Importance of Natural Resources

Viruses: The Good, the Bad, and the Ugly

is with great press pleasure
I’m going to introduce Paul Turner he Paul received his BA from the University
of Rochester and his PhD with Richard Lenski who’s known for his long term
bacterial evolution online outside of his many honors and professional
achievements I’ve seen Paul referred to as and all-around awesome dude
friendly and generous with his time and I’m putting my money on his ideas Paul
is the Elihu professor of ecology and evolutionary biology at Yale and also a
microbiology faculty member at the Yale School of Medicine
Paul has provided us service to our communities in many ways including
mentoring over 60 undergraduate students over the years and many doctoral
students he has donated his time for conversations with non scientists from
mass media including several pieces in the scientist and public lectures such
as this he has also given a series of online lectures for eye biology to
convey about vital biology to those who can’t always make lecture series like
this one if you want to see more form I encourage you to YouTube those Paul has
demonstrated leadership on issues of basic research as well as for public and
health policy for example he was an appointed member on the committee of
gene Drive research in non-human organisms at the National Research
Council he’s also donated his time as an
appointed member of the Biological Sciences Advisory Committee of the
National Science Foundation and he’s served on the council for of the
American genetic Association and my favorite kind of fact is that he was
also a member of the US delegation at the joint USA Russia I a workshop on
infectious disease he encourages us to do research not just in our lab but out
in the broader society paws reach torso is wide spanning and it’s hard to us
summarize it in just a couple minutes but generally he’s interested in viral
evolution and ecology we know that viruses from Paul’s work are important
for parasites and human evolution but today I’d really like to focus on a
specific thread on some of his research recent publications on the renewed
potential of phage therapy so phase 3 actually about a hundred and
50 years old at this point and it read out of favor right after World War 2
when he discovered antibiotics when it was used it was thought to be maybe
effective but the problem is that it’s not broad-reaching
as you know now that we have antibiotics we think the world’s great but we also
now realize that we’re hitting a cliff where our antibiotics are starting to
not work and we have to face the reality that we’re entering into a post
antibiotics that we regime in other words in 50 years the antibiotics that
we use right now to solve common infections like strep throat might not
work can you imagine going back to a time like that so Paul has an ideas
about how we can possibly combat this and say use the idea of phage can we use
phage themselves to force bacteria to still remain susceptible today I’m
products that we use I’ll use them he raises the possibility that we can
actually face this potential post-antibiotic era by hunter silencing
the natural power of its own predator the phage Paul today will tell us about
the good the bad and the ugly of the phages and viruses well thanks everybody for being here on
this must be a slow night in Cambridge for all these people in the room I’m
honored to be here delighted to hold forth for in the next
45 minutes or so and kind of share with you a lot of my own passion and love for
the virus world so in a museum setting like this which is just an awesome and
an inspiring place to catalog and display Earth’s biodiversity I’m into
the kind of biodiversity that you can’t see with the naked eye so that’s a lot
of what I want to focus on tonight is that there’s this amazing biodiversity
that exists on the planet in fact it is so vast it’s hard to even accurately
measure how many viruses there are so to me it’s kind of an endless playground to
study the virus world and as my wonderful introducer reminded I am going
to be able to talk somewhat about how viruses might save your life one day so
I’m trying to have you leave the room on an upbeat note rather than think about
all the pain and destruction that viruses can exact on the human human
population okay so with no further ado thank you very much for being here and
let’s get started I tend to pace a lot when I talk I hope that’s okay I’ve told
as long as I don’t go into this corner and hide out from the cameras we’ll be
all right so I have given outreach talks frequently and I often like to use this
theme of one of my favorite movies and I decided to give a similar lecture and a
friend’s non-majors course at Yale and maybe it was a size about this class
size about this one and I asked all the students to raise their hand if they’d
ever heard of this movie or seen it and I’ll tell you like three hands went up
so I want to know how many people in the room okay that’s not bad if you’re a
young person you have to talk to an older person next to you to keep up
that’s okay see they’re running from the room because they’ve never seen
so I I do love this movie I like Clint Eastwood westerns and other Western soon
I’m gonna eventually get to this theme but first I’m gonna start with this and
this is going to echo something that I mentioned a moment ago I was fortunate
to travel to Alaska recently with my family and we saw many of these
charismatic megafauna right these are very recognizable creatures for the most
part moose caribou bear and these are the so called big five so if you’re on
the equivalent of the Safari in Alaska you’d like to get a glimpse of each of
these organisms which is not easy especially the Sheep because they live
up very high in the mountains so that’s the kind of visible biodiversity that
people walk through the halls of this museum and they recognize some creatures
like these not so much the ones on the right which far outnumber the visible
biodiversity on the planet but this is some of the invisible biodiversity so
this very strange-looking creature that’s Giardia and that’s the reminder
that if you go camping and you want to drink water that has not been boiled you
may not come back from that camping trip unfortunately so these are cartoons
obviously if you can make out the one at the bottom that’s a bacteriophage I’m
going to talk a lot about bacteria phages but most like in the last third
of the talk this is an HIV particle so most people have certainly heard of HIV
