August 4, 2021 • 42 mins
A legend about ancient inoculators on a sacred mountain, and the remarkable story of how the genetic sequence for COVID-19 was first released to the public.
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Speaker 1 (00:08):
School of Humans. What would your life be like right
now if coronavirus hadn't emerged in twenty nineteen, What would
the world be like? I'm Sean Revieve. I'm a full
time freelance journalist. I travel around the country and world
to tell stories. I've reported on HIV, neuro signs, AI,
facial recognition, and a host of weirder topics. In twenty twenty,
(00:32):
I did none of that. Instead, I spent months afraid
of going to the grocery store, afraid of touching door
knobs and hugging my best friends. I worried about keeping
my wife and two year old sons safe. I worked
half time or no time. I got the news that
my aunt died alone in a hospital. I spent a
lot of time on a couch depressed. That's just me.
(00:58):
You've got your own list. Now. Multiply that by seven
point eight billion. Lives ground to a halt after a
novel coronavirus showed up in Wuhan. Nearly two hundred million
people have been infected with coronavirus since December twenty nineteen.
More than four million have died. So many lives disrupted
(01:20):
or damn near ruined we want our old lives back,
if that's even possible. While a truly universal pandemic, one
that affects everyone everywhere, may be unprecedented. In our lifetimes,
humans and viruses have evolved side by side. Our history
(01:42):
has been shaped by plagues, pandemics, viruses and diseases and
the fight against them. Today, they are in combat more
than ever, and vaccines have moved from the background to
the foreground of our daily lives. So as a journalist
and generally curious person, I want to know what went
into them. In this podcast series, we're going to take
(02:07):
you deep into the science and the people behind the
coronavirus vaccines. We'll travel back in time to me the
first innoculators, follow a path from legendary healers in China
to obscure country doctors in the UK, from an enslaved
African in Boston to the man who invented dozens of vaccines,
and we'll draw a direct line between them and the
shots we're getting today. In this episode about Beginnings, we'll
(02:33):
talk to a virologists who played a key role in
releasing the genetic sequence of coronavirus. We'll also hear from
an evolutionary biologist who explores the origins of all coronaviruses
from My Heart Radio and School of Humans. I'm Sean
Revived and this is long shot the two hundred and
fifty year journey to the COVID nineteen vaccines. Ever since
(03:03):
coronavirus became the biggest story in the world, vaccines have
been our greatest hope to stop it. The coronavirus vaccines
were produced in record time, but they're not slap dash
overnight inventions. There are a culmination of centuries of research
and advances and some unbelievable experimentation that began way back
when with smallpox inoculation, which marks the beginning of one
(03:24):
of humankind's greatest achievements, the ability to protect from disease.
It's a practice so old that nobody knows who first
attempted it or exactly where it originated. To even begin
to figure that out, you have to probe nameless. Healers,
myths and legends. Here's writer and actor Leoe I v
(03:44):
Chen to tell us one of them. To get to
the top of the highest of the four sacred the
Buddhist the mountains in China, you must climb sixty thousand
steps over piles of snow in winter, past the water
falls and the large greenery in summer. It will take
(04:06):
you two days to get to the top. Mont er May,
or er May Shan, was created two hundred and sixty
million years ago by a volcanic event so explosive that
it caused the massive extinctions across the planet. The mountain
(04:29):
is ten thousand feet top. It juts into the heavens
above the clouds, like a defined place it is. The
mountain is one of the holiest sites in Buddhism. There
are more than thirty buddha is the temples on mont
er May, including the first one built in China. Like
(04:54):
all holy places, there is a legend about mont er May.
A thousand and years ago, the son of a local
governor got very sick from small pox, which by land
had plagued China for at least a thousand years. The
(05:15):
governor offered the piles of gold to anyone who could
help his son. Three Daoists traveled from mont er May
and offered their services. By washing the small pox, the
Dooists said, you could grant protection from the disease. The
(05:40):
governor asked the Daoists to teach him this practice. The
Daoists agreed, and before they returned to the mountain, they
placed a book containing the secret of inoculation underneath a
medal incense thorible. Upon opening the book, the governor learned
(06:04):
at least tech chniko inoculation had long ago been invented
by a female Daoist. As a reward for her pioneering discovery,
she was turned into a goddess. So this myth, this
(06:26):
one on Mount a Mae. It was written in the
seventeenth century by a man named Fusheng Lin, and fusheng
Lin has his own interesting connection to innoculation. Louise, going
to tell us that story, said about seven hundred years later,
during the reign of teen Emperors sunt there were at
(06:46):
least nine outbreaks of small parks in Beijing, the city
where he lived. Each time there was an outbreak, the
emperor left his home to go to a bid Saw,
a place to quarantine from small parks, including one Bidsa
that was on a literal island. This way, the parks
(07:10):
could not reach across and infect him. Despite these precautions,
the emperor caught a small pox as he lay dying,
the emperor had to decide on a successor among his
six young sons. He chose the second son at a
(07:35):
young age. He'd already survived the small pox. With protection
from the disease, the boy was more likely to have
a long rule be a stabilizing force for the empire,
and he was This Song became the County Emperor, the
longest the ruling emperor in China's history. Low the County
(08:01):
Emperor survived the small parks, he did not escape to
trauma every time there was an outbreak of small parks.
He was haunted both by his foulest death and by
the isolation, and so when he grew into an adult,
the Councy Emperor searched far and wide for the umpire's
(08:23):
best inoculators. Around the sixteen eighty two inoculators were chosen
to protect the emperor's children. One of them was a
full Hunling, the author of the story about Monteur May.
(08:48):
Those early Chinese inoculators used several different methods to protect
people from small pox. One involved blowing the scab of
a small pox sufferer into the nose of a patient
using a bamboo shoot. Another method had the patient wearing
the clothing of an affected person for two or three days.
Yet another had a child lay underneath the quilt with
(09:08):
a sick patient, so that the patients chi would transfer
to the child. Some methods worked better than others. Even
in these early times, the inoculators had standards for who
could or should be inoculated. They avoided the procedure for
medically fragile patients, who were more likely to develop full
blown smallpox. It was not recommended for the week or
(09:30):
otherwise diseased, or for pregnant women. They thought it was
better to inoculate before puberty. It's unclear which innoculation method
was favored by fushang Lin, but the story he wrote
about Mountain Amey and the three Taoists may be evidence
of the earliest known inoculators, so long ago that the
first Crusaders hadn't yet invaded Jerusalem, but it might just
(09:54):
be a story. Real documentation of inoculation doesn't come for
about five hundred more years. In volume six of the
late British historian Joseph Needham's enorm a series Science and
Civilization in China, there is a reference to a fifteen
forty nine medical text by a Ming dynasty physician. That
(10:14):
quote casually mentions smallpox inoculation as if it is already
by then a common practice in China. That's one hundred
and fifty years before the first known inoculation in say, England.
But the point is nobody really knows exactly when or
where innoculation began. All we have our stories. In the
(10:44):
nineteen eighties and nineties, a relatively new disease ravaged the
city of Edinburgh, Scotland. It was called acquired immuno deficiency
syndrome or AIDS, the disease caused by HIV. In Edinburgh,
HIV spread fast, often through the sharing of needles by
intravenous drug users. They would in a drugs and shared
(11:06):
a needle, They passed the needle down, you know, amongst
these people in these kind of tenement buildings that fuel
this massive HIV ant break in Edinburgh. That's Eddie Holmes,
a virologist and evolutionary biologist at the University of Sydney.
