- And friends, I'm Michael Kashgarian,
the outgoing chair of the trustees
of the Cushing/Whitney
Medical Library Associates.
The library associates and I are very glad
to have you spend your afternoon with us.
A few small details.
The lecture is being
live-streamed and recorded,
so please do as I just did.
Silence your cellphones
or any other noise-making devices,
including your voices, I assume.
Please be sure to join us afterwards
in the Beaumont Room for a reception.
I'm pleased to present
our 71st Annual Associate's
Day lecturer, Akiko Iwasaki.
Dr. Iwasaki received her PhD
from the University of Toronto
and her post-graduate training
from the National Institutes of Health.
While still a graduate student
at the University of Toronto,
she was among the first to demonstrate
the role of circulating
antigen-presenting cells
in eliciting the immune
response to vaccines,
which at that time were
always injected into muscle.
And people thought that the muscle
had Langerhans cells or some
other antigen-presenting cell
which then would initiate
the immune reaction.
Dr. Iwasaki joined Yale University
as a faculty member in 2000
and is currently the Waldemar Von Zedtwitz
Professor of Immunobiology,
and Molecular, Cellular,
and Developmental Biology.
She's a principal investigator
at the Howard Hughes Medical Institute,
and she was elected
to the National Academy of
Scientists just last year.
Akiko Iwasaki's research
focuses on the mechanisms
of immune defense against viruses
at mucosal surfaces and the interplay
of innate and adaptive immunity.
Her laboratory is interested
in how our innate immune
recognition of viral infections
leads to the generation
of adaptive immunity
and how adaptive immunity mediates
our protection against a
subsequent viral change.
Please welcome Dr. Iwasaki.
(audience clapping)
- Thank you.
Thank you very much.
Can you hear me?
- [Audience Member] No.
- No?
Okay, maybe I'll stand here.
Okay, can you hear me now?
I'm very honored to give
the 71st annual lecture
of the Cushing/Whitney
Library Association.
Today, what I'd like to do
is to take you through
my scientific journey
by discussing some of the highlights,
some of the findings that are made
by the members of my laboratory.
Still, today I'd like to give stories
of three separate topics.
The first story has to do
with the underlying cause
of infectious disease.
How do infectious viruses
cause disease in humans?
Second story has to do with the warfare
between retroviruses and us.
Vertebrates have been
colonized by retroviruses
ever since the beginning of evolution
and so about 500 million years of battle
has been fought between
the host vertebrate
and the retroviruses.
So I'd like to speak on
the endogenous retroviruses
and how that interacts
with the immune system.
And finally, I'd like to touch
on this very important topic
of the lack of vaccines
against major pathogens.
Viral diseases like HIV,
herpes simplex virus
has no effective vaccines right now.
So that's the title of my talk today.
Can we learn from
studying viral infections
to make better vaccines
against these kinds of agents?
So, how do we develop a new
vaccine that actually works?
So, with respect to how
viruses cause diseases,
many viruses can infect the host
and some viruses are
completely asymptomatic
while others cause disease.
It's thought that viruses cause disease
by causing tissue damage.
So the target cells that
are infected by the virus
is killed by the infection
and therefore causing damage
to that particular tissue.
However, it is equally possible
that it's the immune response to the virus
that causes the damage,
and understanding which of
these scenarios are true
for a particular viral
disease is important
when trying to deal with
such infectious diseases.
So, the first story has to do
with genital herpes infection.
So it's been known for many years
that herpes simplex virus
causes genital herpes
by infecting the genital mucosa
and this virus replicates
in the epithelial layer
of the vaginal tissue
and it infects the innervating neurons,
the sensory neurons that
innervate this tissue,
and it becomes dormant.
The virus can establish latency
within the dorsal root ganglia
and it could stay there
for the rest of your life.
It does stay there for
the rest of your life
and reactivation of this
latent pool of virus
occasionally back to the genital mucosa
is what causes the lesion and disease.
And it was thought that this infection
is confined to these kinds of tissues.