if you haven’t heard of bacteria phages you’ll hear a lot about them tonight I
think this is influenza virus particles and so this one requires some
explanation there are some microbes that interact with other organisms and they
basically will take over the behaviors of those organisms and make them do
something else so this happens a lot with ants and it depends on what the
microbe is but in this case this is a fungus that is infected this ant it’s
altered its behavior in some ways I won’t get into but eventually this
fruiting body will come out of the head of the ant and that’s going to spread
spores and it’s going to go in effect more ants pretty gruesome but that kind
of stuff fascinates me so I hope you’re ready
so what what we know is that we live in a microbial filled world that’s kind of
what I’m emphasizing I’m gonna give you an outline of my talk but I’m gonna give
a few slides first to talk about microbes in general before I focus on
viruses so clearly in my lifetime and you know this is very recent stuff that
has come about but now it is in all biology textbooks the fact that in and
on your body there’s a microbial diversity that we’re still in the
process of characterizing it it’s so vast and interesting and
person-to-person you’ve got differences people live in different geographic
regions they have differences in their microbiomes right so specific to her
body there are different bacteria fungi and viruses living on and in the human
body so the real compelling thing is how much are these microbes driving the bus
so there are these really compelling studies for which the results are
exciting but we’re not quite sure what it means if you take someone who is
obese and someone who’s lean and you take the microbes from their body and
put them in a mouse and the mice will take on the traits of the human and then
you can take the microbes out of the mice and you swap them in to the other
Mouse and they become either obese or lean so this has everybody thinking oh
well I’ll just take a pill eventually and I can get rid of that very expensive
gym membership I’m looking forward to that but sorry that’s not happening
anytime soon this kind of stuff does it gives us hope but it’s also gives you
pause to think about are the microbes in my gut telling me to eat when they are
hungry even though I’m not that’s kind of where this research is going but
there’s all kinds of other things like it’s been all night talking about how
much your microbial fauna and flora whatever you would like to call it
that’s associated with your body how much of it is actually sending you on a
pace for things that are pretty dire in the future like higher disease higher
risk of heart disease and cancer so open questions here’s one that’s gotten a lot
of press and that is most of us in this room but it depends where you grew up as
a child a lot of humans live in pretty clean environments and there’s a popular
idea now that we’re actually living in too clean of an
environment on average such that in childhood especially we don’t see worm
infections whereas people who live in very rural environments and entire
countries are full of people who live almost entirely in these rural
environments they see worm infections at a young age and it Prime’s your immune
system properly so your immune system doesn’t turn on you and cause autoimmune
disease all right so this could be at the root of many mysterious allergy
rates in places like the USA whereas in places in the developing world this is
not occurring however it’s very complex in terms of this might be happening but
there’s also evidence that the time at which you introduce solid food to babies
is also something that dictates how much of a risk of allergy they will have in
the future so this is a really compelling idea might have to do with
exposure to microbes at a young age and yet a reminder that we live in a very
complex environmental world and all kinds of things can influence your
future health especially risk of allergy so this is what I want to cover tonight
though these four bullet points not to anger annoy anybody but I’m gonna assume
that there are people in the room who don’t know what a virus is so thank you
for being here tonight I guarantee after you leave you’re gonna
know what a virus is so I like trivia contests my wife thinks I’m sometimes
pretty trivial but the point is I like to go out with friends and we we often
lose full-disclosure he’s it’s not like we’re really good at trivia contests but
I like to build them into my talks why is that because it’s gonna make you pay
attention and it’s also going to make you challenge yourself and it’s not like
I’m gonna test you on things that I’ve said already instead I’m gonna challenge
you for six questions to see whether you’re gonna get them right and sorry
there are no door prizes it’s only bragging rights so basically keep track
of those six questions along the way turn to your neighbor and boast that you
got all six correct and maybe they got none of them correct and we’ll see who
leaves the room proud that they did well on this quiz that’s built in and then
I’m going to cover viruses in a way a that the movie takes the title of the
movie and flips it on its head right the characters are introduced in the
opposite order as the title of the movie so I’ll talk about ugly viruses first
bad ones and then good ones again so you leave the room on an upbeat tone could a
virus save your life one day I’ll spend some time on that so to begin the upper
portion of this slide and the lower portion of the slide are fundamentally
different so there are three domains of life and they’re all cellular based the
bacteria in the archaea have essentially a one cell body plan but they have some
differences from one another that I won’t get into on the right is an
example of you it doesn’t look like you but it is a relative of yours
it’s another eukaryote it happens to be a typical cell taken from a eukaryote
which these can be single-celled organisms as well is also multicellular
organisms like us so the big difference is that eukaryotes have a nucleus and
their cell if you remember that from your biology course so viruses are most
easily defined by what they’re not they don’t have cells they have a body plan
but it doesn’t have anything to do with a cellular body plan instead they are
generally described as proteins that are protecting nucleic acid and the nucleic
acid could be DNA or RNA some variants of those too
so essentially here on the Left we’ve got a bacteriophage of a particular
