0:00

This week in virology, the

0:02

podcast about viruses, the kind

0:05

that make you sick. From

0:11

microbe TV, this is Twiv this

0:13

week in virology, episode 10 89, recorded on

0:15

February 16th, 2024.

0:22

I'm Vincent Raconiello and you're listening to

0:25

the podcast all about viruses. Joining

0:28

me today from Fort

0:30

Lee, New Jersey, Dixon,

0:32

Dave Palmier. Hello, Vincent

0:34

and everybody else. Let's

0:38

see a brief overview of

0:41

the weather. Looks can

0:43

be deceiving as the name of

0:45

today's weather. It's

0:47

beautiful out. The sun is shining. There's

0:50

hardly a cloud in the sky. And

0:52

if you were to go outside without a coat, you

0:55

may not come back because

0:59

it's below freezing. It's like 28 degrees

1:01

and wind, lots of wind. So

1:06

a very, very deceptive looking day.

1:08

What is it? Daniel quoted

1:10

yesterday. I have to about

1:12

the weather. This is really good. Let me get

1:15

it here. It's right here

1:18

in front of me. No, he

1:20

said it's something like the

1:24

problem with the weather report is

1:27

it's right often enough so you

1:29

can't ignore it. And

1:31

it's wrong often enough so you can't

1:33

rely on it. 100% right

1:35

now. That's accurate. It's

1:40

six degrees C and mostly

1:42

sunny here in New

1:44

York City. Also joining us from western

1:46

Massachusetts. Alan Dove. Good to be here.

1:48

It's 38 Fahrenheit,

1:50

three Celsius here and

1:53

also blustery. Wind

1:55

Northwest at 22 gusting 29 miles

1:57

per hour. So it's challenging. landing

2:00

a small plane in that kind of land. I would

2:02

not. You know? You

2:04

just keep flying into your ground. No, I just

2:06

would not take off into that in the first

2:08

place. There's a very easy solution for that. I

2:10

see. Okay. And from Madison,

2:13

New Jersey, Brianne Barker. Hi. It's

2:16

rather similar here, 41 Fahrenheit,

2:18

five Celsius, and rather

2:20

sunny. We

2:23

had snow for the first time in

2:25

a while earlier this week.

2:28

So we actually have snow on the ground. And

2:31

I think we're supposed to get at least a little teeny

2:33

bit more this weekend. We had

2:35

snow on Tuesday

2:37

night, or yeah, I think it was

2:40

earlier this week. And

2:42

it was forecast to be nine to 13 inches. And

2:46

then the evening forecast changed that to

2:48

two to three inches. Exactly. But

2:50

in the meantime, they had already canceled school. Right.

2:55

So, yep. The AI

2:57

can't even help us here. No. Hey,

3:00

AI. If you

3:02

enjoy these science programs,

3:06

what is it that Nels Eldy said? People are

3:08

saying such good things lately on these

3:10

programs. Let me pull up the latest

3:13

Twivo. He said we

3:15

are building spaces that

3:18

celebrate science. Oh,

3:22

I like that. I do like that. I

3:25

guess if we built an incubator. Yeah,

3:27

you built a space that celebrates science. You

3:29

really did. That's right. I guess

3:31

so, but not spaces, right? He

3:34

means inferential spaces. Well, knowledge doesn't exist

3:36

in the vacuum. If you

3:38

like that, if you enjoy

3:40

building spaces that celebrate science and hearing

3:42

us talk about science, we'd

3:44

love your support. Microbe.tv slash contribute.

3:47

It doesn't have to be huge. It

3:49

can be a few dollars a month, but

3:51

we'd like it and we'd like it

3:54

every month because we use it for

3:56

our expenses, which grow

3:58

on a monthly basis. basis

4:00

because a nonprofit is not

4:03

simple to run. You have to keep

4:05

track of everything. I

4:07

don't remember anything passed last week, which

4:10

means I have to have other people doing it. Anyway,

4:14

microbe.tv slash contribute to viruses of

4:17

microbes. Twenty twenty four is going

4:19

to be in Cairns,

4:22

Australia. Cairns. Cairns

4:25

Friday. Let's see. What's the date? It's

4:28

this summer. Oh, my gosh. I should

4:30

have this, you know, right at

4:32

the tip of my tongues. But there's

4:34

a website, VOM, twenty

4:36

twenty four dot org. Org. Fifteenth

4:39

through the nineteenth of July. So I'll

4:41

be going to do a twiv and

4:44

Jolene is attending the meeting. So she's going to

4:46

join me on the twiv and we'll have a

4:48

couple of guests for the meeting. Now, that's the

4:50

middle of winter. I was just about

4:53

to point that out. North Queensland. So it should

4:55

still be warm. Oh, no, it's warm at that

4:57

time of the year, all year. It

4:59

is a tropical paradise,

5:01

basically. That sounds fabulous. I

5:03

feel like I want to go to the meeting just because it sounds fabulous.