The vaginal mucosa and
the dorsal root ganglia.
However, work from our
laboratory has shown
that it's not the case.
That in fact, the virus can travel
from the dorsal root ganglia
to the enteric neurons
and they're infecting the neurons
that control the peristalsis of the colon
and that results in the
block of peristalsis
and therefore, mice actually
die of toxic megacolon
and not by encephalitis,
where some other diseases that
are caused by the infection
of the central nervous system.
So, this led to this understanding
that in fact viral
diseases can be extended
to unexpected consequences.
In this case, genital herpes
results in chronic constipation.
Now, when we published this,
this was thought of as a
sort of a mouse finding
that in humans this doesn't happen.
But it turns out to be
that's not the case.
I'm getting emails and
phone calls from people
all the time, almost daily,
telling me that they have
developed chronic constipation
just as if time of their
acquisition of genital herpes
and in three cases,
people have contacted me
and they didn't know they had herpes.
Sometimes these herpes infections
completely asymptomatic
and these women took acyclovir
and cured themselves of
chronic constipation.
So it turns out that this type of disease
may be actually occurring in human hosts
and finding this cause of disease
for an unexpected outcome provides us
with a medical tool to deal
with these types of infections.
Another example that I like to give
is how Zika virus causes infection.
As you know, Zika virus transmits
by the bite of mosquitoes.
However, it's also known that
it's sexually transmitted
to an infected person to
an uninfected partner.
And in most cases,
these types of diseases
are transient and acute
and are cleared in healthy adults.
However, in rare cases,
people develop
Guillain-Barre-like syndrome
which is an autoimmune disease
that attacks the peripheral neurons,
thereby debilitating a person's ability
to walk and control their motor functions.
In another case we know very well
from the epidemics in Brazil in 2015,
that in pregnant mothers that
are infected with Zika virus,
microcephaly and other neurologic disease
can result from these kinds of infections,
as well as cases of spontaneous abortion
as the result of Zika infection.
So we wanted to understand
how these diseases actually manifest.
Particularly, we need to understand
how sexual transmission of Zika virus
leads to diseases and how the host
deals with these kinds of infections.
So we asked how does Zika
virus cause fetal demise.
And this was a question that was tackled
by a graduate student, Laura Yockey
who developed a first model
of vaginal transmission
of Zika virus infection
whereby she demonstrated that the virus
can enter the vaginal mucosa
and replicate very well
within this tissue.
So unlike if you were to inject
the same amount of virus into the skin,
in which case the virus is cleared,
the vaginal mucosa can host these viruses
to high titer replication,
even in wild-type animals.
And she showed that in pregnant mice,
if you were to infect those
mice with Zika virus vaginally,
this infection then results in infection
of the fetal brain
and in the follow-up study,
she demonstrated that the fetal demise
actually occurs as a result
of maternal immune response
to Zika virus.
So when a mother is infected
with the Zika virus,
she will produce these
type one interferons
which are antiviral factors
that usually protect the host.
Unfortunately, in the
case of pregnancy however,
this interferon acts on the fetal tissue,
especially the placenta,
to arrest its development
and thereby resulting in fetal demise.
So this work laid sort of
an overarching understanding
of the mechanism of congenital disease
that can occur as a result
of viral infection during pregnancy.
The next question was how does Zika virus
cause this Guillain-Barre-like Syndrome.
So, our work demonstrated that
the central nervous system
including the brain and the spinal cord
is in fact infected by the Zika virus
but it's not the virus infection
that makes this
Guillain-Barre-like Syndrome.
And in fact, it's the
cytotoxic T-cell response
which is the immune response
against the Zika virus
that results in the killing
of the infected neurons
resulting in the paralysis
of these animals.
So this provided the first insights
into how Guillain-Barre
Syndrome might result
from a Zika viral infection
by demonstrating it's the cytotoxic T-cell
which the host immune response
that ultimately results
in killing of the neurons
that paralyzes these animals.
Because until then, it was thought that
it was the antibody cross-reactivity
between the Zika virus
and the neuron antigen
that resulted in this disease.