virus family and you can see it’s really cool I think a really beautiful
structure to it of morphology but I’m pointing to this capsid this is a
protein shell that protects the DNA from degradation from environmental factors
and on the right might be something that’s more familiar to you that’s an
influenza virus particle it happens to have also protein that shielding nucleic
acid but in that case it’s RNA so the simplest lay version of what a virus
does is shown in this diagram so if there are any viral just in the audience
I apologize by reducing it down to this level
but this is going to have everybody essentially understand what I’m talking
about a virus particle encounters some cell and if it in bind and the genetic
material gets in essentially that cell gets taken over as a little factory to
make more viruses that’s all you have to know so that could be happening in a
bacterium so if this is a bacterial cell this virus I’ll talk about this more can
infect this bacterium and eventually kill it and release more viruses or it
could be happening in your respiratory tract or your liver if there are viruses
that are specific to pertinent organs this is happening and it’s going to
cause symptoms usually a lot of virus illnesses are symptomatic not
asymptomatic or not all of them this is just a general idea of how viruses
replicate so despite the fact that I can kind of give you a common basis for how
they replicate I think that there’s a beautiful amount of morphology in the
virus world and that’s what’s shown here in this cartoon so maybe you’ve heard of
some of these herpes viruses are quite common and successful and infecting
humans rhabdo virus that’s rabies virus is a rhabdo virus again this is one of
those what I think are quite beautiful bacteria phages and then others have
very humble morphology like this tube that’s not very interesting is it but
that’s what that virus has so notice one thing here this is a scale this is one
micron this this bar that is one one millionth of a meter so I can now
impress upon you that most viruses are sub microscopic you can’t see them with
light microscopy and that’s why they were missing from the detection of
microbiologist for a very very long time I don’t have a slide of it today but I
should in case you’ve heard of it there are some viruses that are quite
giant-sized they are literally equivalent to the size of the smallest
cells and that was something that was recently found so we can talk about more
more about those in the Q&A if you want first question so we live in a very
virus filled world but I haven’t told you where viruses come from I’m an
evolutionary biologist I care about origins of organisms
and here are some ideas for where viruses could have come from did they
appear billions of years ago preceding cellular life and then they evolved and
remain to the current day are they parasites that came out of
cellular genome so this is a DNA replication picture so imagine some
little bit of this goes rogue and it has an autonomous state next and it just
goes around in infecting other cells and replicating are they devolved cellular
life so you take them all the way down the path of cells evolving and then they
reduce all the way down to viruses again for the youngsters in the audience this
is Devo the evolution do they come from outer space so this is literally the
title of a paper I know some scientists are in the audience because I recognize
you I haven’t pointed you out yet but I might I know that none of you wrote this
paper this went through a peer review it says is bacteriophage Phi X 174 DNA a
message from an extraterrestrial intelligence I will hold my comments and
the morphology of a bacteriophage relative to a lunar lander maybe that
paper has a point or is the answer e that more than one of the above is
probably true so I’ll give you entirely ten more seconds to think about this and
I want you to answer this keep track of how you’re doing is at the end you’re
gonna have a score sheet to tell you how well you did so I would have you shout
out the answer except it might embarrass you when I give you the true answer what
do you think it is II so basically more than one of these
is probably true but not D okay so I would say that biologists that care
about this question are pretty split on what the answer would be and as I was
mentioning who I was saying this to someone before the talk
the problem is viruses leave absolutely no fossil record it’s very hard to go
back in time and even genomes if you know anything about genome sequencing
it’s possible to create file in genetic trees of relatedness between things that
you’ve sequenced but the signal for viruses is very very weak especially if
there are any viruses that mutate a lot okay so I hope like despite what you
shouted out I hope you got that right viruses grow very quickly so this is a
Drosophila lifecycle Drosophila were one of the earliest organisms to really be
used in evolutionary genetics and genetics research in the early 1900s
because they grow very quickly they’re convenient to grow them in the lab a lot
of amphibians these are also eukaryotes they grow very very quickly that’s a
handful of amphibian eggs of some species that I don’t know I’m a
biologist I don’t know anything about bacteria also impressed me with the rate
at which they grow they were the first microbes that I studied as a PhD student
and each bacterial cell is female by definition it can split into two and
create two daughter cells very efficient if there’s enough food to go around to
feed them now this is a bacterial cell for which one of these phages has
infected taken over in the machinery of the cell and this cell is about to burst
open and release these particles even though there are a bunch of other ones
that naively believe that they could get in this is obviously a cartoon but this
reminds me to say in your respiratory tract or somewhere in your body each one
of the cells in that organ could be themselves a virus production factory
producing thousands of particles and no wonder you would have a sore throat
right now they thrive in all environments that you would find life
which is pretty impressive given that in the extreme cold the extreme heat the
deep ocean under high pressure in all these environments you find
viruses and they tend to outnumber any cellular life that you find there so
ergo or therefore this is not a very controversial statement they’re the most
numerous thing on the planet the human global population size is
pretty impressive and worryingly so but viruses at any one time it’s estimated