5:06

You should do it. You should do it. You

5:08

should go. No, really, you should do it.

5:10

You have to fly, I guess you fly

5:12

to Sydney and then you fly up to Cairns. No,

5:14

you don't. You can fly to Hawaii first and then

5:16

winter over there for a while. And

5:19

then continue on a couple weeks

5:21

later. There are probably no international

5:23

flights to Cairns. Or you

5:25

can catch the trade winds from San Diego

5:27

west to Fiji and then down to now.

5:30

Cairns is not too far away from

5:32

Brisbane, so you could fly to Brisbane

5:34

direct and then get a

5:37

puddle jumper up to Cairns. Cairns.

5:40

Cairns, Cairns. Sorry, Cairns. Drop the

5:42

I and the R. Right,

5:44

Cairns. So

5:47

anyway, check that out. It

5:49

is vom2024.org. And

5:54

also don't forget the... at

6:00

the Food and Drug

6:03

Administration, in particular, the

6:07

Center for Biologics Evaluation and Review. She

6:10

has a research assistant position where

6:12

you could go in the lab

6:15

and do experiments on enteroviruses. You

6:18

could investigate cross-reactive antibodies and

6:20

their roles. You

6:22

can help make animal models for

6:24

enteroviruses. And the oldest

6:26

is BSL2 work, so

6:28

you don't have to suit up. And

6:31

if you wanna know more, we'll have a link to

6:33

a PDF in the show notes and you can email

6:36

Amy Rosenfeld. And

6:39

don't forget to buy The

6:41

New City, which

6:46

is Dixon's new

6:48

book. It is receiving

6:50

accolades. I

6:53

think someone bought it. There you

6:56

go. My copy's in the living room.

6:59

My 20 copies

7:01

are in my

7:04

closet. Can I make

7:06

a plea at this moment? The

7:08

book is doing well, but not great. And

7:10

it's probably because of the lack

7:13

of the number of reviews. So

7:15

if anybody has bought the book already and

7:18

hasn't written a review, I would really encourage you

7:20

to do so. It's easy. And

7:23

it's easy. And Aylin wrote a

7:25

wonderful, very long review. And

7:28

you don't have the right one that long, but just

7:30

an honest opinion about what you thought of the book.

7:32

And I would very much appreciate that.

7:36

Can do. Great. Also

7:41

this week, Paul Offit published a

7:43

book. It's

7:46

in the other room. It's

7:49

something like, please

7:53

tell me when it's over, or

7:55

something like that about the pandemic, obviously. And we

7:57

will have Paul on in March to talk about the book.

8:03

Okay, the new city. Now,

8:06

this is not right. Yes, it is right. Some

8:09

news bits. We have

8:11

a bunch of people who sent us articles

8:13

about the first known

8:16

fatal case of Alaskapox. Randall,

8:20

for example, wrote, you

8:22

might be interested in this article in

8:24

our local paper about the first known

8:26

fatal case of Alaskapox. The virus was

8:28

first identified in

8:31

2015, but all the earlier cases

8:33

were mild. The individual was immunocompromised.

8:37

And he

8:39

sent an article in the Anchorage

8:42

Daily News State

8:44

Reports first known fatal case

8:47

of Alaskapox. And

8:49

then there's also an article in the

8:52

Alaska Beacon. I

8:54

don't know if it's been named yet,

8:56

but I think a new group of viruses should

8:58

be part of that in the cryo-virigy. It

9:00

sounds right. It's cold, right. Yeah.

9:03

Well, in the summer, it gets warm. Yeah,

9:06

unfortunately, that is true. I

9:09

asked Rich, what is this? He

9:14

said, I know a little bit,

9:17

discovered 2015 hangs out in

9:19

rodents, voles, I think, interesting in having

9:21

its own branch inside pox phylogeny, but

9:23

closest to cow pox, though branched off

9:26

at the very root of

9:28

cow pox, scattered zoonoses. So in

9:30

this respect, behaves like cow pox.

9:34

I don't know symptoms in humans, but if I had to guess,

9:36

it would be like cow pox. Guy who

9:38

died was old and a transplant

9:40

patient, in any case, immunosuppressed. So

9:42

interesting phylogeny, but otherwise no big

9:44

deal. I

9:46

think it's interesting that it's named after the state.

9:48

And I can't think of any other virus that

9:51

is. Do you guys? No,

9:53

not at all. And I'm also

9:55

just surprised that it was named after the state in the

9:57

first place. I

10:00

mean, back when we were naming them after places,

10:02

it was usually a more specific thing. You

10:05

know, even maybe you could get away with

10:07

this in Rhode Island, but Alaska pox, that's

10:09

kind of a vast area

10:11

to... Yeah. Yeah.

