaccination
that works, right?
A vaccine might work if the
person is there and you can
interact with them.
A vaccination,
for it to work around the
world, has to be inexpensive,
transportable,
possible to use without
advanced medical personnel,
and those kinds of things.
Okay, so let's talk about
the example of smallpox,
which is one of the world's
great successes in the battle
against infectious diseases.
Just to say a little bit about
smallpox, because unlike
chickenpox, which if you haven't
had, you've probably seen a case
of it.
None of us have seen a case of
smallpox, it hasn't existed in
the world for many decades now.
But smallpox was,
at one time,
one of the most frightening
diseases on the planet.
It's a devastating,
frequently fatal infectious
disease.
If smallpox occurred in your
community, about 30 percent of
the people that acquire the
disease would die from it;
the other 70 percent could be
disabled or permanently
disfigured as a result of the
disease.
It's an infectious disease;
it is spread by--through the
air.
So, it first infects you
because you breathe in some of
the infectious agent.
Smallpox is a virus called
variola,
it's a virus that contains DNA.
The name of the virus is
variola.
It's part of a family of
viruses, and we'll talk about at
least one other member of that
family of viruses as we go
through here.
But it can be acquired in the
air, from patients that are
from- from other individuals
that are infected.
You breathe it in,
it infects the cells of your
respiratory tract,
and the virus begins to
reproduce, and then it spreads
throughout your body.
And so during the first period
after you come in contact with
the disease, you have an
incubation period where you get
sort of the kind of symptoms
that we associate with lots of
kinds of viral infections that
we contract through our
respiratory system;
you might have a fever;
a malaise, which is just that
feeling that you don't want to
get out of bed and go to class.
You might have that commonly,
but even more severe than
normal;
aches;
and a rash.
And this is what's
characteristic of smallpox,
is that as the virus spreads
through your body,
it particularly,
it particularly affects cells
of your skin.
So, you get a rash,
or a redness of the skin.
And then you would recover
for a while, that initial phase
of the illness would disappear,
your fever might go down,
you might appear to be normal.
Then you start to get lesions
on your skin that are very
characteristic of smallpox.
They start as what are called
vesicular lesions,
or like blisters,
where they're filled with a
fluid.
They evolve to become very
dense, hard, pustular lesions,
which are filled with what
turns out to be tissue debris.
It's really just the result of
the virus dividing within cells
of your skin,
and producing a lot of dead
cells.
And so that debris fills up a
little spot that would feel,
according to reports,
because again we don't see it
now, feels like a little pellet
underneath your skin.
And this fluid eventually
starts to leak out and those
lesions would heal,
but they leave scars in most
cases.
These are very deep lesions
that go not just on the surface
of your skin like a blister
would,
but down into the dermis or
deeper layers of the skins,
as well.
In fact, certain areas of the
skin would be impacted most,
most dramatically,
the face and the chest,
the arms, but more distal point
of the arms, like the palms of
your hands.
And so you can imagine that
even in its--with all of this
activity on your skin,
even at its most--least serious
level, it's a terrible disease.
I'll show you a picture in just
a moment.
But in some cases,
that progressions of the
disease would start to affect
other organs,
in addition to your skin,
and your body would become
overwhelmed with the infection
and eventually die.
And as I mentioned before,
death would occur in 20-30
percent of the cases that got
the most severe form of
smallpox.
And so, if this was a disease
that entered your community,
you could have expected several
centuries ago.
At the end of this sweep of the
disease through your community,
one in four,
or one in five,
of your neighbors would die
from the disease.
And that says,
that's a dramatic effect on
communities.
Well, smallpox affected
world history,
it's--just as HIV infection is
affecting world history now.
Smallpox affected world history
hundreds of years ago,
and it was a disease that was
common in Europe,
but not common in the Americas
until the Americas were
colonized.
And so there are famous reports
of how the Aztecs,
that whole civilization,
was devastated by smallpox.