Back in the early nineties, he was in Edinburgh studying
the spread of HIV. So what we were trying to
do was trying to work out how the virus was
(11:28):
spreading through that population, how it had diffused, and how
it got into sydy and how it spreading. I do
remember that actually getting in Around that time, he got
a car from Beatrice Hahn. Beatrice harm, who was then
working in virologist then working at the University of Alabama
at Birmingham. Hann asked Eddie if he was interested in
joining her and an HIV related research project. She's been
(11:49):
the person who's done more than anyone else to reveal
the origins of HIV. And she asked me in nineteen ninety,
was I interested in working on that? And I said, no,
I'm going to do my own, my own work on
something else. He turned her down to concentrate on his
own work. By then, AIDS had already killed more than
(12:10):
sixteen million people. It was known that there were two
main types of HIV, HIV one and two. Han and
her colleagues and not Eddie would go on to discover
that neither type of HIV came initially from humans. Both
originated in primates HIV one in chimpanzees and HIV two
in suity manga bays, each of which carry Simian immuno
(12:33):
deficiency virus or SIV. The virus jumped to humans at
least seven times, mostly in areas around Congo. It was
a stunning discovery. Hans said that it was especially sobering
that two very different primate species could serve as a
host for human pathogens. She was even more worried because
(12:56):
she knew that there were dozens more species of primates
that carried their own forms of SIV. Hans blockbuster paper
was exciting to Eddie home, but he had some regrets
knowing that he could have been a part of it.
That was like saying those the Beatles in nineteen sixty three,
you know I missed, I missed my opportunity. It's a
do some great work on that. Instead of discovering the
(13:23):
origin of HIV, Eddie began working in metagenomics, the study
of genetic material taken directly from the environment. So our
focus has always been on these kind of key species,
but with metagenomics you could at anything. So we're looking
at this an these wild Invertibrus and known and looked at,
and we found this amazing diversity of viruses in nature
(13:46):
and everywhere. So these animals we never looked at suddenly
saw this this huge diversity of viruses. The virus sphere
was enormous. Opening that door was facilitated by this this technology,
the methogenomics. By the time coronavirus hits, Eddie has become
a pretty big time evolutionary biologist. He studied the flu,
(14:07):
deng HIV, Hepotatis C and other viruses. He's got grants
and awards and fellowships, but he still hasn't had his
Beatles moment, not since turning down the chance to discover
the origin of HIV back in the nineties. In twenty twelve,
Eddie moves to Australia to work at the University of Sydney.
(14:28):
He begins a partnership with Professor Jong jen Jang, then
working at the Chinese Center for Disease Control and Prevention
in Beijing. He's a character, as they say, I said
this thing where whenever I sent an email to him,
he would reply within fifteen minutes, right because he was
always checking. So I used to send him an email
like at six am in the morning, thinking right now,
I'll get he must be asleep. That's three am in
(14:52):
and then ten minutes later, Hi, Eddie, it's amazing. So
he'd wake up in the night just to check his
email you know he's extraordinarily hard working. I mean off
the scale. Using metagenomic elysis, Eddie and Jang sampled animals
of all kinds looking for RNA viruses, that is, viruses
(15:12):
that have rabuclaic acid as their based genetic material, like coronavirus.
Some of the animals they look at include bats, mice, pigs,
and birds, but also snakes, crabs, spiders, ticks, shrimp, crayfish,
woodlight tapeworm, mosquitoes, centipedes, millipedes, leeches, earthworms, octopus, snails, oysters, muscles, clams, barnacles,
(15:34):
even goddamn sea cucumbers. No species is too obscure In
these animals and their parasites, they discover thousands of new viruses.
A lot of their work is done in and around Wuhan,
an enormous city in central China. It's not very well
known in the West at the time, but with eleven
(15:54):
million people, Wuhan is bigger than New York or Paris.
It's a very big city. It's extremely well connected in China.
It's very famous for being a travel hub because because
the Yancy River goes through it's the big river kind
of delta or big river system brother and the train system.
You can get from basically anywhere in China to Ruhan
(16:15):
about six and a half house as an international airport,
so it's a big hub. It's a really big hub.
Also around Ruhan, it's just this you know, pristine natural environments.
Actually's a very interesting place to sample. In twenty fourteen,
Eddie and Jang even visit the place most associated with
the first cases of coronavirus, the Huanan seafood wholesale market.
(16:38):
The local CDC took me there because they said, look
at this place, it's a really good place for a
disease to emerge. It's probably like two big supermarkets glued together,
the set of indoor alleys with a kind of road
to the middle of it. There's lots of it. It's
like an indoor, big indoor market, and there's lots of stores,
(17:01):
and there's there's kind of gutters, there's lots of things
on sales. There's lots of eye products, lots of fish,
lots of frozen products. And there's one section where there
were wildlife. I mean I saw mammalian wildlife there. There's ice,
saw rodents there, and variety of other things. There's also
these famous kind of like menu boards outside showing some
(17:22):
of the kind of wildlife that they're they're selling. It's
very closed. It feels kind of like, you know, it
feels kind of sweaty and cramped, and it feels like
kind of incubator in a way. You know. I took
the photographs, really crappy photographer took of these raccoon dogs, okay,
(17:42):
in these cages that raccoon dogs are weird. Theircadians in
the dog founding and their fur farm, and I think
they're used for food as well. And what I realized
is that raccoon dogs they were implicated in the first
Stars outbreak of two thousand and two two thousand and
three because there were positive raccoon dogs in these markets
in Grand Dumb and there they were in this market
(18:05):
in Wuhan. During the two years before the outbreak of
COVID nineteen, Eddie and Jang are working on a study
of Central Hospital of Wuhan. They're studying patients with acute
respiratory disease symptoms and trying to find out the cars. Again,
this is before COVID nineteen, But what that meant was
(18:26):
we were kind of like on site almost looking at
the same Z syndrome in the right tissue samples with
the right technology, and so we happen to be in
the wrong place the wrong time. I feel like when
it all kind of started, and that gave us the
kind of an open door to really try and look
(18:47):
at this some of the early first cases to see
what was going on. In mid December of twenty nineteen,
the forty one year old worker at the Huanan seafood
wholesale market begins getting pneumonia like symptoms, fever, calf pain, easiness,
that kind of stuff. A few days later, the patient
(19:09):
is admitted to Central Hospital of Wuhan, among the very
earliest identified novel coronavirus patients in the world, the same
hospital where Eddie and Jang have already been studying patients
with similar symptoms. By this time, Eddie is back in
Australia and Jang is in Shanghai, but because of their
prior work at Central Hospital, they particularly Jang, are in
(19:32):
prime position to see what's going on with these strangely
afflicted patients. Early in the afternoon on January third, Jang
receives a package, a metal box holding a test tube
packed in dry ice. Inside the test tube is a
swabbed sample from the sick market worker. By this time,
(19:52):
word of a new contagious virus is spreading among the
public health community. The first news reports about this mysterious
illness have been published. In China. There are forty four
or so confirmed pneumonia of unknown origin cases. Seafood market
has been closed. Many countries and the World Health Organization
are trying to figure out what the heck is going
on and if this disease is going to cross borders.
(20:16):
Jiang does not know that the test tube in front
of him contains a sample of a virus that would
take over the world within months, but he knows it's important.
Rumors are already spreading that it is SARS like which
in China and especially in Chinese virologist circles, is a
big deal. The first severe acute respiratory syndrome where SARS
(20:39):
epidemic was discovered in the city of Foshan in China
in November two thousand and two. Eventually it's spread to
more than eight thousand people in twenty nine countries. SARS
one was internationally embarrassing for Chinese leadership. They could not
contain the outbreak and could not treat the disease. Western
media reported aggressively on China's failures. The last thing Jiang
(21:04):
or his country wanted was another There are stars, and
Jang strongly suspected he had it. Sitting in that test tube.