that ten to the 31 particles exist on this planet I’m not a mathematician but
this is a bigger number than this one I just want you to understand that so
factoid number two in question number two if you remember from basic biology
or genetics if you’ve had it is that the DNA in your cells of which you have
plenty of DNA in your cells it’s in a compacted form it is possible to unwind
it so if you took all the viruses on the planet and you unwound their genetic
material and you laid them in to end how far off of the surface of the planet
would this extent would it go to the moon to Mars to Pluto which I still
respect as a planet because I learned it when I was a kid the Perseus cluster or
to infinity I’m hearing a D the Perseus cluster 250 million light years so if
you are an amateur astronomer go look up the Perseus cluster and the fact that
this huge cloud is moving around the Perseus cluster and it takes millions of
years to go around the whole thing but I digress the point is that that was 250
million light years off the surface of the planet which is very impressive to
me now getting to the meat of the talk so brace yourselves because some viruses
are quite ugly okay so – Cole is one of these the first main character who’s
really introduced and they had this long list of pretty bad things that he did is
he’s about to be executed but don’t worry kids it gets better what is very
evident is that humans have been suffering from virus illnesses for a
very long time and you can find this as long ago in
hieroglyphics and other remains of say ancient Egypt where this man has a very
characteristic malformed leg and foot okay so polio virus exists in soil it’s
very easy to encounter it the problem is when it gets in your body well actually
you can get in your body and go through your gastrointestinal system and you’d
never know it but what it will do inside your body is invade your nervous tissue
and if it does that as you are growing and developing it can lead to malformed
limbs and of course it could be deadly as well so on the remains of some some
mummies you’ll find also club feet and other characteristic malformed limbs of
polio virus infections now this is a little harder to see I know but the
mummified remains of Ramses v this Pharaoh he had smallpox and he died from
smallpox that’s what we know now I’m sure they were mystified then so this is
a more recent photo of someone with characteristic smallpox lesions but
these are quite evident even though you can’t quite make them out and his
mummified remains so that shows us that at least as long ago as ancient Egypt
you’ve got in the time of the Pharaohs you’ve got smallpox and polio virus
being pretty common and I won’t go into more examples just know that this is
something that humans have been dealing with for a long time and then you can
think about how impactful has this been on humans for mortality and this is some
of the ugly statistics so it’s a little hard to really rank the four examples
that I’m going to give you but some diseases are so-called endemic there in
a region and whatever the host organism is they’re suffering from these diseases
viruses can call can cause epidemics well they’ll come in and cause a lot of
destruction and mortality and a host system and this has happened in humans
so a particularly deadly form of influenza virus in 1918 called the
Spanish flu killed some 50 to 100 million victims increasingly at it I
mean impressively at a time when commercial flight was not happening and
this virus managed to sweep the globe it’s that infectious
that contagious that very very many millions of people died so the next one
I’m color coding in black rather than in red all the ones that are truly viral
are going to be in red the Great Plague and Europe in the middle thirteen
hundreds killed maybe twenty eight million people or some forty percent of
the European population at that time so that’s a bacterial illness called caused
by Yersinia pestis but many people believe that you couldn’t get that much
death due to that bacterium alone it probably was that people were living
under very adverse conditions and they were therefore susceptible to lots of
other things that might infect them including some viruses so this is a
little sketchy in terms of how much of this was due to virus versus bacterial
illness the New World smallpox epidemic circa 1520 it’s hard to know how
destructive this was because we didn’t have good census data on Native American
populations at that time but clearly we know that almost entire tribes were
wiped out due to this when Europeans came in and they brought smallpox to the
new world and there was no Native American resistance to it and then the
last one is what I tell students at Yale and elsewhere is that this is an
epidemic that we are currently living through so the AIDS epidemic started
around 1981 at least that’s when it was defined to have started seventy seven
million people perhaps have been infected since then thirty five million
people have died and currently 37 million are living with HIV so pretty
impressively gruesome numbers in all well and some of that is a topic that I
like to study in my own laboratory and is a very difficult thing for
biomedicine to predict and that is what is going to be the next thing that
sweeps into humans and causes a lot of destruction so that’s a very difficult
thing to predict as you might imagine some of what we try to examine is the
ability for viruses to jump between host species and some viruses are quite good
at jumping directly into humans unfortunately in causing deadly diseases
I’ve got examples here so the tricky
with emergence is it really happens three different ways but it’s thrown
together into one catch-all term so you have something like these flying foxes
these bats they’re really bats they are daytime foragers and in places like
Australia they are nesting or roosting in the trees and also foraging in the
trees and they will pee and defecate and it’ll fall to the ground and this could
be happening on a farm where pigs are rooting around eating and they take in
the virus and it may not kill well in other words he gonna fire someone
I forgot to say bats are quite quite good at carrying viruses and in this
case Nipah virus can be taken up by the pigs and humans who are farming the pigs
or if you eat undercooked pork you can get a NEPA virus infection which can be
deadly so that’s a form of emergence it’s going from the reservoir host
ultimately to humans and that’s why we care about it