10:13

Well, you have viruses in the Flevity

10:15

group. It should be Fairbanks pox. Fairbanks

10:19

pox, that's right. So you

10:21

remember in 1993, they tried

10:23

to name Sinombre

10:26

Muerto Canyon virus. And

10:29

they said, nope. Nope. So...

10:31

Yeah, but St. Louis and St. Louis, the St. Louis Nefalitis

10:33

exists. That's just... Well, right. If

10:36

you go back 20, 30 years further than people

10:39

were not so upset about having

10:41

Norwalk virus named after the

10:44

town of Norwalk in what state, Dixon? I

10:46

believe it's Ohio. Ohio. Just a

10:49

wild guess. Just a wild guess. So

10:54

the other one is Koxaki

10:57

virus, right? That's right. People

11:00

in Koxaki are proud to have a

11:02

virus. I have someone on the livestream

11:04

who lives in Koxaki. She thinks it's

11:06

really cool. Yeah. Some leaky

11:08

forest virus. Don't forget that one. Yeah. Yeah.

11:12

That's in Russia, I believe. Yeah. Do

11:14

you know the story of some leaky forest virus? I don't. So

11:17

there was a guy in

11:20

Africa. He

11:23

had isolated it and

11:25

he asked someone, what's

11:28

the name of the place where we are? And

11:31

the guy said, it's Simleaky. And

11:34

so the guy called it Simleaky Forest, but Simleaky

11:36

means forest because the guy said, we're in the

11:38

forest. Right. Whatever language that is.

11:40

You guys know that story? Stop to ask for

11:42

directions. Where am I? You're in a

11:45

car. Yeah. You're in a

11:47

coma. A very helpful guide there. Well,

11:49

we've all the virus. Is there

11:52

something with California in the name? I'm sitting here going

11:54

through states in my head. Yeah. California

11:56

and Cephalitis. Western, equine and Cephalitis. But it

11:58

isn't exactly where. Yeah,

12:02

Ebola certainly says where it is.

12:05

There's Japanese encephalitis virus. Yeah,

12:07

that's a whole country. It's a country, that's

12:09

right. I mean, there's VSD

12:11

Indiana. There was the Spanish flu.

12:14

I was like, I'm going through states in my head. Yeah.

12:17

That doesn't get passed. But when you talk

12:19

about that, most people only hear VSD, right?

12:22

The Indiana is a lab thing. There's

12:26

a VSD New Jersey, I believe. That's

12:29

true. Yeah. So

12:31

once you get past the name, I couldn't think. If

12:34

anyone can think of one, let us know.

12:37

Okay. So, Alaskapox, generally

12:39

mild sporadic cases, zoonotic

12:41

and this fellow. You

12:44

said transplant patient, but some of the news reports

12:46

say he was being treated for cancer. In

12:49

any case, he was immunosuppressed and got

12:51

a bad fatal infection. So,

12:53

try and stay away from the voles in

12:55

Alaska. Okay. Well, you

12:57

know, what did I hear? Well,

13:00

Michael Schmidt said Wednesday night, 30%

13:02

of rodents west of the Mississippi

13:04

have the

13:06

bacterium that causes plague. Oh, yeah. That's

13:09

right. That's right. Pastoral

13:12

opacitus used to be called. No,

13:14

it's not pastural opacitus. Yersinia. Yersinia.

13:17

Yersinia. You were going to say

13:19

Yersinia, huh? Well...

13:22

Yes. There's sort of a

13:24

fabulous historical story behind why that is,

13:26

and there are great books about it.

13:29

So, if that's something someone ever wants to geek

13:31

out about, history-wise. We

13:35

have an article from Emerging Infectious

13:37

Diseases where

13:42

they have looked... This is very

13:44

interesting. So, MERS coronavirus is

13:47

endemic and dromedary camels

13:50

from the Arabian Peninsula and Africa.

13:54

MERS is over 75% seroprevalence. And

13:57

now and then it gets into people. So,

14:02

people always want to know how that

14:04

happened. So, in

14:06

this study, they did, they

14:10

sampled workers in an abattoir

14:12

in northern Kenya. An

14:15

abattoir, of course, is a slaughterhouse. And

14:19

there, they slaughter camels because

14:21

people eat them. And

14:24

they sampled camels. Oh,

14:29

they sampled camels, not the workers, I'm sorry. And

14:34

they found it

14:36

was a biphasic pattern of seroprevalence in the

14:38

camels, you know, two times in the year.

14:41

And I

14:43

think they also looked at people because

14:45

the title says, biphasic MERS coronavirus incidence

14:48

in nomadic dramadaries with putative transmission to

14:50

humans in Kenya. So,

14:53

these are nomadic dramadaries.

14:57

So, they have some evidence of transmission to

14:59

slaughterhouse workers because some of them were positive

15:01

as well. So, why isn't there a big

15:04

MERS outbreak like there was in the beginning?