For the next two days, working around the clock, Jang
and his team worked to sequence the virus. Around two
am on the fifth, it was done. Eddie gets an
(21:29):
email from Jang. Jang emailed me and says, please call
me immediately. I was driving to the beach and my
in laws for breakfast, right because it's January. It's summer
in Sydney, right, And that was that was like eight
am in Sydney time, so it must have been like
five o'clock in the morning in Shanghai. And so I
ranging on. I was in the phone my inlaws and
(21:50):
he said they managed to get the complete genome on
the fifth in January. And they they they literally worked,
you know, non so it took forty hours. They worked NonStop.
So just put it in context, it's actually very interesting.
So it took forty hours for some to gain the
full genome. Okay, two years, two years for HIV to
(22:14):
be described as the cause of AIDS and took forty
hours to find this virus. Okay, Now Jang knows he's
a virus very closely related to SARS one. He reports
his findings to China's Ministry of Health and to public
health officials in Wuhan. He also submits the genetic sequence
for review to a database run by the US NIH
(22:37):
and as part of a paper co authored by Eddie
for the journal Nature. But the genetic sequence has not
been released publicly, which means researchers can't study it's thousands
of bits of data and use it to start figuring
out how to stop it, how to build a vaccine
to protect people from the virus. To put it in perspective,
there is at most one reported death at this point.
(22:57):
No other countries have known cases. Nobody could have guessed
this virus would change the world. Still, the idea that
there could be another SAR or MIRS is terrifying. MRS
or Middle East Respiratory Syndrome was another coronavirus that had
spread in twenty twelve and killed nine hundred people in
eighteen countries. Nobody wants to see a third coronavirus outbreak.
(23:20):
Six days after Jang finishes sequencing the virus. The genetic
information is still not out there, but rumors of the
novel coronavirus have spread, as has word of the embargoed
paper in Nature. But Jang doesn't know how Chinese officials
will react to him releasing the sequence, and a few
days earlier the government told local authorities not to publish
(23:42):
information about the virus because the Ministry of Health were
controlling everything and they wanted they wanted to control the message,
they wanted to damp down on rumors, they wanted to
be in control of the situation. And as the days
went on, more information was slowly being kind of released,
and so there was I think the Wall Street Journal
(24:02):
in January eighth published that it was a corona virus.
I think the Chinese authorities on the ninth announced it
was a coronavirus. As as the days wore on, it
got more and more kind of ridiculous that they weren't
saying exactly what it is, and this is this is
the sequence, right. We sent our paper off to Nature,
(24:22):
off to the journal Nature, and they were very keen
for the sequence to be released as well. On January eleventh,
jan gets on a plane in Shanghai and it's about
to take off when a phone buzzards. It's Eddie and
(24:47):
I said, we need to release these data. Nokay, I've
been emailing about this and we have to get this release.
And he said, okay, okay, do it, do it, do it?
And I said, can you send me the seat I
haven't got the seats myself. Can you please send it
to me right? And so he got I think he
got one of his one of his post docs to
email me that the sequence. So it arrived on my
on my email and I thought, oh, you know, Franky,
(25:07):
I'm knowing. I better get it's done right. So and
that whole process for me getting the sequence in the
email to releasing it, I think it's like fifty two
minutes or something like that. If I didn't even chet
what it was. And after I said I've posted it,
it could have been any odd chunk, but luckily it
was actually the virus. So and then that was that moment.
(25:30):
Then that was a huge kind of burden off my shoulders.
At that point, he posts the sequence on a website
called Virological, a somewhat obscure open access epidemiology discussion board
founded by one of Eddie's friends. Jang is not the
first to sequence the virus by this time. It's already
(25:51):
been done at private labs in Wolhuan as early as
late December, but Jang and Eddie's sequence is the first
to catch international notice. Eddie tweets out a link to
the sequence in January eleventh, Sydney time. This is the
moment kicking off development for the COVID nineteen vaccines. One
of the first replies to the tweet is from a
(26:13):
professor of microbiology and Mount Sinai in New York City.
He sends a gift of hundreds of planes taking off
in unison, along with the words and so it begins.
(26:44):
What if it never began? That is, what if we
were never struck by the coronavirus known as SARS cove two.
What if twenty twenty was just a normal year. We
never quarantined, never wore masks, never sanitized groceries, We just lived.
(27:05):
I spoke with another evolutionary biologist. His name is Joel Wortheim.
He's an associate professor of medicine at you See, San Diego.
He ran these computer based simulations of the virus going
back and forward in time. The goal was to describe
the likeliest version of the way the virus spread after
it first infected a human being. But while doing so,
(27:26):
he discovered that the very likeliest outcome was that we
never had a pandemic to begin with, That coronavirus infected
one person and never a second. That coronavirus dematerialized as
quickly as it materialized, and before we even knew it existed,
it was gone seven out of ten of our simulations
(27:47):
when extinct on their own, So without any mitigation efforts,
without any sort of attempt to slow down transmission of
the virus, the natural progression of seventy percent of stars
CoV two introductions into the human population result in natural extinction.
So we were sort of unlucky in that we were
(28:09):
part of at thirty percent where it did not go extinct. Yeah,
it was really just bad luck in that regard. Joel
specializes in taking viruses back in time using something called
the molecular clock. I'll let him explain. The molecular clock
is a really important tool and one of my favorite
(28:31):
to use in research. It basically helps us estimate the
number of changes that are happening in a viral genome
over time, over weeks, months, and years, and by sampling
a lot of different viruses at different time points, we
can estimate that rate of change, and then we can
(28:51):
basically count to the number of mutations going back in
time that it would have taken to get back to
the ancestor of all of the viruses we saw. So
we can put a date on a virus that was
never observed based on looking at the rate of change
in viruses that we did observe. In KSE, you didn't
(29:14):
get that. Joel and his colleagues take RNA of viruses
at different times, count the differences in the number of
mutations at each point, and use the differences to estimate
when viruses start to diverge from each other. In twenty twenty,
Joel and some colleagues use the molecular clock to estimate
when the first cases of COVID appeared in Hubei. Hube
(29:36):
is a landlocked central province in China. Uhan is the capital.
Using all the information available on all known cases in
hube they determined that the first case, the index case,
appeared in hube sometime between mid October to bid November.
That's weeks before anyone knew of a mysterious virus making
people sick. Even local experts like Jang had no idea
(29:59):
at this point, so the first outbreak of the virus
almost certainly occurred much earlier than even the first reports
in China. In the US, we're all out trick or
treating for Halloween twenty nineteen, and the virus that would
eventually halt all our lives may have already been spreading
across the world. Crazy, maybe even crazier is another study
(30:23):
by Joel. This one was done way back in twenty thirteen.
This is a bit of a hipster coronavirus paper. We
were studying it before it was cool. I'm still proud
of this paper where actually we're proud of it than ever.
More people, and by that I mean more scientists have
read this paper in the last year than read it
in the previous eight years. More people are downloading it,
(30:45):
more people are citing it. We are shocked that this
paper was rediscovered. I'm not shocked that the paper was
rediscovered in our case by Gabby Watts, the producer on
this series. And the reason I'm not shocked is that
the paper has the tantalizing title a case for the
ancient origin of coronaviruses. That's exactly the case Joel and
(31:08):
his colleagues make in the paper that coronaviruses are super
damn old. They looked at a lot of coronaviruses. So
you have turkey coronaviruses, you have magpie robin coronaviruses, you
have bovine coronaviruses, various different back coronaviruses. I don't even
(31:29):
have the names of them. I just have the They
just have boring names. Yeah, I'm sorry, I kind of disagree, Joel.