so HIV I kind of hinted at this before HIV is a very interesting virus it’s
actually evolved many times independently so SIV there are many SIV
strains that are in chimps and other primates like sooty mangabey monkeys and
as long ago as 1930s these viruses were getting into people and yet the chains
of transmission were pretty weak and it took all the way until the 1980s before
we realized that this virus was in people and it has a very long latent
period like ten years before you’d know you’re even infected and then when that
happens your immune system starts to crash because the virus is destroying
your immune system cells so the point is it’s very good at going from non-human
primates into humans and it happened independently several times to evolve
into hiv-1 and hiv-2 so that’s a form of emergence and then on the right even
viruses that we see all the time and it’s circulating humans like influenza
virus you can get much more deadly strains like I told you happen in 1918
the real fear is that the main reservoir of influenza viruses on this planet is
in waterfowl especially there’s much much more of that virus in birds than
there is in humans and humans don’t do very well when they get avian flu
it can be deadly so that’s a looming high likelihood a possibility that
you’ll get a deadly flu outbreak happening eventually in humans and the
source will probably be from birds so I can give you many examples to kind of
sober you before I try and give you some good news
Zika virus is yet another virus that has been known for some period of time in
Africa more recently you’ve got the spread due to global warming of
mosquitoes that are capable of transmitting this virus and therefore
the virus is spreading to places that it hadn’t been traditionally and more
humans are encountering it and you probably know that one of the very
unfortunate outcomes is that this can lead to microcephaly in children so you
don’t have the brain case developing properly and therefore brain size is
limited so that’s where we started let’s just take a breath it’s gonna be
okay now we’re gonna talk about the bad viruses here’s where I introduce angel
eyes or Lee Van Cleef from the movie again go watch the movie if you don’t
know what I’m talking about so this is a quote that my mom would say around the
house they can put a man on the moon but they can’t cure the common cold so I was
born in 1966 it was that precious time when we were trying to get to the moon
we did it successfully and yet I think people were kind of awestruck that we
could do that meaning that there were some things that were quite annoying in
medicine that we didn’t solve and I’m not I’m pretty certain my mom didn’t
come up with this quote but she heard it somewhere and she would just say it
around the house Rhino viruses and other viruses
rhinoviruses by the way have nothing to do with rhinos rhino means nose right so
some viruses make you sick but they won’t kill you I won’t go into gender
differences and how much people whine when they get a cold I whine a lot when
I get a cold I really sometimes wish I was dead but it’s not you know actually
these can be very dangerous to people who have asthma so there are there are
people who have a very debilitated state from having a common cold and yet
you know you’re ideally staying at home you’re not going to school you get
through it over the course of three or so days but some colds as you know can
last weeks so it’s very annoying and it is not something that has been attempted
to be fixed through vaccines lately there was actually in a tip that at some
time ago and it didn’t sell that’s because the virus has evolved so quickly
that you produce a vaccine and basically it’s ineffective because the virus says
have moved on genetically and they’re not targeted by the vaccine so other
viruses that are not so important in this country but kill people around the
world I’m going to give you an example of this rotavirus
now this is a virus that if you get infected with it you do wish you were
dead you basically have inability to keep fluids in your body if you could I
will get more graphic than that so this I know this intimately because my
daughter when she was two years old we were living in New Haven she had a
rotavirus infection and she had to be on an IV for rehydration therapy for at
least 24 hours I think it might have been two days and it gave me a clearer
understanding of a lot of people live in this world without access to clean water
and all you really need usually to get through this infection is rehydration
with clean water but lots of kids don’t have that so this is perhaps 5% of
children around the world this is the thing that kills them is rotavirus it’s
untreatable by drugs vaccines exist there’s been some challenges getting
those vaccines really to the people who need them so think about a lot of
viruses are pretty bad we don’t struggle with them so much in this country but
they’re pretty bad and a lot of harm comes including death in other countries
now I want to move on to talking about other organisms than humans I like to
impress people with this because it makes them think that I read literature
which is not really true because I’m a sci-fi buff but I did read watership
down and it’s a pretty cool fantasy novel and in this book and if you’ve
ever seen the cartoon version of it they talked about white blindness as
something that if the rabbits in the colony or whatever the group of rabbits
are called has this then they kicked them out so
this is a real thing I know if you can make it out this rabbit has
an unfortunate kind of tumorous growth on its face that’s because it’s infected
with this virus that causes myxomatosis and eventually the rabbits gonna go
blind okay so this is a virus infection so myxoma virus was purposefully
released in a country because they had a rabbit invasion problem okay what is it
yes Australia which is famous for its bio
control strategies that don’t always work in 1950 myxoma virus was released
in Australia so I fortunately when I blow this picture up it’s so low
resolution that you can’t see what it is but it is a watering hole surrounded by
rabbits and you look in the distance and all you see is rabbits so this is the
state of Australia at that time and they grew the virus some scientists grew the
virus in the lab it was quite deadly in the laboratory and then they released it
and it worked initially and then they didn’t quite factor in through basic
epidemiology that a rabbit has to be infected for long enough and live long