That disease was brought to
them by the Spanish when they
came to these continents in the
16^(th) Century.
And the Spanish,
a much smaller group of people
was able to overtake the Aztec
civilization,
very well established,
because that group of people
was devastated by the disease.
And they were weakened as a
result, and so the Spaniards,
even in fewer numbers,
were able to conquer.
So these are just some
pictures to show you what the
smallpox lesions look like on
the face of a child,
and then distributed over the
whole body of an adult,
to give you some better idea of
what kind of a disease this was.
So, the process of developing a
vaccine occurred over a long
period of time.
In fact, there's evidence that
even thousands of years ago,
Indian and Chinese healers were
using a form of something that
we would recognize as
vaccination.
And they did this by
taking--they recognized that
somehow, if you had a mild
exposure to the disease,
your body could then develop
protection against more severe
forms of the disease.
And so, the older way,
the more ancient way of
exposing you to disease,
was in the case of smallpox,
to take pieces of tissue from
somebody that was infected,
and usually it was one of the
scabs that formed as a result of
these skin lesions,
and to grind up that scab
somehow and expose it to
somebody who you wanted to
protect from the disease.
And the way that India
healers did this was by putting
pieces of this in your nose,
or injecting it under your
skin.
And there was a feeling that
this could protect you against
the disease.
And it turns out that there is.
We now know what the scientific
basis of that is,
it involves activation of our
immune system.
And it was a practice that was
not broadly used until somebody
really studied systematically.
And that person who really
studied it systematically,
and is given credit for
developing the first vaccine,
is a Scottish physician named
Edward Jenner.
And he started with a similar
but different observation,
and that was that cows get a
disease that's very similar to
smallpox.
We know now that it's caused by
a related virus,
called vaccinia,
remember the virus that causes
smallpox is called
variola.
But variola,
which causes smallpox in
humans, and vaccinia,
which causes a disease called
cowpox in cattle,
turned out to be,
we now know,
viruses that are molecularly
very similar.
What was known at that time
was that there was a disease in
people, and there was a
different disease in cows,
and they looked the same some
way.
And Jenner made the observation
that others had made,
that people that were around
cows a lot tended not to get
smallpox.
And in particular,
dairy maids,
whose responsibility was to
milk cows, and so they had a
very intimate relationship with
cattle,
often didn't get disease.
And sometimes they developed a
mild form of the disease.
They would get lesions on their
hands, for example,
the part of their body that was
really in close contact with the
cows.
And he hypothesized that they
were getting the disease in
cows, which the disease from
cows that caused a milder
disease than smallpox,
and that protected them from
getting the more severe forms of
smallpox later.
Well, I mentioned that this
was just sort of a more modern
observation of one that had been
made in the past.
This process,
I said, this ancient process of
taking scabs from patients and
introducing them to people you
wanted to protect,
was called variolation.
And Jenner was making another
observation that might be useful
that way.
There were other individuals
that were making this
observation at that time.
In addition to Jenner,
there was a farmer named
Benjamin Jesty,
who recognized that farmers,
being in contact with cows,
didn't get disease as often as
non-farmers did.
So, he intentionally inoculated
his wife and two children with
fluid that he got from one of
his sick cows.
Right.
So, he took fluid from a cowpox
lesion on a cow,
and he injected it into his
children and his wife,
reasoning that this would
protect them from disease,
even though they didn't have as
much contact with cows as
farmers did.
And he was right;
they got immunity and were
protected from smallpox when it
affected their community.
Jenner did this in a much
more systematic way.
He used not just his family,
but he used whole populations
of people.
And he produced a fluid from
cowpox lesions,
so these were these lesions,
these skin lesions on cows.
He took this pustular fluid
that was produced at this very
specific phase of the disease,
and he developed a way for
giving that to people.
So, 'vaccination',
the word vaccination,
comes from this event.
Vacca is the,
I'm sure there's a Latin
scholar in here that will
correct my pronunciation,
but vacca is the Latin
word for cow.