15:07

Well, there wasn't really a big one in the beginning.

15:10

There was a single case. There

15:12

was a series of

15:14

cases in South Korea where a guy

15:17

acquired the infection in the

15:19

Arabian Peninsula. He flew to Korea. He had a

15:21

respiratory disease. They stuck him in the hospital. They

15:23

didn't know about MERS yet. And

15:25

they didn't do any infection control. So, he infected a

15:27

bunch of other people. Yeah. I think part of

15:29

it also was that he went to multiple hospitals

15:31

to try and get a diagnosis. And so, he

15:33

was in multiple hospital waiting rooms. So,

15:37

yeah, I think that it doesn't transmit very well

15:39

person to person. Yeah. Unless

15:41

it's in one of those healthcare-associated

15:44

situations. And so, that's, I

15:46

think, the reason why the outbreaks are

15:49

particularly small with this is

15:51

that we're not being allowed person to person.

15:53

You have to come in contact with the

15:55

camera. Never becomes a SARS-CoV-2. Never becomes a

15:57

human virus. Okay. So, in this paper, they

15:59

put... They have seven out of

16:01

48 abattoir workers who were seropositive.

16:06

And none of them have had- The biphasic

16:08

pattern that they see in

16:11

the camels, right, peaks

16:14

in October and February, which

16:17

I think is, I think that

16:19

correlates with transitions between wet and dry

16:21

seasons. Is that right? Yeah, that's correct.

16:24

Sounds right. And

16:29

they looked at- by Elisa,

16:31

and that's where they find the antibodies. But none of these-

16:34

oh, none of these workers had any symptoms as far as

16:36

they could remember. All

16:39

right, then there's an interesting article in

16:41

CEPI news. CEPI

16:44

is the Center Coalition

16:46

for Epidemic Preparedness and

16:48

Innovation. It's a nonprofit

16:50

that raises money and then

16:54

tests vaccines, pays for vaccine development. In

16:56

this case, they're paying for rapid

16:59

on-the-spot diagnostics for NIPA

17:02

and LASA viruses, because

17:05

we need that and nobody

17:08

seems to want to do it. So CEPI

17:11

is pumping some money into it and

17:13

hopefully something will come out of that.

17:17

Because we need it. We need to know who's

17:19

got one or the other. Yeah, and you'd want

17:21

to have tests that could be done

17:24

in the field and the places where people get

17:26

these viruses. This

17:28

is a comment peripheral to what

17:30

we were just discussing. But I

17:33

had a wonderful Zoom conference with two

17:36

students from Indiana University who

17:39

wanted more information about building a vertical

17:41

farm. And their whole

17:44

idea was to use the vertical

17:46

farm to prevent NIPA

17:48

virus in Africa by

17:51

moving whatever farm there was outdoors,

17:53

indoors, and keeping out the bats.

17:55

And they had a

17:57

wonderful course in epidemiology. I'm

18:00

very impressed with the four

18:02

students who are part of that small group. I said, you

18:04

need to be a bigger group. Because

18:08

you have the terrific

18:10

idea. And it needs

18:12

to be heard by people that can do

18:14

something about it. Next

18:17

little news item is from

18:19

CDC. Human Papillomavirus

18:22

Vaccination Coverage in Children 9 to 17

18:24

Years of Age in the US in

18:26

2022. 38.6% of children

18:29

9 to 17 had one or more HPV doses. It's

18:36

not a lot, folks. Not a lot. People

18:39

with children with private health insurance were

18:43

more likely. Their coverage was 41.5%. Compared

18:47

to children with Medicaid coverage, 37%. Other

18:51

government coverage, 30%. And those without

18:53

insurance, 20%. It's expensive.

18:56

So that's why you see this. So

18:59

this is not good because

19:01

this prevents cancer in

19:04

both men and women. So you should vaccinate your

19:06

kids. And

19:08

the government should pay for it. The government

19:10

should just pay for everything. Not

19:13

everything, but health care for sure. And I'm

19:15

working on education too. But

19:19

that will happen. I

19:21

think there are two things that every

19:24

human on Earth should have. And

19:27

you can add your own. But these are my two.

19:30

These are Vincent's two. Education

19:35

and health care. Nobody should go without

19:37

either. Not fair.

19:40

I would add shelter, clean drinking water. Well,

19:42

yeah, that's good too. I

19:44

agree with that. But I can't ask for everything. You have

19:46

to add it. I think that's good to include on that

19:48

list. But those

19:50

programs largely exist in a lot of

19:52

parts of the world. And what Vincent

19:55

is saying is programs that don't exist

19:57

in all countries, even maybe. very

20:00

wealthy countries that don't provide those things to

20:02

everybody. My big

20:04

wish is that everybody is literate. And

20:07

once you can read and write and make judgments

20:09

based on what you read, then the rest will

20:11

follow. I think that follows

20:13

with some education. Yep, that follows under the edge.