What about duck coronavirus, thrush coronavirus, widgeon not pigeon coronavirus,
and porcine epidemic diarrhea virus. Before Joel's paper, molecular clock
(31:55):
analysis suggested that the common descendant of coronaviruses, the sort
of coronavirus zero or coronavirus eve, existed about ten thousand
years ago, but this seemed far too recent for Joel,
especially since bats and birds, the most common carriers of coronaviruses,
have been around for millions of years. The molecular clock
(32:16):
works really well for viruses in the short term. You
can watch a virus like SARSCOBE two or influence a
spread around the world, and you can count those mutations
and see how quickly they occur, and you can then
estimate going back in time, well, this virus probably existed
six months ago, this ancestor a year ago, this answer
ten or fifty or one hundred years ago. But once
(32:38):
you start getting past that point in time, things start
to get a little weird for viruses. And the reason
we think that is because those mutations that used to
click off regularly, well, the same mutation seemed to be
happening over and over and over again. So instead of
mutation indicating a week or a month or a year,
(33:02):
you're gonna count one mutation and that's actually going to
be ten or one hundred years because that same change
has happened ten or one hundred times. So you start
to undercount. So instead of looking at a virus and say, well,
if we just put the evolutionary rate on this virus
and it's you know, ten thousand years old, your virus
is there could actually be ten million years old and
(33:24):
they would look the same. In other words, Joel believed
the molecular clock for RNA viruses was broken. When you
think about evolution and change in animals or other living things,
you tend to think of evolution favoring change, adaptation to
different environments, promotion of new positive traits. But with viruses
(33:47):
it's different. In fact, it's not even agreed upon by
scientists whether viruses are living things. They have an impact
on living things, but as one virologists put it, viruses
exist at the border between chemistry and life. If viruses
may not even be alive, it stands to reason they
(34:08):
would evolve differently than living things, and they do. Viruses,
when they evolve, tend to remove negative mutations rather than
accentuate the positive ones. That's called purifying selection. Mostly when
we think about viruses or evolution in general, we like
to think about a natural selection evolution favoring changes. We
(34:31):
adapt to this, and we adapt to that, And we
think about this doubly so for viruses, where they're constantly
adapting to the host environment, to the immune system, to
drugs that we try and throw at them. But really
the main driver of evolution in viruses is actually to
stay where you are, to keep your genetic sequence where
(34:55):
it is, and that's purifying selection, and that it removes changes.
And what we notice is that if a virus is
able to change from one, say genetic position to another,
what it's going to do is it's probably just going
to keep making those same changes again and again. And
that's strong purifying selection. And when you're forced to make
(35:16):
the same change again and again and again rather than
making any change you want, that's strong purifying selection. And
that's going to hide the ticking of the molecular clock.
It's going to make it look like only one hundred
or a thousand years have passed, when really it's taken
a million years, but we've only made the same changes
again and again and again. So after factoring in all
(35:41):
the potential mutations that the molecular clock may have missed
and that strong purifying selection may have hidden, Joel came
up with an estimate for the age of coronaviruses. Now
that's not Sars covi two, our current adversary, or STARS one,
or even poor signed epidemic diarrhea virus. That's all bat
and bird coronaviruses, which likely originate from a common ancestor.
(36:06):
The age they came up with not ten thousand years
two hundred and ninety three million years Some things were
different then. For one, the Earth had just one giant
land mass, a super consonant. Dragonflies and amphibians have just evolved,
while primitive ancestors of mammals and cockroaches are on the way.
(36:29):
No people, no dinosaurs, no netflix. Two hundred ninety three
million years ago is also not long after the time
that mammals and birds first diverged from each other. This
implies that ancestors of coronaviruses, which we find mostly in
bats and birds, could be as old as bats and
birds themselves. Maybe they developed in sinc Maybe coronaviruses are
(36:54):
wondering where do these humans come from? These humans that
infected our world. But Joel isn't super confident in his number.
He says, it's an extremely rough to it. As much
as I'd like to think, in all of that noise
and all of that uncertainty, we managed to hit the
nail on the head, going back hundreds of millions of
(37:15):
years and identifying the split between bats and birds. I
just think that that's a lucky happenstance. So we said, look,
it's possible that these viruses have been around in bats
since bats became bats, And these viruses have been around
in birds since birds became birds. And you can't use
the molecular clock to argue that they're younger, because the
(37:39):
molecael clock says they can be well, they can be
as old as time. Sometimes we tell stories because it
makes us feel better. I'm a writer. Sometimes I tell
(37:59):
stories to make me feel better, sometimes to make others
feel better or worse. If I'm being honest. Joel Wortheiman
says that the story his paper tells that these viruses
were around two hundred ninety three million years ago. It
may not be true at all. Coronaviruses might be far younger.
It's just a PhD educated, calculated and simulated guests. But
(38:23):
another virologists we've already heard about, has also studied ancient viruses.
Jeong Jenjang, Eddie Holmes's close collaborator, one of the heroes
of COVID. I wasn't able to speak directly with Jang,
but here he is in a World Signed Summit video
in twenty twenty. Just to make sure you understand, I'll
speak along with Jang. Are these carraviros low Wart Brice sambled.
(38:50):
The discovery of viruses in low vertebrates sampled from the
ocean indicate that the RNA viruses that still infect us
today are ancient and have evolutionary histories that date back
to the first vertebrates and perhaps the first animals. So
for the first time we can definitely show that RNA
viruses are many millions of years old and have been
(39:13):
in existence since the first vertebrates existed. Viruses are everywhere,
and our work makes it clear that there are still
many millions more viruses still to be discovered. He's coward,
so your rivrsphea has to be redefined, and ours I
would change the pupil's honest thanguable. Like Joel's ancient coronavirus story,
(39:42):
the story of Mountain a May, where the divine doctor
comes down from the mountain and heals the governor's son
is probably made up, at least according to the source
where I read it. I found the story in a
University of London thesis by the medical historian Chia Feng Chang.
In the paper, she makes clear that there is no
contemporaneous written record of innoculation at the turn of the
(40:04):
second millennium, ad. In her thesis, Chang surmises that this
legend was used to justify smallpox inoculation in a sixteen hundreds,
when it was certainly practiced under the cloak of a
heavenly goddess. She says it would be easier to convince
people to get inoculated. She says these stories may have
been told to persuade patients or even doctors of the
(40:24):
practice's worthiness. It's good pr for inoculators. Her theory is
not quite as cool as a mystical doctor, a secret book,
and a healer transformed into a goddess of innoculator's working
a whole millennium ago on a sacred mountain. But it's
still a pretty good story. And how about Eddie Holmes's story.
(40:57):
He may have passed on the chance to discover the
origins of HIV, but he hit it big by posting
the genetic sequence for coronavirus so that the word world
could start fighting the virus create vaccines. It's finally Eddie's
Beatles moment. Right, You mentioned at the beginning of a
conversation that you sort of missed out or you may
(41:17):
have missed out in the Beatles moment of you know,
tracking HIV back to Congo or Cameroon. Um. But now
do you feel like this, this was your sort of
similar moment that you're able to sort of be there
at the very very beginning of this of this virus.
I wish it never happened. I honestly, I would change
anything to not be in this position I have to
(41:38):
say anything, So you know, maybe it's I don't regard
any of this is good at all. I regard this
as an absolute miserable thing to be involved in. So yeah,
I think it might be the defining point of my
of my career. I think I'll always be remembered for this.
But I mean I'd rather I wish I wasn't. I
honestly wish I wasn't. I wish it never happened. On
(42:02):
the next episode of long Shot, We're going to meet
a family of an oculation entrepreneurs and we'll speak to
one of the first people to ever get a COVID
nineteen Veccine. Long Shot is a production of School of
Humans and iHeartRadio. Today's episode was produced, written, and narrated
by me Sean Revive. My co producer is Gabby Watts.
(42:24):
Executive producers are Virginia Prescott, Brandon Barr, and ELC. Crowley.
Special thanks to Noel Brown at iHeartRadio and actor and
writer Leuis ivy Chen. Thank you to Falling Walls for
the clip of Young Jen j long shot was scored
by Jason Shannon with sound design and mixed by Harper
Harris at Tuonewelder's School of Humans.