Vaccination from cows,
and that's where the first
vaccine came from.
And Jenner, because he was a
trained physician,
because he knew something about
the scientific method,
did something that these more
ancient healers had not done in
the past, was that he wrote down
what he did.
And he kept track of how many
people he gave the vaccines to,
and then he kept track of what
would happen to those people
when a smallpox infection
occurred in their community.
And as a result of writing it
down and keeping track,
he produced a very clear
record,
and scientific evidence,
that using this procedure could
protect a population of people
from the disease.
So, that was the start of the
modern practice of vaccination.
There were problems with
Jenner's approach,
and you can imagine what some
of those problems are.
One is that you got to get the
vaccine from cows,
so you got to have an infected
cow in order to produce the
vaccine.
So, it's awkward to have to
wait for a cow to get infected
before you can vaccinate a
population.
What if you're talking about a
group of people that don't have
any cows in their vicinity,
let alone a sick cow?
How do you get the vaccine to
them?
Well, that problem was partly
solved by saying,
'Well, if I'm giving the
inoculation to one person,
and they develop a lesion
locally…'
and that's what would happen.
When you would take the fluid
from the cow,
and you would inject it
underneath the skin of a person
you wanted to protect,
then at that site where you
injected it, you would get a
lesion that looked like a
smallpox or cowpox lesion.
And it would go through these
same phases that I described
before.
And it would,
you'd get a clear blister-like
region, it would turn pustular.
Eventually you develop a scab,
as it healed,
and then it would--and then the
scab would fall off,
and you'd be left with a scar.
But what if instead of
taking the fluid from a cow,
I inoculated--he inoculated me,
let's say, and waited until I
had the lesion at the right
stage, then took some of my
fluid and gave it to Brian and
Nate and Mirtalla and spread it
through the community around me.
Now we don't need the cow
anymore because you could pass
it from one person to another,
and pass the immunity from one
person to another.
And that works.
The problem with it is that you
also can spread other diseases
in that way.
You're not only spreading the
infection.
If I happen to have some other
infectious disease,
then not only would you passing
the protection to smallpox,
but you'd be passing that
disease among the population as
well.
And it turned out that another,
not quite as deadly,
but still very serious disease
called syphilis was also common
in this part of the world at
that time.
And so you could pass diseases
like syphilis from one
individual to another.
And that's not great, right?
That's not perfect.
The other problem is that
as it was passed from me to
another individual,
to another individual,
then the vaccine could change
in some ways that were hard to
predict because what accumulates
in the lesion in my arm is
different in some way than what
accumulates in the lesion on a
cow.
And as you move through the
human population,
the kind of response that you
get could change because the
virus itself mutates or because
you're also passing on some
factors that provide some
protection that changes the
course of disease in the
recipient.
So, as the vaccine was passed
from arm to arm,
it became less potent,
and the length of protection
that it would give you varied.
So, if you were someone that
was getting it after it had been
passed through many people,
you wouldn't have as strong or
as lengthy a protection as the
first individual did.
And we're going to just keep
that in mind.
We're going to talk about the
reasons for that as we go along,
particularly at the beginning
of class next time.
But what was really needed
in order to do this was a
defined preparation,
right?
We--what you would like to give
is everybody in the community
exactly the same preparation,
so that you could predict what
everybody's response to the
vaccine would be.
It wasn't until the 20^(th)
century, so almost 200 years
later, that we learned how to do
this.
And it was based on a couple of
things.
One was, a better understanding
of what you were doing when you
vaccinated.
And I've already given you some
clues about this,
in that this process of
vaccination that Jenner had
developed was intentionally
injecting into healthy patients,
a microorganism.
In this case the virus
vaccinia,
which causes a serious disease
in cows but only a mild disease
in people,
and injecting that--because it
was similar to variola,
or the smallpox causing virus
in some way,
so that your immune system
would develop a response to
vaccinia.
But because of the
similarity of the viruses,
the immune response that people
developed would also protect
them against natural infections
with variola.