enough so that the chain of transmission goes to the next rabbit and it’s sort of
pushed the system back to a more moderate form of the virus it evolved in
the wild to be less virulent than you found in the laboratory and basically
the biocontrol effort failed okay so now let’s talk about the good we’re gonna
we’re gonna wait to get upbeat I’m gonna tell you how viruses might save your
life one day and Clint Eastwood who’s supposed to be
the good person the good character I forgot to say this at the beginning
basically all these characters are very very flawed that’s why this is a classic
movie it has a an almost nonsensical title because it categorizes the
characters into these bins and you see them moving from Ben – Ben okay well
we’ll just say that Clint was the good guy because he likes to be the good guy
usually in his movies so we live in an area that’s well I live in an area
that’s very close to the epicenter of Lyme disease I know you’re worried about
it here as well but it’s an example of if you take a system and you throw it
out of balance because some species are missing you can create problems so lots
of deer live in Connecticut in other areas of the Northeast where Lyme
disease is prevalent and deer are often blame for the fact that oh there’s so
there’s so many of them and we don’t have any wolves anymore in this area
it’s not keeping the deer population down and deers or deer deer deer are
important as amplification hosts for ticks that are feeding on the deer and
the ticks have the Lyme disease bacterium in them and if the ticks get
no blood meals and clearly they wouldn’t be problematic
now I’m not showing you pictures of rodents where rodents are actually the
key species many people believe for amplification of Lyme disease but the
point is that in an ecosystem if you remove a predator things can become
sometimes more problematic than you’d think so now I’ll get obscure with you
and talk about the world’s oceans and it’s a reminder that there are these
very plentiful bacteria in the oceans called cyanobacteria and they are
photosynthetic so they capture sunlight they use that for energy and they grow
on it they are very ancient you can find
fossils of these from some three-and-a-half billion years ago which
is not that long after life was predicted to or inferred to have arisen
on the planet and they did us a big favor in the process of doing this
abundant photosynthesis they changed the atmosphere and they elevated the oxygen
making it possible for large bodied organisms like you to be on the planet
so you can thank them for that cyano phages are their main predator in the
oceans and the outnumber cyanobacteria and in a way they must be regulating the
numbers of cyanobacteria in the oceans so where am I going with this if the
oceans which are providing nearly half of the photosynthesis on the planet and
therefore contributing so much to Earth’s oxygen levels if these bacteria
were capturing sunlight and blooming I’m not showing you a picture of that but
these bacteria can bloom – giant sizes meaning high densities that you can
visualize it from you can see it from space okay so they can go through these
boom and bust cycles but as soon the phages keep them more or less
constant so that in a way is keeping the oxygen level constant on earth which is
a good thing okay if it’s going through boom and busts and increases in
decreases wildly in oxygen levels then a lot of us would be a lot of the species
on the planet would be in big trouble so I now want to go to one thing that was
seen in sequencing of scientist ages they carry photo synthesis genes okay
and that’s a strange thing what it means I’ll just go to the you know go to the
punch line if you have a phage and it’s infecting a bacterium it’s got to keep
the bacterium’s and molecular machinery churning in order to make baby phages
and it was a mysterious to see well why do these pages have photosynthesis genes
that’s because they bring to the cell the ability to keep the cell churning
and keep energy going as they’re in the process of killing the cell and making
more progeny so what happens is that the oxygen in the atmosphere can sometimes
be coming from these genes in sign of ages instead of genes that are residing
elsewhere that are responsible for photosynthesis so how many of your
breaths today do you think you must thank the cyano phages in the oceans for
producing the oxygen that you breathe then was it one in 20 of your breaths
one in a hundred one in a thousand none of them at all or
every single breath that you took not so easy this one is it this is not
Australia what is what do you think all of them I’m hearing all hey hey okay
that’s pretty impressive to me especially as you sit here and you
listen to me gab for an hour if you count up how many breaths you take you
know a lot of them came from cyano phage genes creating the oxygen from there
photosynthesis genes okay so this one is probably the trickiest one
I’m gonna go immediately to the next question so at some point in time
somebody did this crazy thing they traded something related to viruses for
for tons of wheat ate tons of rye four large oxen ate large pigs 12 large sheep
to hogshead wine whatever hogs head is four barrels of beer two barrels of
butter thousand pounds of cheese a thousand pounds of cheese one bed
inexplicably one full dress suit and a silver goblet
so somebody traded one thing for all of that and it related to a virus was it a
vaccine a flower a ship a horse or royal family member you thought they were all
gonna be Australia weren’t you any idea eh II see who here is a horticulturist
you should be ashamed you didn’t get this right so during the tulip craze all
of that stuff was traded for a single bulb of this kind of tulip a broken
tulip and had this amazing color pattern and it didn’t have only one color it had
two that’s because it was infected by this virus and the plant was producing
these bulbs that make broken flower coloration okay so that you can easily
do through genetic engineering now you just make these tulips that have the
broken color formation but anyway so now we’re gonna end with whether viruses can
help solve health problems as we heard at the introduction antibiotics have
worked historically but not very well lately so all the time you hear in the
news of mersa which is a form of an antibiotic resistant staph aureus
bacterium you can hear about extreme drug-resistant tuberculosis so there’s
all sorts of very nasty illnesses caused by bacteria that are now resurging
because we are running out of antibiotics to treat them so this is a