School of Humans. What would your life be like right
now if coronavirus hadn't emerged in twenty nineteen, What would
the world be like? I'm Sean Revieve. I'm a full
time freelance journalist. I travel around the country and world
to tell stories. I've reported on HIV, neuro signs, AI,
facial recognition, and a host of weirder topics. In twenty twenty,
(00:32):
I did none of that. Instead, I spent months afraid
of going to the grocery store, afraid of touching door
knobs and hugging my best friends. I worried about keeping
my wife and two year old sons safe. I worked
half time or no time. I got the news that
my aunt died alone in a hospital. I spent a
lot of time on a couch depressed. That's just me.
(00:58):
You've got your own list. Now. Multiply that by seven
point eight billion. Lives ground to a halt after a
novel coronavirus showed up in Wuhan. Nearly two hundred million
people have been infected with coronavirus since December twenty nineteen.
More than four million have died. So many lives disrupted
(01:20):
or damn near ruined we want our old lives back,
if that's even possible. While a truly universal pandemic, one
that affects everyone everywhere, may be unprecedented. In our lifetimes,
humans and viruses have evolved side by side. Our history
(01:42):
has been shaped by plagues, pandemics, viruses and diseases and
the fight against them. Today, they are in combat more
than ever, and vaccines have moved from the background to
the foreground of our daily lives. So as a journalist
and generally curious person, I want to know what went
into them. In this podcast series, we're going to take
(02:07):
you deep into the science and the people behind the
coronavirus vaccines. We'll travel back in time to me the
first innoculators, follow a path from legendary healers in China
to obscure country doctors in the UK, from an enslaved
African in Boston to the man who invented dozens of vaccines,
and we'll draw a direct line between them and the
shots we're getting today. In this episode about Beginnings, we'll
(02:33):
talk to a virologists who played a key role in
releasing the genetic sequence of coronavirus. We'll also hear from
an evolutionary biologist who explores the origins of all coronaviruses
from My Heart Radio and School of Humans. I'm Sean
Revived and this is long shot the two hundred and
fifty year journey to the COVID nineteen vaccines. Ever since
(03:03):
coronavirus became the biggest story in the world, vaccines have
been our greatest hope to stop it. The coronavirus vaccines
were produced in record time, but they're not slap dash
overnight inventions. There are a culmination of centuries of research
and advances and some unbelievable experimentation that began way back
when with smallpox inoculation, which marks the beginning of one
(03:24):
of humankind's greatest achievements, the ability to protect from disease.
It's a practice so old that nobody knows who first
attempted it or exactly where it originated. To even begin
to figure that out, you have to probe nameless. Healers,
myths and legends. Here's writer and actor Leoe I v
(03:44):
Chen to tell us one of them. To get to
the top of the highest of the four sacred the
Buddhist the mountains in China, you must climb sixty thousand
steps over piles of snow in winter, past the water
falls and the large greenery in summer. It will take
(04:06):
you two days to get to the top. Mont er May,
or er May Shan, was created two hundred and sixty
million years ago by a volcanic event so explosive that
it caused the massive extinctions across the planet. The mountain
(04:29):
is ten thousand feet top. It juts into the heavens
above the clouds, like a defined place it is. The
mountain is one of the holiest sites in Buddhism. There
are more than thirty buddha is the temples on mont
er May, including the first one built in China. Like
(04:54):
all holy places, there is a legend about mont er May.
A thousand and years ago, the son of a local
governor got very sick from small pox, which by land
had plagued China for at least a thousand years. The
(05:15):
governor offered the piles of gold to anyone who could
help his son. Three Daoists traveled from mont er May
and offered their services. By washing the small pox, the
Dooists said, you could grant protection from the disease. The
(05:40):
governor asked the Daoists to teach him this practice. The
Daoists agreed, and before they returned to the mountain, they
placed a book containing the secret of inoculation underneath a
medal incense thorible. Upon opening the book, the governor learned
(06:04):
at least tech chniko inoculation had long ago been invented
by a female Daoist. As a reward for her pioneering discovery,
she was turned into a goddess. So this myth, this
(06:26):
one on Mount a Mae. It was written in the
seventeenth century by a man named Fusheng Lin, and fusheng
Lin has his own interesting connection to innoculation. Louise, going
to tell us that story, said about seven hundred years later,
during the reign of teen Emperors sunt there were at
(06:46):
least nine outbreaks of small parks in Beijing, the city
where he lived. Each time there was an outbreak, the
emperor left his home to go to a bid Saw,
a place to quarantine from small parks, including one Bidsa
that was on a literal island. This way, the parks
(07:10):
could not reach across and infect him. Despite these precautions,
the emperor caught a small pox as he lay dying,
the emperor had to decide on a successor among his
six young sons. He chose the second son at a
(07:35):
young age. He'd already survived the small pox. With protection
from the disease, the boy was more likely to have
a long rule be a stabilizing force for the empire,
and he was This Song became the County Emperor, the
longest the ruling emperor in China's history. Low the County
(08:01):
Emperor survived the small parks, he did not escape to
trauma every time there was an outbreak of small parks.
He was haunted both by his foulest death and by
the isolation, and so when he grew into an adult,
the Councy Emperor searched far and wide for the umpire's
(08:23):
best inoculators. Around the sixteen eighty two inoculators were chosen
to protect the emperor's children. One of them was a
full Hunling, the author of the story about Monteur May.
(08:48):
Those early Chinese inoculators used several different methods to protect
people from small pox. One involved blowing the scab of
a small pox sufferer into the nose of a patient
using a bamboo shoot. Another method had the patient wearing
the clothing of an affected person for two or three days.
Yet another had a child lay underneath the quilt with
(09:08):
a sick patient, so that the patients chi would transfer
to the child. Some methods worked better than others. Even
in these early times, the inoculators had standards for who
could or should be inoculated. They avoided the procedure for
medically fragile patients, who were more likely to develop full
blown smallpox. It was not recommended for the week or
(09:30):
otherwise diseased, or for pregnant women. They thought it was
better to inoculate before puberty. It's unclear which innoculation method
was favored by fushang Lin, but the story he wrote
about Mountain Amey and the three Taoists may be evidence
of the earliest known inoculators, so long ago that the
first Crusaders hadn't yet invaded Jerusalem, but it might just
(09:54):
be a story. Real documentation of inoculation doesn't come for
about five hundred more years. In volume six of the
late British historian Joseph Needham's enorm a series Science and
Civilization in China, there is a reference to a fifteen
forty nine medical text by a Ming dynasty physician. That
(10:14):
quote casually mentions smallpox inoculation as if it is already
by then a common practice in China. That's one hundred
and fifty years before the first known inoculation in say, England.
But the point is nobody really knows exactly when or
where innoculation began. All we have our stories. In the
(10:44):
nineteen eighties and nineties, a relatively new disease ravaged the
city of Edinburgh, Scotland. It was called acquired immuno deficiency
syndrome or AIDS, the disease caused by HIV. In Edinburgh,
HIV spread fast, often through the sharing of needles by
intravenous drug users. They would in a drugs and shared
(11:06):
a needle, They passed the needle down, you know, amongst
these people in these kind of tenement buildings that fuel
this massive HIV ant break in Edinburgh. That's Eddie Holmes,
a virologist and evolutionary biologist at the University of Sydney.