And so we call that now,
that process of infecting with
a life virus,
that produces an immune
response that cross-reacts with
another,
that's called a naturally
occurring, attenuated vaccine:
naturally occurring because we
took a virus that occurred in
nature;
attenuated because it causes an
immune response in people but a
mild form of disease,
not the full form of disease.
And so this is an example of a
naturally occurring,
attenuated vaccine.
So, how could you produce--the
question is, how could you
produce large quantities of
this- of this microorganism,
this virus vaccinia
under controlled conditions?
Now, you know,
because we talked about cell
culture already,
that a great--that we talked
about last week,
manufacturing of cells.
We talked about two weeks ago,
that if you had a population of
cells, you could grow those
population of cells and you
could make,
if they adapted the culture
properly, you could make an
infinite number of cells from
one starting solution.
Well, if you knew a cell that
could serve as a host for a
virus, you could use this
process of cell culture to make
large quantities of virus,
right?
You just grow up cells until
you've got a lot of cells.
You infect them with the virus,
and you let the cells,
in culture, produce the virus.
Well, it turns out that we
could not identify,
at least at that point,
a cell culture that would serve
as a host for vaccinia.
So cell culture production
wasn't an option.
The only way that we knew
how to grow it reliably was to
grow it in its natural host:
cows.
And so in the 1940s,
a group of people led by
Collier started to develop a
large scale production method
for making a reliable source of
vaccinia virus.
And they did that by
intentionally infecting calves,
by harvesting their skin when
they were at a certain point of
the disease,
and by isolating the virus from
the skin of the calves.
And of course,
you could imagine that this
took some time to develop.
You'd want to make sure that
you separated the virus from all
the other parts of cow skin so
that your ultimate preparation
was enriched in the virus and
didn't contain quantities of
other things that would be
hazardous.
And so that's what was done in
the 1940s.
And then they found that
they could freeze-dry this
preparation of virus,
and freeze-drying to lower the
temperature,
freeze it, then extract out all
the water, so you're left with a
powder, basically a powdered
form of the virus,
that could be shipped all over
the world, and then
reconstituted by adding water to
it.
Right, so it's like--it's like
Kool-Aid, but more potent.
But used the same way, right?
The powder you could ship
anywhere, and reconstitute it
onsite, and then it gets
injected.
And they also developed a very
reliable way for introducing the
virus, so that when they had a
defined preparation of virus,
then you want to make sure that
everybody gets it in their skin
in the right way.
So, they developed this
bifurcated tool,
which would be appl--you'd put
the stuff on the surface of the
tool and then you'd scratch the
skin in a certain way so that
you could produce sort of a
reproducible introduction of the
vaccine into the skin.
Availability of this
freeze-dried vaccine made it,
then, possible to think about
vaccinating people all over the
world.
And so it didn't take long,
once this vaccine were--was
available, for people to want to
get organized and think about
ways of delivering this vaccine
to all the regions of the world
where people were potentially
infected.
It was the World Health
Organization,
or WHO, which led this effort.
And the goal was to eradicate
the virus, to get rid of it so
that there were no natural
sources of the virus on the
planet.
And that was possible in
smallpox because of a few
characteristics of the disease:
one is that it's a--it's purely
a human disease,
humans are the only organisms
that are affected by it.
That's important, right?
Because if it was a disease
that was carried by both humans
and squirrels,
for example,
then in order to get rid of it
on the planet,
you'd have to vaccinate not
only all the people but all the
squirrels,
right?
Otherwise you could have a
squirrel host--I'm using
squirrels, because I think
that's funnier than other
animals to think of--but it
could be any potential host,
right?
And it would be really
difficult to vaccinate a
wildlife.
So there are no non-human
reservoirs.
There were no asymptomatic
carriers.
So if you got infected with
smallpox, you got the disease.
There weren't people that got
infected, like you can get
infected with hepatitis B or
tuberculosis,
and not even know you're
infected.