very sobering picture I’m gonna get to better news in a moment but by 2050
especially in the most populated parts of the world this is annual deaths
project projected for drug-resistant infections okay to the tune of you know
maybe four million people a year will be dying in Asia and also in North America
right at our doorstep hundreds of thousands of people will be dying so
this is what people talk about when it may be the end of the antibiotic era so
what you can do about it is look to an old idea and trying to update it so
phages I’ve talked about them they kill only bacteria and they could be
efficiently used as drugs that make copies of themselves so now pretend that
this growth cycle where you’re seeing the phage come in and infects the cell
it makes progeny viruses so if this is a pathogen this is different than an
antibiotic because it’s not only killing the cell but it’s making copies of
itself to go kill other cells of similar type so you shouldn’t have to take as
high of a dose because the thing creates its own increased dosing so this was
adopted long ago by the Russians Polish scientists and now former USSR countries
Oranje so when Western countries were investing
in antibiotics other countries were not it’s far cheaper to do this kind of
technology to the point that a lot of Russian soldiers were given vials of
phage when they were out in the field in case they got wounded and they couldn’t
get to medical care fast enough it’s a good way of rubbing that on the wound in
order to protect your wound from having an invasive bacterial infection cholera
is a bacterial disease it’s another one for which rehydration therapy should
work and get you through it if you give somebody cholera bacteria specific pages
in other words viruses that kill cholera bacteria they recover faster that’s been
shown so there’s an obvious problem though we live in a world full of
bacteria that have evolved to be resistant to antibiotics so if you go
around using phages instead I would predict as an evolutionary biologist
you’re just going to select for resistant bacteria instead so this is
the question we’ve grappled with for a couple of years is whether you can
develop a strategy that gets back to this old idea and updates it because I
know that this is inevitable I know that the phage will be seen as a deadly
predator and the bacteria are going to evolutionarily respond to be resistant
to them so the way this works the way that we think we’ve solved that problem
is that in my career I’ve studied evolutionary trade-offs evolution often
involves compromises so something is seen as a challenge organisms adapt to
better meet the challenge but it doesn’t mean that they’re becoming super fit in
all ways they might be improving in Fitness in one thing that’s important
for selection and they might actually be doing worse at something that they had
done better in the past so selection can improve a trait at the expense of
another humans walk upright all of the time and other great apes do not I don’t
hear gorillas and chimps complaining about neck pain and lower back pain well
if they could talk maybe they would but you don’t expect them to because they
don’t have they shouldn’t have it their musculature and their architecture
shouldn’t create those problems whereas that is a problem in humans another
example would be these two organisms are quite familiar they’re very successful
in their environments but they’re built differently cheetahs are adapted for
speed and they can chase down a gazelle if they tried to chase down a zebra jump
on its back they probably break their fragile long bones in the process
whereas a lion is not fast enough to chase down a gazelle
but it is big enough and fast enough to chase down a zebra jump on its back
break the Zebras back and get a meal so they’re very successful in their
environments but they’ve been taken to an adaptive solution that doesn’t make
them good at exploiting the entire environment so back to phages and
bacteria our innovation as we look for phages in the natural world out in the
environment that have evolved to do something interesting and that is to
attack bacteria by binding to what are called virulence factors of pathogenic
bacteria so that’s illustrated in this cartoon imagine this bacterium and it’s
got some proteins on it in yellow and blue decorating it for a variety of
purposes but in this purpose these are important proteins that contribute to
the virulence of this pathogen and causing disease in humans so you can go
find phages that are specific to these different proteins and if you can see at
the bottom here it sort of pushes the bacteria evolutionarily to a solution
where they avoid phage attack but they lose or they alter those binding spots
making them less virulent so you’ve got a drug that works and when it fails it
works because you’ve still pushed the system to a lower pathogenicity okay so
I hope you understood that I went through that kind of quickly so there
are lots of things that decorate bacteria that are virulence factors and
if you can make it out in this cartoon I’m showing this red coloured phage
interacting with a pilis that’s coming out of this bacterium that’s important
for something like burrowing into the intestine okay there might be things
that allow the cell to bring nutrients in and out that might or even iron
something like that iron uptake to make it good at scavenging iron from your
body and contributing to its pathogenicity and that could also be a
binding site for a different kind of phage so you just work your way around
this bacterium you can think of many things that are already known as
virulence factors that might attract phages to infect them so this is one we
keyed in on recently it’s called an e flux pump it’s responsible I think I
have another picture of it it’s responsible for if antibiotics get into
the cell they’re actively pumped out and it can make some bacteria kind of pen
resistant to antibiotics so we’ve been looking for phages that interact with
these protein structures and try and force the bacteria into a corner they’re
either going to evolve to escape the phage or they’ll die from phage attack
and when they evolve to escape the phage we’re finding that they’re less
effective at pumping antibiotics out they flip to become sensitive to
antibiotics rather than resistant so that’s shown in this diagram again
efflux pumps are decorating that cell an example would be I’ll show you in a
moment soon mamas original it’s
quite famous pathogen that has loaded up with E flex pumps so this cut through of