Back in the early nineties, he was in Edinburgh studying
the spread of HIV. So what we were trying to
do was trying to work out how the virus was
(11:28):
spreading through that population, how it had diffused, and how
it got into sydy and how it spreading. I do
remember that actually getting in Around that time, he got
a car from Beatrice Hahn. Beatrice harm, who was then
working in virologist then working at the University of Alabama
at Birmingham. Hann asked Eddie if he was interested in
joining her and an HIV related research project. She's been
(11:49):
the person who's done more than anyone else to reveal
the origins of HIV. And she asked me in nineteen ninety,
was I interested in working on that? And I said, no,
I'm going to do my own, my own work on
something else. He turned her down to concentrate on his
own work. By then, AIDS had already killed more than
(12:10):
sixteen million people. It was known that there were two
main types of HIV, HIV one and two. Han and
her colleagues and not Eddie would go on to discover
that neither type of HIV came initially from humans. Both
originated in primates HIV one in chimpanzees and HIV two
in suity manga bays, each of which carry Simian immuno
(12:33):
deficiency virus or SIV. The virus jumped to humans at
least seven times, mostly in areas around Congo. It was
a stunning discovery. Hans said that it was especially sobering
that two very different primate species could serve as a
host for human pathogens. She was even more worried because
(12:56):
she knew that there were dozens more species of primates
that carried their own forms of SIV. Hans blockbuster paper
was exciting to Eddie home, but he had some regrets
knowing that he could have been a part of it.
That was like saying those the Beatles in nineteen sixty three,
you know I missed, I missed my opportunity. It's a
do some great work on that. Instead of discovering the
(13:23):
origin of HIV, Eddie began working in metagenomics, the study
of genetic material taken directly from the environment. So our
focus has always been on these kind of key species,
but with metagenomics you could at anything. So we're looking
at this an these wild Invertibrus and known and looked at,
and we found this amazing diversity of viruses in nature
(13:46):
and everywhere. So these animals we never looked at suddenly
saw this this huge diversity of viruses. The virus sphere
was enormous. Opening that door was facilitated by this this technology,
the methogenomics. By the time coronavirus hits, Eddie has become
a pretty big time evolutionary biologist. He studied the flu,
(14:07):
deng HIV, Hepotatis C and other viruses. He's got grants
and awards and fellowships, but he still hasn't had his
Beatles moment, not since turning down the chance to discover
the origin of HIV back in the nineties. In twenty twelve,
Eddie moves to Australia to work at the University of Sydney.
(14:28):
He begins a partnership with Professor Jong jen Jang, then
working at the Chinese Center for Disease Control and Prevention
in Beijing. He's a character, as they say, I said
this thing where whenever I sent an email to him,
he would reply within fifteen minutes, right because he was
always checking. So I used to send him an email
like at six am in the morning, thinking right now,
I'll get he must be asleep. That's three am in
(14:52):
and then ten minutes later, Hi, Eddie, it's amazing. So
he'd wake up in the night just to check his
email you know he's extraordinarily hard working. I mean off
the scale. Using metagenomic elysis, Eddie and Jang sampled animals
of all kinds looking for RNA viruses, that is, viruses
(15:12):
that have rabuclaic acid as their based genetic material, like coronavirus.
Some of the animals they look at include bats, mice, pigs,
and birds, but also snakes, crabs, spiders, ticks, shrimp, crayfish,
woodlight tapeworm, mosquitoes, centipedes, millipedes, leeches, earthworms, octopus, snails, oysters, muscles, clams, barnacles,
(15:34):
even goddamn sea cucumbers. No species is too obscure In
these animals and their parasites, they discover thousands of new viruses.
A lot of their work is done in and around Wuhan,
an enormous city in central China. It's not very well
known in the West at the time, but with eleven
(15:54):
million people, Wuhan is bigger than New York or Paris.
It's a very big city. It's extremely well connected in China.
It's very famous for being a travel hub because because
the Yancy River goes through it's the big river kind
of delta or big river system brother and the train system.
You can get from basically anywhere in China to Ruhan
(16:15):
about six and a half house as an international airport,
so it's a big hub. It's a really big hub.
Also around Ruhan, it's just this you know, pristine natural environments.
Actually's a very interesting place to sample. In twenty fourteen,
Eddie and Jang even visit the place most associated with
the first cases of coronavirus, the Huanan seafood wholesale market.
(16:38):
The local CDC took me there because they said, look
at this place, it's a really good place for a
disease to emerge. It's probably like two big supermarkets glued together,
the set of indoor alleys with a kind of road
to the middle of it. There's lots of it. It's
like an indoor, big indoor market, and there's lots of stores,
(17:01):
and there's there's kind of gutters, there's lots of things
on sales. There's lots of eye products, lots of fish,
lots of frozen products. And there's one section where there
were wildlife. I mean I saw mammalian wildlife there. There's ice,
saw rodents there, and variety of other things. There's also
these famous kind of like menu boards outside showing some
(17:22):
of the kind of wildlife that they're they're selling. It's
very closed. It feels kind of like, you know, it
feels kind of sweaty and cramped, and it feels like
kind of incubator in a way. You know. I took
the photographs, really crappy photographer took of these raccoon dogs, okay,
(17:42):
in these cages that raccoon dogs are weird. Theircadians in
the dog founding and their fur farm, and I think
they're used for food as well. And what I realized
is that raccoon dogs they were implicated in the first
Stars outbreak of two thousand and two two thousand and
three because there were positive raccoon dogs in these markets
in Grand Dumb and there they were in this market
(18:05):
in Wuhan. During the two years before the outbreak of
COVID nineteen, Eddie and Jang are working on a study
of Central Hospital of Wuhan. They're studying patients with acute
respiratory disease symptoms and trying to find out the cars. Again,
this is before COVID nineteen, But what that meant was
(18:26):
we were kind of like on site almost looking at
the same Z syndrome in the right tissue samples with
the right technology, and so we happen to be in
the wrong place the wrong time. I feel like when
it all kind of started, and that gave us the
kind of an open door to really try and look
(18:47):
at this some of the early first cases to see
what was going on. In mid December of twenty nineteen,
the forty one year old worker at the Huanan seafood
wholesale market begins getting pneumonia like symptoms, fever, calf pain, easiness,
that kind of stuff. A few days later, the patient
(19:09):
is admitted to Central Hospital of Wuhan, among the very
earliest identified novel coronavirus patients in the world, the same
hospital where Eddie and Jang have already been studying patients
with similar symptoms. By this time, Eddie is back in
Australia and Jang is in Shanghai, but because of their
prior work at Central Hospital, they particularly Jang, are in
(19:32):
prime position to see what's going on with these strangely
afflicted patients. Early in the afternoon on January third, Jang
receives a package, a metal box holding a test tube
packed in dry ice. Inside the test tube is a
swabbed sample from the sick market worker. By this time,
(19:52):
word of a new contagious virus is spreading among the
public health community. The first news reports about this mysterious
illness have been published. In China. There are forty four
or so confirmed pneumonia of unknown origin cases. Seafood market
has been closed. Many countries and the World Health Organization
are trying to figure out what the heck is going
on and if this disease is going to cross borders.
(20:16):
Jiang does not know that the test tube in front
of him contains a sample of a virus that would
take over the world within months, but he knows it's important.
Rumors are already spreading that it is SARS like which
in China and especially in Chinese virologist circles, is a
big deal. The first severe acute respiratory syndrome where SARS
(20:39):
epidemic was discovered in the city of Foshan in China
in November two thousand and two. Eventually it's spread to
more than eight thousand people in twenty nine countries. SARS
one was internationally embarrassing for Chinese leadership. They could not
contain the outbreak and could not treat the disease. Western
media reported aggressively on China's failures. The last thing Jiang
(21:04):
or his country wanted was another There are stars, and
Jang strongly suspected he had it. Sitting in that test tube.