So, I hope I was able to demonstrate
that by studying these
infectious diseases,
the mechanism underlying such diseases
in some cases it's the virus infection
that kills the target tissue,
such as the enteric neuron,
in the case of herpes simplex virus,
that results in the disease manifestations
such as chronic constipation.
And this is a very unexpected
sort of cause of disease
for chronic constipation,
which currently very little is understood
about how this occurs and millions,
actually billions of people suffer
from chronic constipation.
Whereas in the case of Zika virus,
we demonstrated that
it's the immune response
to the virus and not the virus infection
of the target tissue per
se that causes disease.
Both in the case of pregnancy
in eliminating or arresting
the fetal development
by type one interferon of the mother
and in the case of the
Guillain-Barre-like Syndrome
in which the CD8 T-cells,
the cytotoxic T-cells
attack the infected neurons.
So, why is this important to
study disease manifestation?
Well, first, in order to
treat infectious disease,
we need to understand what
aspect of infectious disease
we need to target
because the target strategy
will greatly depend
on whether it's the
pathogen, the virus itself
that's causing a disease or
whether it's the immune response
to the virus that's causing the disease.
And by studying these fundamental
infectious disease biology
in animal model will give us insights
into diseases that were
previously completely unexpected
such as the constipation resulting
from herpes simplex virus.
So now I'd like to move
to the second topic
which has to do with
endogenous retroviruses
and the immune system.
So, over the last 100 years or so,
the immunology community has focused
on bacteria as pathogens.
How do these pathogenic
bacteria make us sick,
such as Salmonella or E. coli outbreak?
However, over the last 15 years or so,
the community has shifted
its focus on the microbiome,
which is the collection of
bacteria that inhabits us
which outnumber us by about 10-fold.
And so this has brought
us enormous insights
in how microbiome controls
health and disease
in variety of settings.
However, how the virome
controls the host and vice versa
is much less understood.
Part of the reason is that the microbiome
is easy to identify because we can use
a specific tag which is
people use 16S RNA sequencing
to identify the nature of the bug
that is inhabiting us.
In the case of virome, it's very difficult
because there are no conserved sequences
that we can target to identify
the virome and to study them,
let alone to eliminate
one virome versus another.
So this is a question that
we became interested in
a few years ago.
And we focused on the most
fundamental of all viromes
which is the endogenous retroviruses
because it has integrated into
our genome over millennia.
And so this is just demonstrating how vast
the real estate that is occupied
by the LTR retrotransposons
which are remnants of
exogenous retroviruses
that have integrated into our
genome, ancestral genomes,
compared to the two percent of our genome
occupied by protein coding sequences.
So the vast majority of the community
focuses on this 2% of
the protein-coding gene
whereas we wanted to study what this 8%
of our genome is doing,
which is occupied by these retroviruses
that have integrated into our genome.
And just to point out that
not only LTR retrotransposons
but there are vast majority
of this genomic real estate
which is about 40% occupied
by these transposable elements
which are jumping genes that can go
from one locus to another.
And again, much less is
studied about what these things
are doing in our body.
So we focus first on this
autonomous LTR retrotransposons
which look just like the
genome of the retrovirus.
Essentially, these are the retroviruses
that have integrated into our germline,
ancestors over millions of years
and they basically contain
the same kinds of genes
that an HIV virus might contain.
Gag, pol, and envelope,
and they're able to express themselves
and sometimes recombine with each other.
In mice, they can make
infectious retroviruses
by recombining from one locus to another.
And so what we wanted to dig in
is the immunology at the genomic level.
How does the immune system
control these kinds of elements
from within the genome
and there are at least two types of ways
we deal with this.
One is to silence the expressions
of this retro elements by binding
to specific locus, conserved sequences
that are found within these
integrated retroviruses.
And the other is to chop up
the nucleic acid intermediate,
replication intermediate
that are generated
from these elements.
In both ways, we deal with suppressing
the re-emergence of
these kinds of viruses.