the bacterial cell with these proteins showing the antibiotics going from the
inside of the cell to being pumped out that’s the same protein that this page
is interacting with and it pushes the bacteria into that solution they’ll
evolve to escape the phage but instead of becoming instead of maintaining
resistance to antibiotics they suddenly become sensitive to antibiotics and the
physician is going to have a lot of options and using an antibiotic to kill
these bacteria and sort of reverse the problem that we’re seeing around the
world so I wouldn’t be talking about unless it worked right so we did find a
phage the first one we found was in 2016 we were looking in aquatic samples in a
lake in Connecticut called dodge pond pretty randomly science is full of
serendipity we found a phage that did exactly what I showed you in that
cartoon it forces the bacteria to trade fade-resistance resistance for
antibiotic sensitivity and it turned out that we quickly found of a man who had
run out of therapeutic options at the hospital in New Haven
he had an artificial part of his heart and aortic arch replacement surgery that
became infected with what’s called a biofilm are very tight chronic infection
of bacteria that they had no drugs to remove the bacteria because they were
paying drug resistant so we talked about in many places in the media and people
wrote about this man he volunteered for the surgery
sorry it’s not surgery actually he was too elderly to undergo this surgery
again so instead we administered the phage directly to the site of the
infection and the story goes like this Ben Chan who’s in my group they’re in
the operating room with the surgeon and the sky they’re ready to take a needle
and try and place the phage close to the site of the infection and they found too
much scar tissue they couldn’t get to it so instead they took advantage of what
this man unfortunately had it’s called an oozing fistula his infection was so
bad it had broken through his chest wall and was out so they took the
and they injected it instead there and it traveled to the site of his infection
cleared the infection whereas he had this chronic infection for four years
that his physicians couldn’t do anything with and he went back to work in New
Haven as an ophthalmologist so this is where we are thanking him in his office
and we’re giving him a phage plush toy it’s like thank you for your volunteer
surgery that or you know the treatment that saved your life and here’s a plush
toy so we’re doing a lot of what Ben and my lab likes to call pond to bedside
personalized medicine so this is an example this is a picture of dodge pond
and it’s just one of the many locations we’ve sampled we find new phages to
science that have never been known before and here’s a young woman in Texas
who has cystic fibrosis and she had a bacterial infection in her lungs that
was again pan drug-resistant so he is handing her this example of the phages
that they’re going to be putting in in her inhaler her fabulous her and she’s
going to inhale these over the course of the next eight days and it saved her
from undergoing a lung transplant and it didn’t eradicate the bacteria entirely
that’s very hard to do and the CF lung because it’s filled with mucous it’s a
very good place for bacteria to reside but she no longer needs a lung
transplant and she’s as healthy as a CF patient could be now we’ve been tracking
her so we are also doing this to target mersa infections and other bacterial
infections of the lung and we’ve treated very many people and this is really
taking off quickly we’d like to do clinical trials about this so literally
been every day gets emails about this from somebody in the USA or around the
world who has an untreatable bacterial infection and we’re trying to help them
with this and others are doing it as well there’s sort of this resurgence of
phage therapy right now all right so the question is why would
the FDA think that that’s a good idea turns out that now must be about twelve
years ago the US fda approved that phages could be sprayed on food and I
bet you didn’t know it did you yeah so you can go to the store and purchase
food that has been sprayed with phages to protect that food from being
colonized by a form of deadly foodborne bacteria is it lettuce
apples strawberries deli meat or raw chicken who said D I’m hearing a deli
meat okay so next time you go to Stop & Shop and you get the sliced ham this is
so safe in the eyes of the FDA that you don’t have to see this on the label it’s
just sold to you in the store so that helps people like me who are trying to
create these novel treatments because already it’s it’s considered safe for
human consumption okay all right so I’ll end with that was some upbeat news about
how a virus could be good for you and now I’ll end with you might not even be
in the room if it weren’t for viruses so one factoid from the Human Genome
Project that surprised people is that you you get the genome map for humans
and almost ten percent of it is recognizable as viral that means that
this long ago in the past what gave rise to humans interacted with viruses and
sometimes took up that genetic material and incorporated it into human
chromosomes okay some of it what’s generally called endogenous retroviruses
that’s the the majority of them and some of them can be maybe bad for you if
they’re really condone going area of research don’t leave the room thinking
that this is well founded and ironclad it’s not but some people think it could
relate to some cancers some autoimmune diseases like MS maybe diabetes there’s
lots of ideas out there but they’re very much under ongoing research something
that is known is that useful protein so genes that make useful proteins can come
from these genes that are recognisably viral and they’re in your DNA especially
since Siffin protein which is essentially essential for placenta
formation so these come from viruses that long ago were infecting things that
gave rise to humans one they actually to all placental mammals
at one point and these are viruses that are quite good at hiding out from the
human body and avoiding detection so that they’re not fought which in a way
you can think of as a baby developing in mom might be perceived as something that
is a foreign body that should be rejected and instead these proteins from
these genes kick in to say that no that’s not the case this organism should
be there okay so thank you thank the viruses because you

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