20:17

Absolutely. Great idea. It's

20:19

a good idea. All right. Finally, our last little bit

20:21

here. Hey, guess what new infections there are this week?

20:24

Yeah, in the U.S. measles. More

20:26

measles. Arizona and

20:28

Minnesota. You'd think it was infectious.

20:31

Well, you know what, Dixon? Vaccination

20:34

will prevent you from getting the

20:36

disease known as measles. Is that

20:38

correct? And I do

20:41

not understand why, I guess now it may

20:43

also be access, right? Maybe

20:47

a lot of parents don't have access, but

20:49

the government ought to pay for it. The

20:52

government does pay for a lot of these vaccines. And

20:55

this is one, I mean, childhood

20:58

vaccination is pretty

21:00

widely available. And

21:02

I think a lot of the failure

21:04

to vaccinate is not related

21:06

to availability. Right. Yeah,

21:10

I also wonder in the HPV

21:13

case, how much of it has to do with

21:15

the age group? You know,

21:17

I think kids go to the pediatrician with

21:20

more regularity when they're a little younger. And

21:22

they get some of the vaccines, the

21:24

younger vaccines more frequently than maybe they

21:26

do when they're slightly older. But

21:30

all of these kids should be getting these vaccines.

21:33

There's also a well-documented effect. I've

21:36

heard it called the Kodak effect, where

21:38

the second child often

21:40

doesn't get vaccinated as promptly as

21:42

the first child. Kind

21:44

of like you have more pictures of your first

21:46

child. Apparently, I only have one. But,

21:50

yeah, you know, the parents say, yeah, we did this

21:52

already. We're not going to, we'll get

21:54

them vaccinated when we get to it. I think

21:56

it's more that there's so good. busy

22:00

with you kids. That, yes,

22:02

that too could have an

22:04

effect. All

22:07

right, onwards to the literature,

22:09

our snippet today, PNAS,

22:13

virus-derived circular RNAs populate

22:15

hepatitis C virus-infected cells

22:18

by Shan Kao, Pak Boon

22:20

Boon Shwen, Xu Shen Shen,

22:23

Xiao Hale, Kun Lai Sun

22:25

Boon Wiwat, and Peter Sarno.

22:29

Peter Sarno I know very well. He

22:32

followed me in the Baltimore lab as a postdoc. I

22:34

went out the door the day he came in. So,

22:39

it is about

22:41

circular RNAs, very interesting

22:43

molecules, and

22:46

most eukaryotic cells have them.

22:49

They are made by a weird splicing mechanism.

22:52

So splicing, you take a

22:54

precursor to mRNA in a eukaryotic

22:56

nucleus, and introns, which are

22:58

sequences in between the parts that code for

23:00

the protein. They are removed by a process

23:02

called splicing to form the final

23:05

mRNA. But sometimes the splicing can go

23:07

in an opposite direction, and you get

23:09

circular RNAs as a

23:11

consequence. And eukaryotic cells

23:14

can have like 25,000 of these

23:16

circular RNAs per cell. And

23:22

then- Dr. Seheult This is one of those

23:24

things that was discovered after I got out

23:26

of graduate school. And I was fully aware

23:28

of what the basics

23:30

of molecular biology. And

23:32

then along came this finding that

23:35

there's all this- well, first of

23:37

all, the circular

23:39

RNAs get produced, and then

23:41

that they're everywhere. And

23:45

they're apparently doing things. And

23:48

we have some clues about what some of them are

23:50

doing, but no idea what the rest of them are

23:52

doing. There's this whole additional

23:54

level of probably regulation

23:56

that's going on throughout

23:59

eukaryotic that just popped

24:01

up. And I think that it's

24:05

important to think about them, because I also

24:07

don't think about them particularly often, but I think we're probably underestimating

24:10

them, because

24:12

they're really stable, and

24:14

they can soak up other stuff. So

24:16

they can bind to a maybe sequester

24:19

or use, or who knows what, other

24:22

proteins, other nucleic acids, things like that. So

24:25

if you start to imagine that, you're suddenly like, whoa,

24:28

there's a lot of stuff that could be

24:30

going on and regulated by this. It's kind

24:32

of like that dream where you discover all these extra rooms

24:34

in your house. It's like, whoa,

24:36

where'd this come from? Discovering milk and milk

24:38

of it. So

24:46

yeah, they can act as sponges,

24:48

as Brianne said, to

24:51

hold other things. They actually

24:53

can bind proteins that

24:55

bind RNA, or they can bind microRNAs. They

24:58

don't actually, though, transcribe anything, or they

25:00

do. Translate? Yep.