So, this question about
how does the immune system
control endogenous retroviruses
at the genomic level
was tackled by a graduate
student, Rebecca Treger,
who solved a 50-year old puzzle
by cloning genes that are responsible
for controlling these
elements in the mouse genome
and these turned out to be two related
KRAB-containing zinc-finger proteins
that can recognize and
suppress the expression
of these genes.
And they turned out to be the locus
that controls lupus susceptibility
in the animal as well.
So there's a link between
endogenous retrovirus expression
and lupus disease.
So, the way to make this long story short,
essentially what Rebecca found
was as I mentioned,
she found two different
KRAB-containing zinc-finger proteins
that have these fingers,
literally fingers that project
and bind specific DNA sequences,
and she found a conserved
region near the LTR
of vast majority of mouse
endogenous retroviruses
that combine and control the
expression of these genes.
And we named them SNERVs.
SNERV one and two.
So in wild-type animal,
this KRAB zinc-finger protein
can recruit KAP1 which can silence
the expression of these
endogenous retroviruses
by imposing epigenetic marks.
And so the basal level
of these endogenous
retroviral gene expression
is quite low.
Whereas in the case of lupus-prone animal,
these KRAB zinc-finger
proteins are missing
and therefore the expression of these ERVs
are elevated without any control
and this results in
not only the expression
of these viral genes on
the surface of the cell,
but also resulting in the secretion
of these viral genes that
then end up becoming a target
of antibody that recognizes these kinds
of enveloped genes.
And that's what's
causing the lupus disease
in the animal.
So these SNERVs that are usually bound
to our genomic loci at the LTR region
of the endogenous retroviruses
are missing in the lupus-prone animals
which results in the over-expression
of these viral genes
encoding the envelope gene,
which then becomes the
target of auto-antibody
and it's the antibody-antigen complex
that deposit into the kidney
that causes lupus nephritis in the mice.
So, this story demonstrated
at the epigenetic regulation of ERV
is a critical step in preventing
diseases such as lupus.
Now, how do we study ERVs
in the human population?
The major challenge in studying these ERVs
is that there is no way
to know the identity
of many of these ERVs because
they're so highly repetitive
and similar to each other.
There's no way of saying
this ERV came from this
gene locus versus another.
So, Maria Tokuyama in the lab
solved this problem by making a program
called ERVmap, whereby you can
take your RNA sequencing data
and this is publicly available and free
to anyone who wants to use this.
And plug it in to this website
and out comes the sort of identity
of all the ERVs that are expressed
in a particular sample of interest.
And so she made this first tool
in order to characterize ERV expression
at the genome-wide level
and now we can do some amazing
things with this ERVmap,
which a couple of examples I'll show you.
So, every cell type turns
out to have different sets
of ERVs that are expressed
to different extent.
So you can take a fibroblast
or epithelial cells
or macrophages, T-cells,
whatever cells of your choice
and ask what are the
ERVs that are expressed?
It turns out to be distinct
between all of these cell types.
In fact, you can use the
ERV information alone
to predict the different subsets of cells
that are present in our body.
And so Maria was able to
show that just by looking
at the ERV expression pattern alone,
she was able to cluster
different cell lines
in different locations within
these kinds of analysis.
And moreover, when she
looked at the blood cells
collected from lupus patients,
she found these ERVs
to be highly expressed.
So there are about 124 different ERVs
that are up-regulated in the lupus patient
peripheral blood cells,
and this is just demonstration
of the different kinds
of ERVs that are expressed
in lupus patients
that are highly up-regulated in red,
compared to the healthy control,
which have these dark blue lines
indicating that they have low expression.
And not only that,
this kind of links what we
found in the mouse model
where we demonstrated
that in the mouse lupus,
it's the lack of these SNERV genes
that elevates the envelope expression
that becomes the target of autoantibody.
In the case of lupus,
Maria demonstrated similar over-expression
of endogenous retroviruses
and something akin to SNERV
is regulating the expression
of these genes.
We're actively looking
for what these genes are.