For the next two days, working around the clock, Jang
and his team worked to sequence the virus. Around two
am on the fifth, it was done. Eddie gets an
(21:29):
email from Jang. Jang emailed me and says, please call
me immediately. I was driving to the beach and my
in laws for breakfast, right because it's January. It's summer
in Sydney, right, And that was that was like eight
am in Sydney time, so it must have been like
five o'clock in the morning in Shanghai. And so I
ranging on. I was in the phone my inlaws and
(21:50):
he said they managed to get the complete genome on
the fifth in January. And they they they literally worked,
you know, non so it took forty hours. They worked NonStop.
So just put it in context, it's actually very interesting.
So it took forty hours for some to gain the
full genome. Okay, two years, two years for HIV to
(22:14):
be described as the cause of AIDS and took forty
hours to find this virus. Okay, Now Jang knows he's
a virus very closely related to SARS one. He reports
his findings to China's Ministry of Health and to public
health officials in Wuhan. He also submits the genetic sequence
for review to a database run by the US NIH
(22:37):
and as part of a paper co authored by Eddie
for the journal Nature. But the genetic sequence has not
been released publicly, which means researchers can't study it's thousands
of bits of data and use it to start figuring
out how to stop it, how to build a vaccine
to protect people from the virus. To put it in perspective,
there is at most one reported death at this point.
(22:57):
No other countries have known cases. Nobody could have guessed
this virus would change the world. Still, the idea that
there could be another SAR or MIRS is terrifying. MRS
or Middle East Respiratory Syndrome was another coronavirus that had
spread in twenty twelve and killed nine hundred people in
eighteen countries. Nobody wants to see a third coronavirus outbreak.
(23:20):
Six days after Jang finishes sequencing the virus. The genetic
information is still not out there, but rumors of the
novel coronavirus have spread, as has word of the embargoed
paper in Nature. But Jang doesn't know how Chinese officials
will react to him releasing the sequence, and a few
days earlier the government told local authorities not to publish
(23:42):
information about the virus because the Ministry of Health were
controlling everything and they wanted they wanted to control the message,
they wanted to damp down on rumors, they wanted to
be in control of the situation. And as the days
went on, more information was slowly being kind of released,
and so there was I think the Wall Street Journal
(24:02):
in January eighth published that it was a corona virus.
I think the Chinese authorities on the ninth announced it
was a coronavirus. As as the days wore on, it
got more and more kind of ridiculous that they weren't
saying exactly what it is, and this is this is
the sequence, right. We sent our paper off to Nature,
(24:22):
off to the journal Nature, and they were very keen
for the sequence to be released as well. On January eleventh,
jan gets on a plane in Shanghai and it's about
to take off when a phone buzzards. It's Eddie and
(24:47):
I said, we need to release these data. Nokay, I've
been emailing about this and we have to get this release.
And he said, okay, okay, do it, do it, do it?
And I said, can you send me the seat I
haven't got the seats myself. Can you please send it
to me right? And so he got I think he
got one of his one of his post docs to
email me that the sequence. So it arrived on my
on my email and I thought, oh, you know, Franky,
(25:07):
I'm knowing. I better get it's done right. So and
that whole process for me getting the sequence in the
email to releasing it, I think it's like fifty two
minutes or something like that. If I didn't even chet
what it was. And after I said I've posted it,
it could have been any odd chunk, but luckily it
was actually the virus. So and then that was that moment.
(25:30):
Then that was a huge kind of burden off my shoulders.
At that point, he posts the sequence on a website
called Virological, a somewhat obscure open access epidemiology discussion board
founded by one of Eddie's friends. Jang is not the
first to sequence the virus by this time. It's already
(25:51):
been done at private labs in Wolhuan as early as
late December, but Jang and Eddie's sequence is the first
to catch international notice. Eddie tweets out a link to
the sequence in January eleventh, Sydney time. This is the
moment kicking off development for the COVID nineteen vaccines. One
of the first replies to the tweet is from a
(26:13):
professor of microbiology and Mount Sinai in New York City.
He sends a gift of hundreds of planes taking off
in unison, along with the words and so it begins.
(26:44):
What if it never began? That is, what if we
were never struck by the coronavirus known as SARS cove two.
What if twenty twenty was just a normal year. We
never quarantined, never wore masks, never sanitized groceries, We just lived.
(27:05):
I spoke with another evolutionary biologist. His name is Joel Wortheim.
He's an associate professor of medicine at you See, San Diego.
He ran these computer based simulations of the virus going
back and forward in time. The goal was to describe
the likeliest version of the way the virus spread after
it first infected a human being. But while doing so,
(27:26):
he discovered that the very likeliest outcome was that we
never had a pandemic to begin with, That coronavirus infected
one person and never a second. That coronavirus dematerialized as
quickly as it materialized, and before we even knew it existed,
it was gone seven out of ten of our simulations
(27:47):
when extinct on their own, So without any mitigation efforts,
without any sort of attempt to slow down transmission of
the virus, the natural progression of seventy percent of stars
CoV two introductions into the human population result in natural extinction.
So we were sort of unlucky in that we were
(28:09):
part of at thirty percent where it did not go extinct. Yeah,
it was really just bad luck in that regard. Joel
specializes in taking viruses back in time using something called
the molecular clock. I'll let him explain. The molecular clock
is a really important tool and one of my favorite
(28:31):
to use in research. It basically helps us estimate the
number of changes that are happening in a viral genome
over time, over weeks, months, and years, and by sampling
a lot of different viruses at different time points, we
can estimate that rate of change, and then we can
(28:51):
basically count to the number of mutations going back in
time that it would have taken to get back to
the ancestor of all of the viruses we saw. So
we can put a date on a virus that was
never observed based on looking at the rate of change
in viruses that we did observe. In KSE, you didn't
(29:14):
get that. Joel and his colleagues take RNA of viruses
at different times, count the differences in the number of
mutations at each point, and use the differences to estimate
when viruses start to diverge from each other. In twenty twenty,
Joel and some colleagues use the molecular clock to estimate
when the first cases of COVID appeared in Hubei. Hube
(29:36):
is a landlocked central province in China. Uhan is the capital.
Using all the information available on all known cases in
hube they determined that the first case, the index case,
appeared in hube sometime between mid October to bid November.
That's weeks before anyone knew of a mysterious virus making
people sick. Even local experts like Jang had no idea
(29:59):
at this point, so the first outbreak of the virus
almost certainly occurred much earlier than even the first reports
in China. In the US, we're all out trick or
treating for Halloween twenty nineteen, and the virus that would
eventually halt all our lives may have already been spreading
across the world. Crazy, maybe even crazier is another study
(30:23):
by Joel. This one was done way back in twenty thirteen.
This is a bit of a hipster coronavirus paper. We
were studying it before it was cool. I'm still proud
of this paper where actually we're proud of it than ever.
More people, and by that I mean more scientists have
read this paper in the last year than read it
in the previous eight years. More people are downloading it,
(30:45):
more people are citing it. We are shocked that this
paper was rediscovered. I'm not shocked that the paper was
rediscovered in our case by Gabby Watts, the producer on
this series. And the reason I'm not shocked is that
the paper has the tantalizing title a case for the
ancient origin of coronaviruses. That's exactly the case Joel and
(31:08):
his colleagues make in the paper that coronaviruses are super
damn old. They looked at a lot of coronaviruses. So
you have turkey coronaviruses, you have magpie robin coronaviruses, you
have bovine coronaviruses, various different back coronaviruses. I don't even
(31:29):
have the names of them. I just have the They
just have boring names. Yeah, I'm sorry, I kind of disagree, Joel.