25:03

Well, we're going to see in this paper that they do,

25:05

or they can, yeah. But

25:07

they're mostly made from DNA

25:09

viruses, right, because DNA viruses

25:11

undergo splicing of their mRNAs.

25:15

Right, so on the viral side,

25:17

they mostly come from DNA viruses. On

25:20

the cellular side, they're just coming from mRNAs, right? Yeah,

25:23

although in this paper, they're coming

25:25

from an RNA virus. Yes, so,

25:27

right. We're getting a

25:29

lot of secrets here. Yeah, we're finished. These

25:32

are the existing cells that are

25:34

produced in mRNA splicing that are

25:37

doing all kinds of probably important

25:39

stuff. It turns out

25:41

viruses, DNA viruses, have been shown

25:43

to have some of their transcripts

25:46

spliced into these little circles. And

25:48

then we get to this paper. We want

25:50

to know if they're in RNA viruses, so they looked at

25:54

hepatitis C virus infected

25:57

cells, and that's what this paper

25:59

does. about and

26:02

they said

26:04

they looked at circular

26:08

RNA libraries and

26:10

they say astonishingly we found hundreds

26:13

of putative eculom V-circ

26:15

RNA species from the 10,000 base

26:19

hepatitis C virus genome. So the HCV

26:22

genome is a long positive

26:24

single-stranded RNA which

26:26

is packaged into the envelope virus which

26:28

is a hepacy virus. I

26:31

was just about to do Rich's little introduction.

26:33

Yeah you can go ahead. No that's all

26:35

right you just did it. It's good enough.

26:38

Long single-stranded RNA. And

26:42

at the

26:45

five prime end of this RNA is an internal ribosome

26:47

entry site so these RNAs are not

26:50

translated by the usual method of the

26:52

ribosome interacting at the

26:54

very five prime end with the cap

26:56

structure but they internally initiate and

26:59

then translate the plus-stranded genome. And

27:02

so they found lots of small

27:05

circular RNAs and

27:08

they're most of them from the positive strand. They

27:11

have a couple of clusters they're not random they're

27:13

not all over the place they're from certain places.

27:15

One place near the five prime end

27:18

and the internal ribosome entry site was

27:20

intact in some of those

27:23

and then they had a couple of

27:25

other clusters but they were they range in size from

27:27

130 nucleotides to 2,000 nucleotides with an average of two

27:29

to three

27:33

hundred. So

27:35

this is a bioinformatic interrogation

27:40

because they're looking at libraries and they wanted

27:43

to verify that this actually

27:45

happens in virus infected

27:47

cells so they extract

27:49

RNAs and they reverse transcribe

27:52

the RNAs into cDNA's and what they do

27:54

is they know where

27:56

these circles are coming from from the genome

27:58

so they can make primers that will

28:01

bridge the circle at the junction.

28:04

And those places in the genome go

28:06

in opposite directions. So if there are no

28:08

circles made, you would never see them

28:10

by amplification. Right. Can you

28:13

make interfering RNAs to that process?

28:15

Yeah, we'll get to that. You

28:17

know? You got the right experiment.

28:19

I don't have the full article because I

28:21

can't pay that much for

28:23

this particular... Didn't you get the email? Is that

28:26

what they say? Didn't you get the email?

28:28

Probably not. No, no, no, I didn't get the

28:30

message. I

28:32

did not get the message. I was a message.

28:34

You're right. I can't get the message in my

28:36

email. I'm putting

28:38

all the papers in a folder in the

28:40

Google Docs from now on. So

28:43

you no longer have an excuse to

28:45

not read the paper. I don't. I

28:48

don't. But you do ask the right

28:50

questions and that's fine. All right. So

28:53

they do PCR to amplify these...

28:55

And they find that in fact they do

28:59

see these circles. They have

29:01

verified 14 predicted circular

29:03

RNAs by this kind of

29:06

PCR. So that's good. They

29:09

do exist in virus infected cells. Then

29:13

they ask are they translated? Now many

29:17

years... So for years, people

29:19

never... A lot of people didn't believe that there

29:23

was this non-canonical translation method where it

29:25

involves an internal ribosome entry site. They

29:27

said, now it's an artifact, blah, blah,

29:29

blah. It's got to bind to the

29:31

5'N. The ribosome has to bind

29:33

to the 5'N. So Peter Sarno did an

29:36

experiment where he circularized an mRNA and showed

29:38

it would not be translated, which is

29:41

true for the 5'N model, unless you

29:43

put an internal ribosome entry into the

29:45

circular RNA. And then it would be

29:47

translated, proving that you don't need an

29:50

end to translate as long as

29:52

you have an iris. There's some clever thing

29:54

there. I can just see it for me. It

29:56

probably is, yeah. So

30:00

they decided to see if these circular

30:03

RNAs could be translated with, some of them

30:05

have an iris in them, remember, as I

30:07

mentioned, they're derived from the 5' end. And

30:10

so they put some GFB, green fluorescent

30:13

protein, into these circular RNAs,

30:15

and in fact they can be translated. And

30:19

they'd look at it in several different ways, by

30:22

green fluorescence and also by

30:24

luminescence as well, bioluminescence. So

30:27

these RNAs can

30:29

be translated.