But in any case, these ERVs are elevated,
but do they become
target of auto-antibody?
So, in order to address this issue,
Maria with Arvind, who is
a undergraduate student
in our laboratory,
made these proteins that are expressed
by the highest-expressed
ERVs in the lupus patients
and she was able to show
that these kinds of antigens
that are basically enveloped protein
from the endogenous retroviruses
become target of antibody
that can stimulate leukocytes
within our circulating
blood cells very well.
Stimulate them to excrete
these toxic molecules
that would be detrimental to the host,
perhaps drying these lupus-like diseases.
So, in this program what we demonstrated
is that we now have a tool to study
these endogenous retroviruses
which is the most fundamental member
of the virome that we carry.
Second, we discovered the two genes
that control ERV expression in the mouse
without which, we'd
develop lupus-like disease.
And finally, we saw similar
elevation of ERV expression
in the human lupus patients
which also become the target
of auto-antibody reaction.
So, these collectively demonstrated a link
between again, completely
unexpected link between
endogenous retrovirus
expression to lupus disease
in two different types of models.
So, whether ERV envelope is
driving the lupus disease or not
this is a sort of target
for research in the future
and what is controlling ERVs in the human
is also unknown at this point.
So now I come to the third topic
which has to do with lack of vaccines
against very major infectious agents,
viruses that transmit and cause diseases.
So major challenges in
current vaccine strategy
for which we don't have
successful vaccines
such as HIV and HSV is
that current vaccines
rely on antibodies.
And many viruses are known
to evade antibody responses.
So herpes simplex virus
expresses different glycoproteins
on the surface that completely block
the activity of antibody.
HIV can mutate its surface
antigen very quickly
to evade the recognition by antibody.
And influenza virus does
this very well every year.
It changes the coat protein slightly
so that the previous year's antibody
can't detect the coats very well.
So all of these viruses have
figured out the immune system
way before we even knew antibodies.
So that's a problem
for developing vaccines
against these kinds of agent.
And the other thing to remember
is that most infections
start from a local tissue,
likely the mucosal surface of the nose,
the genital tract, the gut.
These are the mucosal
surfaces that are favored
by these viruses and these
kinds of current vaccines
are not designed to
generate antibody responses
at these sites.
So current vaccines
really fail to establish
not only antibody but T-cell responses
in these sites of infections.
However, we don't know whether
circulating memory T-cells
may be sufficient to control
these kinds of infections.
If the virus evades the antibody response,
can we rely on the circulating T-cells
to protect us from
further viral challenge?
So, in picture form, what we're studying
is upon immunization which
is given intramuscularly,
we develop T-cell responses.
T-cells circulate throughout the body
and see many organs.
But they feel to see certain organs
such as the brain, the
skin, the airway epithelia,
and female reproductive tract
are devoid of memory cells, T-cells,
that circulate and see these tissues.
And this is a major problem
because sexually-transmitted pathogens
enter through the genital mucosa
and yet, we are not
establishing T-cell responses
at the site of viral entry
for many of these pathogens,
such as HIV, human papilloma virus,
and herpes simplex viruses.
They all enter through the genital mucosa
and yet, none of the conventional vaccines
are generating T-cell response at the site
of entry of the virus.
And these are a staggering
number of people
who are currently infected
by these pathogens.
In the hundreds of millions.
And so how do we deal with this problem?
Well, first we have to ask the question
if we were to just vaccinate people
with a conventional vaccine
and we generate these
circulating memory T-cells,
are they gonna be sufficient
to protect the host?
So, in order to address this,
we've developed a mouse
model of genital herpes
to study this in which we give animals
an attenuated herpes virus intra-vaginally
and then we know that after weeks,
there are memory T-cells that are resident
within the vaginal tissue.
So what we can do now is to take an animal
that's been immunized this way
with lots of memory cells
in the genital mucosa
and fuse it to an animal
that has never seen
the vaccine before and this
is sort of a old technology
known as parabiosis in
which we suture the skin
between the two animals
and these two animals
share the circulation,
the blood circulation.