What about duck coronavirus, thrush coronavirus, widgeon not pigeon coronavirus,
and porcine epidemic diarrhea virus. Before Joel's paper, molecular clock
(31:55):
analysis suggested that the common descendant of coronaviruses, the sort
of coronavirus zero or coronavirus eve, existed about ten thousand
years ago, but this seemed far too recent for Joel,
especially since bats and birds, the most common carriers of coronaviruses,
have been around for millions of years. The molecular clock
(32:16):
works really well for viruses in the short term. You
can watch a virus like SARSCOBE two or influence a
spread around the world, and you can count those mutations
and see how quickly they occur, and you can then
estimate going back in time, well, this virus probably existed
six months ago, this ancestor a year ago, this answer
ten or fifty or one hundred years ago. But once
(32:38):
you start getting past that point in time, things start
to get a little weird for viruses. And the reason
we think that is because those mutations that used to
click off regularly, well, the same mutation seemed to be
happening over and over and over again. So instead of
mutation indicating a week or a month or a year,
(33:02):
you're gonna count one mutation and that's actually going to
be ten or one hundred years because that same change
has happened ten or one hundred times. So you start
to undercount. So instead of looking at a virus and say, well,
if we just put the evolutionary rate on this virus
and it's you know, ten thousand years old, your virus
is there could actually be ten million years old and
(33:24):
they would look the same. In other words, Joel believed
the molecular clock for RNA viruses was broken. When you
think about evolution and change in animals or other living things,
you tend to think of evolution favoring change, adaptation to
different environments, promotion of new positive traits. But with viruses
(33:47):
it's different. In fact, it's not even agreed upon by
scientists whether viruses are living things. They have an impact
on living things, but as one virologists put it, viruses
exist at the border between chemistry and life. If viruses
may not even be alive, it stands to reason they
(34:08):
would evolve differently than living things, and they do. Viruses,
when they evolve, tend to remove negative mutations rather than
accentuate the positive ones. That's called purifying selection. Mostly when
we think about viruses or evolution in general, we like
to think about a natural selection evolution favoring changes. We
(34:31):
adapt to this, and we adapt to that, And we
think about this doubly so for viruses, where they're constantly
adapting to the host environment, to the immune system, to
drugs that we try and throw at them. But really
the main driver of evolution in viruses is actually to
stay where you are, to keep your genetic sequence where
(34:55):
it is, and that's purifying selection, and that it removes changes.
And what we notice is that if a virus is
able to change from one, say genetic position to another,
what it's going to do is it's probably just going
to keep making those same changes again and again. And
that's strong purifying selection. And when you're forced to make
(35:16):
the same change again and again and again rather than
making any change you want, that's strong purifying selection. And
that's going to hide the ticking of the molecular clock.
It's going to make it look like only one hundred
or a thousand years have passed, when really it's taken
a million years, but we've only made the same changes
again and again and again. So after factoring in all
(35:41):
the potential mutations that the molecular clock may have missed
and that strong purifying selection may have hidden, Joel came
up with an estimate for the age of coronaviruses. Now
that's not Sars covi two, our current adversary, or STARS one,
or even poor signed epidemic diarrhea virus. That's all bat
and bird coronaviruses, which likely originate from a common ancestor.
(36:06):
The age they came up with not ten thousand years
two hundred and ninety three million years Some things were
different then. For one, the Earth had just one giant
land mass, a super consonant. Dragonflies and amphibians have just evolved,
while primitive ancestors of mammals and cockroaches are on the way.
(36:29):
No people, no dinosaurs, no netflix. Two hundred ninety three
million years ago is also not long after the time
that mammals and birds first diverged from each other. This
implies that ancestors of coronaviruses, which we find mostly in
bats and birds, could be as old as bats and
birds themselves. Maybe they developed in sinc Maybe coronaviruses are
(36:54):
wondering where do these humans come from? These humans that
infected our world. But Joel isn't super confident in his number.
He says, it's an extremely rough to it. As much
as I'd like to think, in all of that noise
and all of that uncertainty, we managed to hit the
nail on the head, going back hundreds of millions of
(37:15):
years and identifying the split between bats and birds. I
just think that that's a lucky happenstance. So we said, look,
it's possible that these viruses have been around in bats
since bats became bats, And these viruses have been around
in birds since birds became birds. And you can't use
the molecular clock to argue that they're younger, because the
(37:39):
molecael clock says they can be well, they can be
as old as time. Sometimes we tell stories because it
makes us feel better. I'm a writer. Sometimes I tell
(37:59):
stories to make me feel better, sometimes to make others
feel better or worse. If I'm being honest. Joel Wortheiman
says that the story his paper tells that these viruses
were around two hundred ninety three million years ago. It
may not be true at all. Coronaviruses might be far younger.
It's just a PhD educated, calculated and simulated guests. But
(38:23):
another virologists we've already heard about, has also studied ancient viruses.
Jeong Jenjang, Eddie Holmes's close collaborator, one of the heroes
of COVID. I wasn't able to speak directly with Jang,
but here he is in a World Signed Summit video
in twenty twenty. Just to make sure you understand, I'll
speak along with Jang. Are these carraviros low Wart Brice sambled.
(38:50):
The discovery of viruses in low vertebrates sampled from the
ocean indicate that the RNA viruses that still infect us
today are ancient and have evolutionary histories that date back
to the first vertebrates and perhaps the first animals. So
for the first time we can definitely show that RNA
viruses are many millions of years old and have been
(39:13):
in existence since the first vertebrates existed. Viruses are everywhere,
and our work makes it clear that there are still
many millions more viruses still to be discovered. He's coward,
so your rivrsphea has to be redefined, and ours I
would change the pupil's honest thanguable. Like Joel's ancient coronavirus story,
(39:42):
the story of Mountain a May, where the divine doctor
comes down from the mountain and heals the governor's son
is probably made up, at least according to the source
where I read it. I found the story in a
University of London thesis by the medical historian Chia Feng Chang.
In the paper, she makes clear that there is no
contemporaneous written record of innoculation at the turn of the
(40:04):
second millennium, ad. In her thesis, Chang surmises that this
legend was used to justify smallpox inoculation in a sixteen hundreds,
when it was certainly practiced under the cloak of a
heavenly goddess. She says it would be easier to convince
people to get inoculated. She says these stories may have
been told to persuade patients or even doctors of the
(40:24):
practice's worthiness. It's good pr for inoculators. Her theory is
not quite as cool as a mystical doctor, a secret book,
and a healer transformed into a goddess of innoculator's working
a whole millennium ago on a sacred mountain. But it's
still a pretty good story. And how about Eddie Holmes's story.
(40:57):
He may have passed on the chance to discover the
origins of HIV, but he hit it big by posting
the genetic sequence for coronavirus so that the word world
could start fighting the virus create vaccines. It's finally Eddie's
Beatles moment. Right, You mentioned at the beginning of a
conversation that you sort of missed out or you may
(41:17):
have missed out in the Beatles moment of you know,
tracking HIV back to Congo or Cameroon. Um. But now
do you feel like this, this was your sort of
similar moment that you're able to sort of be there
at the very very beginning of this of this virus.
I wish it never happened. I honestly, I would change
anything to not be in this position I have to
(41:38):
say anything, So you know, maybe it's I don't regard
any of this is good at all. I regard this
as an absolute miserable thing to be involved in. So yeah,
I think it might be the defining point of my
of my career. I think I'll always be remembered for this.
But I mean I'd rather I wish I wasn't. I
honestly wish I wasn't. I wish it never happened. On
(42:02):
the next episode of long Shot, We're going to meet
a family of an oculation entrepreneurs and we'll speak to
one of the first people to ever get a COVID
nineteen Veccine. Long Shot is a production of School of
Humans and iHeartRadio. Today's episode was produced, written, and narrated
by me Sean Revive. My co producer is Gabby Watts.
(42:24):
Executive producers are Virginia Prescott, Brandon Barr, and ELC. Crowley.
Special thanks to Noel Brown at iHeartRadio and actor and
writer Leuis ivy Chen. Thank you to Falling Walls for
the clip of Young Jen j long shot was scored
by Jason Shannon with sound design and mixed by Harper
Harris at Tuonewelder's School of Humans.
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