30:34

Let's see, where is that? I guess it's later.

30:36

Okay, so what about functions? They

30:39

do also have an siRNA

30:41

for Dickson here. Yes.

30:43

Against the junction

30:45

site. So they used an interfering

30:47

RNA to attack

30:50

these, basically. Yes, they make

30:52

si-small interfering RNAs to decrease

30:55

the abundance of specific ones. I

30:58

keep forgetting how much I remembered. Yes,

31:00

in infected cells. And they

31:04

show that when you knock down the cluster

31:07

one or two, which are two abundant

31:09

clusters of circular RNAs, you reduce the

31:11

abundance of viral RNA in infected cells

31:13

and you reduce the yield of infectious

31:15

virus. Figure

31:18

5c. Wait, so stop there. They

31:21

actually measure viruses by infectivity.

31:23

Right. When you get rid

31:25

of all that extra viral circular

31:29

RNA, then what happens to the activity of

31:32

the cell that it's found in?

31:34

Does it do something different and

31:36

better or is it neutral? What

31:40

do you mean, like does it not kill

31:42

the cell? They don't actually say that. No,

31:44

they don't report it. Well, yeah. But in

31:46

a sense, it does say, though, that lots

31:49

of the peptides produce are pro-viral function. Yeah.

31:51

The word pro-viral, or yeah, when you get

31:53

rid of it, does that make it a

31:56

pro-cell function? Well, when you get rid of

31:58

it, there's less virus and I think less viral. would

32:00

be procell. But they didn't

32:03

look in greater detail at

32:05

the, I mean, they'd

32:07

already found a pretty darn cool thing. Oh,

32:09

absolutely. Well, you know, it could get even

32:11

cooler. Yeah. And you know, it's interesting. And

32:13

you can leave something for the next paper. Yeah. So,

32:16

so here's, this is, this is an interesting slight divergence.

32:18

So the

32:21

replication of hepatitis C-fis requires

32:23

two cellular microRNAs

32:25

to bind to the 5' end of the genome

32:28

and their liver specific.

32:31

So the virus does not reproduce in

32:33

other tissues because they don't have these

32:35

two small RNAs which seem to stabilize

32:37

the 5' end. So a company has

32:39

made antagamiers.

32:42

So MIR is a microRNA.

32:45

And they've made antagamiers that bind

32:47

to this MIR-122 and prevent

32:49

it from binding

32:52

the viral RNA. And it's an antiviral,

32:54

basically. And it actually works except

32:57

the other ones that have been developed are much

32:59

better. So nobody gets it. So the other question

33:01

that would arise at that point then is what

33:03

are they doing there to begin with without the

33:05

virus? Well, they have

33:07

a cellular function actually. They have a role

33:09

in cholesterol metabolism. Yeah. So

33:11

I'm going to ask them if you interfere

33:13

with that process of a normal cell activity,

33:15

then what happens? Yeah. The patients who went

33:17

through the trial were fine. It's a, you

33:19

know, it's a transient treatment. It's not forever.

33:22

Okay. So there's a bit of a

33:24

point of this is that you can make antagonists

33:26

of RNAs. And so in theory, you

33:28

could antagonize some of these circular RNAs

33:30

as an antiviral approach if you wanted.

33:33

But it's not ever happening because the double

33:36

and triple therapy that we have, the

33:38

direct acting antivirals, right, which

33:41

act on viral polymerase and other

33:43

proteins, those are great. Those

33:45

are great. Yeah. But I don't think, I

33:48

don't think finding more HCV antivirals

33:50

is really what they're going for here.

33:52

This is a phenomenon that if HCV

33:54

is doing it, I would bet that

33:56

many other RNA viruses are doing it

33:59

too. And we

34:01

already know DNA viruses are doing it. I

34:03

think this is going to be pretty widespread.

34:05

Everybody's doing it. What you're saying, Alan, if

34:08

we don't look, we won't find. That's exactly

34:10

right. That's the doodle. It's

34:12

very wise. And what's... So

34:15

one of the weird things, I mean, there are a

34:17

few weird things going on here, but one of them

34:19

is HCV

34:22

replicates, it's entirely in the cytoplasm. Right.

34:26

And RNA splicing is in the nucleus.

34:29

And they don't... Right. I

34:32

think they looked and they don't see any evidence that

34:34

the splicing enzymes are getting pulled out of the nucleus

34:36

to do this or that the virus is going into

34:38

the nucleus to do this. So how is

34:42

it getting these circular RNAs made?

34:44

Right. Yeah, that's a good question.