You might not know have any
symptoms, you might just have a
latent source of the
microorganism somewhere in your
body.
And that didn't happen with
smallpox.
That's important,
too, because you need to be
able to tell if the virus is
present in the human population.
And so because of those two
things you could think about
eradicating the virus.
They did this very
systematically,
by giving quantities of the
vaccine to countries all over
the world.
That's part of it, right?
Give enough of the vaccine so
you have a dose for everybody in
the world, or a large fraction
of the people.
We'll think about it in
section, how you don't need to
vaccinate everybody,
but you just need to vaccinate
a critical number in order to
stop the disease from
progressing through a community.
And we'll think about that in
section on Thursday.
But so you needed enough
doses, but this is real,
and this is a lot of people,
right?
So you need hundreds of
millions of doses,
at least, and you need a way to
distribute that around the
world,
and you need a way to keep
track of who got sick and who
didn't after they got
vaccinated.
So you needed some way of
reporting.
And the WHO had all those,
had that whole infrastructure
in place.
So they kept track of
country-by-country,
when cases of smallpox
occurred, and as it was
eliminated from regions of the
country,
they then certified those
regions to be smallpox free.
And so it went,
through the years from the
1950s through the 1970s.
The last reported case of
smallpox in the--naturally
occurring smallpox,
was in 1977,
a man in Somalia was infected.
There were no reported cases
after that, and so by the late
'70s, the world was certified
sort of free of smallpox
worldwide.
The U.S.
was certified free in the early
'70s, years before that.
I was born before 1970,
I got a smallpox vaccination.
None of you got smallpox
vaccinations,
because once a country was
certified to be smallpox free,
there was no reason to--there
was no reason to vaccinate
people any longer.
So, none of you in this room,
I'm 100% confident,
never ever got a smallpox
vaccine.
Well, that's a great story,
and it's an example of a great
success in medicine.
But it's also an example of a
great success in biomedical
engineering.
And the engineering part of
that is sort of the part that I
talked about in one slide,
when I talked about how do you
convert this scientific advance
into something that can be
delivered all over the world.
And the technology that was
used in this case was growing
the vaccine in a natural source,
harvesting it,
figuring out how to produce a
preparation that could be
distributed but was still
biologically active;
that is, still could protect
against the disease.
We now know,
and I'm going to talk about
next time, lots of ways to do
this, alternatives to this
method of bioengineering.
And you could guess what those
techniques are.
You could use cell culture,
so you don't have to grow the
virus naturally in animals.
But you can grow it in cultured
cells, and the advantages of
that are that you can do this
under very reproducible
conditions.
Much easier to keep a flask of
cells under very sterile,
very reproducible conditions
than it is to keep a small
animal, right?
Even--or a large animal like a
cow.
And much easier to purify and
know what you have at the end,
than if you're trying to
harvest it from a whole complex
organism.
We have techniques of
recombinant DNA,
and those can be used to
produce either modified viruses,
we'll talk about that.
So maybe I could take an
infe--maybe I could instead of
getting lucky,
like we did in smallpox and
finding a naturally occurring
organism that causes an
attenuated form of the disease,
maybe we could genetically
engineer a virus,
to make it less pathogenic,
right,
but still immunogenic, right?
And those words mean different
things: immunogenic means that
it stimulates your immune system
for a response;
pathogenic means that it causes
a disease.
So maybe you could figure out
how to use what we know about
molecular biology,
to engineer a new virus that's
still immunogenic,
but not pathogenic any longer.
And that's a new approach to
producing vaccines.
Or maybe you don't need the
whole virus.
Maybe you don't need the whole
virus, but you could just use a
piece of the virus,
right?
Just use a piece,
an antigenic piece of the
virus.
And then I don't have to
produce the whole virus in order
to make a vaccine.
I just have to produce many,
many copies of a piece of the
virus, a protein,
say.
And how would you produce a
protein in large quantities?
Well, again you could use
recombinant DNA technology.