So whatever that's in the
blood of this one mouse
will transfer to the other.
So, in this setting, what
we have is this mouse
which only has circulating memory T-cells,
whereas this mouse has
circulating memory T-cell
as well as the resident
T-cells in the genital tissue.
So we can use these animals to ask
whether circulating memory
cells are sufficient
to confer protection against herpes.
So what we can do is...
Well, first of all, this
is a baseline control
where if we parabiose
naive animals together
and then infect one of them with herpes,
all of these animals succumb to infection
within about a week.
However, if we were to immunize the animal
in which only circulating
memory T-cells are present,
then many of them succumb to infection.
Whereas if we were to
infect with lethal herpes
into the animal that has this
tissue resident memory pool,
100% of these animals are protected.
So these experiments demonstrated
that circulating memory T-cells
are only partially protective
against genital herpes disease
whereas the tissue resident memory cells
confer 100% protection against
challenge by lethal herpes.
And we showed that the
reason for the advantage
of the tissue resident memory T-cell
is because they can secrete
this antiviral proteins
known as interferon gamma
rapidly upon infection
and this timing as well as the robustness
of the interferon gamma response
conferred by the tissue
resident memory cell
is what controls the
viral infection very well.
Whereas the circulating memory cells
takes them a while to get to the tissue,
find the antigen, start
secreting interferon gamma,
and it's too late by that time
because the virus has
entered the neuron already
and there is no turning back from there.
In addition, we discovered
these new lymphoid clusters
known as memory lymphocyte clusters
that are key in maintaining this kind
of tissue resident memory cells
within the vaginal mucosa.
And what we find is this
local cluster of T-cells
that are kept there by macrophages
that are stimulating these T-cell
by presenting their viral antigen
and having a forward loop to maintain
these types of T-cell in the tissue
for a very long time
and these are the MLCs,
these structures are what is protective
against the challenge by
genital herpes infection.
So, Norifumi Iijima who did this work
discovered this new structure
that maintains these tissue
resident memory cells
in the genital tissue and
that is really confers
100% protection against herpes disease.
So, however, even though it's
a very, very effective mode
of immunizing a host,
which is to use this attenuated
herpes virus locally,
this is not gonna fly in the face of FDA
as a childhood vaccine.
So we needed to come up with a safer way
of eliciting similar response.
We knew from the work of Yusuke Nakanishi
that you can actually
call in killer T-cells
by a two-step process
in which this is during
primary infection with
herpes simplex virus.
CD4 T-cells enter the tissue first.
They see the antigen,
they start secreting interferon gamma
and this induces chemokines
which are these attractants
that would recruit
the killer T-cells into the tissue.
And so we thought maybe we can override
the requirement for infectious vaccine
by making a similar setting
by mimicking this kind of activity
by just giving the mice a vaccine,
which is a conventional vaccine
that's injected intramuscularly,
to generate T-cells but then we can pool
in these T-cells using the same chemokines
that the nature uses to recruit
these kinds of killer cells.
And this led to the development
of a new vaccine strategy
called Prime and Pull
in which we prime the
animal with a vaccine
and then we generate these
effector killer T-cells
which have these chemokine receptors
that can be used to lure them
into the tissue of interest,
in this case the vaginal mucosa,
by providing recombinant chemokines
that are specific for these receptors
that are expressed by the killer T-cells.
So as a peripheral principle,
Haina Shin in my lab
tested whether this kind
of prime and pull strategy can recruit
the killer T-cells into the tissue.
To do this, she immunized
animals subcutaneously,
just what we do normally
in the case of vaccines,
and then pulled these T-cells
into the vaginal tissue
using recombinant chemokines.
So, because these vaccines are given
in a distal site, not the vaginal tissue,
they do not elicit local
tissue-resident memory
by themselves.
However, we were hoping
to recruit the T-cells
with recombinant chemokines
and then we analyzed the
distribution of the T-cells
in the host animal.