Get a gene, put it in a
plasmid, get that plasmid
expressed in a host,
could even be a bacterial host,
right?
Like we talked about with
insulin;
make large quantities of this
recombinant viral protein,
and use that as a vaccine.
And we're going to talk about
how that--how those steps can
happen next time.
I want to end with this
picture.
So this is the cover of the New
England Journal of Medicine,
one of the most famous and
influential medical journals in
the world.
And this is from April of 2002.
And I talked about eradicating
smallpox in 1977,
right when officially the last
case was reported,
and it was certified to be
eradicated shortly after that.
But on this cover,
you can see that there are
several stories about smallpox.
One is called the 'Clinical
Responses to Undiluted and
Diluted Smallpox Vaccine';
one is called 'Current
Concepts, Diagnosis and
Management of Smallpox.
' Why would one of the most
prominent and influential
medical journals in the world be
publishing a review article
about how to manage cases of
smallpox when there had not been
any cases of smallpox for 25
years?
Yeah.Student:
Bioterrorism?Professor
Mark Saltzman:
So, the concern at this time,
and still remains a concern,
is that infectious agents,
particularly very deadly
infectious agents like smallpox,
could be weaponized in some
way, or converted into a weapon.
And if smallpox was somehow
introduced into a city like New
York City, what would happen?
Well, there's a whole
population of people who are
younger than me that never got
smallpox vaccines,
right?
You don't have it,
you don't have any immunity to
smallpox, you don't have any
reason to immunity to smallpox.
And so you would be susceptible
to infection by this organism.
In addition,
even people--I got vaccinated
40 years ago,
right?
Is my vaccine still protective?
Probably not.
And so even people that got
vaccinated, most of us either
have questionable or no
protection against the virus at
this point.
And who,
where would--If it was,
if it was converted into a
weapon, where would the vaccines
to protect the rest of the
country come from?
There's no company that's
making smallpox vaccine anymore
because there's no reason to
make smallpox vaccine,
because nobody would buy it,
right?
Because there's no naturally
occurring smallpox.
And so there was great concern
that we were vulnerable in this
way, because the disease is
still a disease that could
affect people.
There are still some active
smallpox virus specimens kept in
the world, and there are two
sources of small--two places
where smallpox is stored now.
One is in the U.S.
at the Centers for Disease
Control, where there is a sample
of variola,
which is kept,
you know, frozen on ice in a
heavily guarded facility.
There's another sample which is
in Russia, part of the former
Soviet Union,
where there are samples that
were stored.
And these samples are used for
scientific purposes.
They are kept track of very
closely, but because there's
still smallpox that exists on
the planet,
there is some concern that that
could be obtained and used to
develop a weapon.
So, that's the reason for it.
Shortly after this,
and why did that come up 2002?
Because of what happened in
2001, is why that became a
concern.
The government,
after this time,
did issue contracts to
manufacturing companies to
produce new quantities of the
virus.
They also found some stockpiles
of the virus from the 1950s that
they still had on an Army base
in Maryland, I think.
They tested those to see if
they were still active,
and they were.
So, there's been an active
effort to reestablish the
process of smallpox vaccination
in case that's needed.
There are even some military
personnel now who get immunized
against smallpox in the event
that when they're going into
areas,
they might be exposed when
they're in combat areas.
And so, I give you this
example to say even though
tremendous progress was made.
This is one example that,
without fail,
people would say is a marvel of
medicine and bioengineering,
but that it's still something
to keep track of.
There are still opportunities
to use what we know about this
to develop even better methods.
I think the smallpox vaccine we
made now would probably be
better, more effective,
and safer than the vaccines we
made in the '50s.
So, I'm going to continue
talking about vaccines on
Thursday.
In particular,
we're going to focus in the
beginning, on polio virus,
which is another great success
story,
but where a very different
approach to vaccine development
was used.
That will be instructive in
thinking about what vaccines in
the future might look like.
Questions?
Great, see you on Thursday.