And what we saw was actually
a very remarkable increase
in the number of T-cells that
are specific to herpes virus
that's elicited by the vaccine,
that can be recruited
by this pull strategy
into the animal,
and prime alone was
completely unable to do this
which we knew from our previous studies.
And of course, if you infect
the animal intra-vaginally
with a recombinant virus,
of course you can elicit
a very good tissue-resident memory cells.
But we wanted to do this
in a more safer manner,
and in fact the prime and pull strategy
only affected the
population of CD8 T-cells
within the vaginal tissue
and not anywhere else.
So this is a very fine local control
of recruiting T-cells and
maintaining them over weeks.
But the important thing is
we need to be able to protect
the host animal against the disease.
So, Haina took this prime
and pull immunized animal
and then challenged them
with wild-type herpes
into the vaginal tissue.
And here what I'm showing
is the disease score
or the survival curve of animals
that have received prime and pull
and virtually it completely diminishes
any diseases that's
resulting from the challenge
and 100% of the animals
survive this kind of challenge
if they are immunized by prime and pull
compared to the prime alone.
So this is sort of the
conventional vaccine
that is given.
You can see that the
disease is elevated here
and many of these animals
succumb to infection.
So, Haina's work led to a
development of a new vaccine.
A whole new vaccine that overcomes
the failed vaccine strategies
that have been tried
in thousands of people.
So herpes vaccines have already been tried
in phase three clinical trials
by a variety of different companies,
all which unfortunately have failed,
and we think we can rescue these vaccines
using the prime and pull strategy.
So, we're taking this to the next level
to see whether we can use
the prime and pull vaccine
to treat an existing disease.
So what I showed you just
now in the mouse model
is a preventative vaccine.
But can we do this is an
already infected people
and I showed you there
are hundreds of millions
of people already infected with herpes
around the world.
So what we can do is to
use a guinea pig model
of genital herpes and
the advantage of using
guinea pig model is that
they have a naturally-recurring
genital herpes disease,
unlike the mice which do not.
And so we can mimic better
what happens during infection in human
using guinea pigs.
And so we infect a whole
bunch of guinea pigs
through the vaginal tract
using wild-type herpes simplex virus
and then we let them
become fully infected.
So these animals have full lesion,
reactivation, the whole gamut of diseases
that you might expect
from a viral infection,
and then we divide these animals
into four different arms.
Some of them we give
no vaccines or no pull.
Another group we give the prime,
which is the HSV-2 glycoproteins
that have been tried and failed
in the clinical settings.
And then we also give pull,
which is a chemical
compound called imiquimod
which stimulate the innate immune system
to induce the chemokines of interest,
in our case the CXCL9 and 10
and so we compare the ability
of these kinds of vaccines
to protect the host and what we see
is that the prime and pull group
pretty much completely shut down
any recurrent diseases in the animal
that received this vaccine
two weeks after the
infection is already ongoing,
whereas the prime alone,
which is the green bar here,
green dots here, confers
very little protection
over just PBS control.
So this is the conventional vaccine
that have tried and failed
and this is our vaccine.
So you can imagine that
this vaccine approach
will have a very promising
kind of treatment option
for women who are already
infected with genital herpes.
So we're now taking this
to the next, next level
which is to ask whether we
can use the prime and pull
vaccine to prevent cancer formation
in women who are already
infected with HPV,
which is the human papilloma virus
that causes cervical cancer.
So, we are collaborating with
two fantastic clinicians,
Alessandro Santin and Sangini Sheth
who recruit patients who have
these cervical inter-epithelial neoplasia
which is a precancerous
lesion in the cervix
that could develop into a cervical cancer
and we were recruiting this woman
to give the prime and pull vaccine.
In this case, we gave prime
which is the Gardasil 9 vaccine
that's FDA-approved and are
given to children already.
But the Gardasil 9 vaccine alone
is already known not
to work in the setting
of women who already have HPV.
But then we're adding this pull step
which is the imiquimod
applied to the cervix
which induces the
chemokines of our interest
and what the interim analysis is showing
is that compared to the observation arm
in which about a third of the women
go on to progress in disease,
the pull only group has some effect,
but the prime and pull group of women
none of them have developed
progressive disease
and they have all reduced
the level of the lesions
during this clinical trial,
indicating that this may
be a promising new way
of dealing with HPV infection.
And so these people, along with Jieun Oh,
who is a postdoc in my laboratory
is really trying to understand
how we can use this
prime and pull strategy
to prevent cancer from
forming in the cervix
of women who already have HPV infection.
And they're really revolutionizing
the way we treat precancerous lesion
in the cervix and this
often are detected in women
of childbearing age and this
kind of preventative strategy
can really preserve the
integrity of the cervix,
which enable women to go on
and have a successful pregnancy later on.
So, why this is important?
We think that the development
of the new vaccine strategy
that can rescue a failed vaccine strategy
is a very promising way of
approaching this problem.
We don't have to invent new
vaccines for every disease.
We just have to basically
combine a prime to a pull
to a given tissue of interest.
And many existing failed vaccines
can be rescued, we believe,
using the Prime and Pull vaccine
and the Prime and Pull can be applied
to vaccines against cancer.
We've already shown that for HPV.
But even for cancers that
are not virally driven.
As long as we understand which antigens
are expressed in those cancers,
we can theoretically do Prime and Pull
against a variety of different cancers.
So, just to finish up, what
is the outlook for the future?
We think that the studying viral infection
and disease mechanism is
really a great way to learn
about the immune system and
host physiology in general.
And I hope I was able to demonstrate
that using these basic research tools
such as the mouse model,
the guinea pig model,
and this in-vitro system allows us
to gain insights that
can ultimately be applied
to improving human health.
And we need to leverage
this natural immune response
against viruses for vaccine development.
So Prime and Pull is one of those examples
but I believe that we can gain insights
into how the immune
system naturally protects
against viral diseases and then apply that
to different kinds of vaccine strategies.
And similar thought process can be applied
to understand and treat cancer.
So, all the examples that I gave you today
is about viruses, but
there are many similarities
between cancer and viruses
and we might be able to
learn from viral diseases
and immunity against viruses
and apply that insight
into the treatment of cancers as well.
So in final reflection,
I'd like to take just two minutes
to kind of discuss my other passion
which is to increase diversity
in the science and technology
and engineering and math,
and this slide just demonstrates
that about 50% of the graduates
from PhD programs and medical schools
are about women and men are about 50/50,
and yet, if you look at the
deans and department chairs
and full-time professors,
the percentage drops to 16%, 15%, and 21%,
and this is true all across this country.
It's not just a problem
of certain schools.
And I think that what I've
learned over the years
is that diversity is
what drives excellence.
And we must promote women and minorities
to excel in science and
encourage them to succeed
because we are really
kind of an on-top resource
of talents that are wasted out there
without this kind of support.
And it's not just words.
I think we need to invest
money in infrastructure
that supports women and
particularly mothers
to succeed in science
because not having childcare
and child support, especially
during early pregnancy,
or early after having child,
is where the pipeline kind of drops.
So the women who are
in the system drop out
mainly after having a child
and this is a major
problem that we can solve.
We know how to do this.
I think we need to invest
into these kinds of programs
to enable the rest of
the 50% of the population
whose talent is being untapped.
And I also talk about many of my thoughts
in my Twitter.
So if you wanna follow me,
you're welcome to do so.
And this is the most important slide
which is all the lab members
that have kind of made my scientific life
such an enriching environment
and past and current
members of the laboratory
that kind of makes me happy
every time I wake up in the morning
and want to come to work.
And scientific discovery
is really quite addictive.
I wouldn't wanna do any other job.
This is a wonderful
environment to do science
and I want to thank all of you
who have contributed to the joy in my life
as a scientist.
So, thank you very much
for your attention.
(crowd applauding)
- [Moderator] To some questions.
- [Lecturer] Sure, I'd be
happy to take questions.
- [Moderator] We don't have
a traveling microphone,
so if you have any questions,
you'll have to yell.