34:46

That's a great question. Yeah, I was more

34:48

on the, wait a minute, if

34:50

the virus is making these and these are so

34:52

stable and perhaps more stable

34:55

than RNA, what does that do in

34:57

terms of infection in the cell

34:59

and sort of persistence in

35:02

the organism and things like that? And if these

35:04

are acting as sponges, could

35:06

they be impacting a lot of other

35:08

cellular processes by attracting other cellular

35:10

proteins or things like that? Those are the places

35:13

I went off of them. Yeah.

35:15

So outside of the cell, if you had

35:17

a collection of these RNA molecules that had

35:19

not circularized yet, could

35:21

you just shake the test tube and all of a sudden they're

35:23

all circles? Could they sell the needle? Well,

35:26

we don't know the mechanism by which they form,

35:29

right? Alan was just asking. Well, that's what Alan

35:31

was asking. And if they could sell a needle,

35:33

then you wouldn't need... That's more than that. It's

35:35

a covalent bond that's formed, right, to make a

35:37

circle. Yeah. I mean, you need the actual

35:40

back splicing. Yes. So you think you

35:42

would need the splicing factors. But

35:44

they're not in the cytoplasm. And

35:46

yet... Right. Right. Cytoplasmic extract

35:49

biochemistry is in somebody's future. Yes.

35:52

There you go. Absolutely. There

35:54

you go. Absolutely. And by the

35:56

way, there are some peptides made

35:58

from these little circles. and

36:00

so they actually over produce

36:03

the peptides in infected cell

36:05

and it increases viral expression,

36:10

gene expression, so they're pro-viral

36:13

and that's really interesting

36:15

to see what they're doing. I'm sure they're looking at

36:17

that now. Pro-viral meaning,

36:20

not pro-helping the virus,

36:22

not pro-viral in the

36:26

retroviral sense. Yeah, that's unfortunate. A

36:28

little confusing bit of terminology there.

36:30

I wouldn't have used pro-viral. No.

36:33

But every time they voted, they voted viral. Yes.

36:37

These are not amateur viruses. They

36:39

are not amateur viruses by any

36:41

means. And they

36:44

live by a circular economy. This

36:46

is introducing many people to circular

36:48

RNAs, I'm sure, who don't know

36:50

about, but I talk

36:52

a little bit about them in my

36:54

lecture on transcription and

36:56

RNA processing. What's

36:59

really interesting is that cancers

37:03

seem to have a circular RNA

37:05

signature. All

37:08

right, so they're different from what you

37:10

would find in a non-transformed cell. And

37:12

so people are going a little bit crazy

37:14

trying to figure out if they could use

37:17

that in some way. Could you imagine, anything

37:19

that's different about a cancer cell is potentially

37:21

useful. Absolutely, absolutely. That's the value there.

37:25

Okay, on to some immunology now.

37:29

This is very cool because as you know, we're

37:31

big fans of T cells here. And this is

37:33

about T cells, and a specific kind of T

37:35

cell. This is an article in Nature, Prevention

37:38

of Respiratory Virus Transmission by

37:40

Resident Memory CDA Positive T

37:42

Cells. Do

37:45

we have co-first authors here? I

37:48

don't know. Oh yes, we have

37:50

these authors contributed equally. Ida Uda

37:52

Bach and Sarah Mikaleta, two co-first

37:55

authors. And then we have Jacob

37:59

Kollmeyer. who is the corresponding author.

38:01

By the way, last week we talked

38:03

about, remember the Measles paper in Rodents?

38:09

Dixon is the only one of you guys that was

38:11

there. But

38:13

basically the two senior authors wrote

38:15

me and said, thank you so much. People

38:18

told me now, they heard

38:20

it on Twiv and then they went to read the

38:22

paper. A new paradigm in literature. They

38:25

got a Twiv bump. Well, I'm glad they went to

38:27

read the paper and didn't just rely on Twiv. That's

38:29

right, that's right. Ha ha ha

38:31

ha ha ha ha. Yep. So

38:35

we love T-cells, as you know. But

38:38

the vaccines that have been

38:40

made are mainly making

38:43

antibody responses that we know of

38:45

that prevent disease. Yeah, I was

38:47

gonna say, the vaccines that we think about, we've

38:50

mainly measured the antibody responses and so

38:52

we assume that the antibody responses are

38:55

doing all the work. Right,

38:57

and you know, when viruses

39:00

change as influenza viruses and

39:02

SARS-CoV-2 viruses, coronaviruses change, that

39:06

makes it difficult for the antibodies to

39:08

do their thing. But T-cells, there's

39:12

not very little change in the virus and

39:15

so T-cells can always work. T-cells

39:17

are not easily fooled. Exactly. T-cells

39:20

are not easily fooled. That would be a good

39:22

title also. That's good. For this paper. Very, I'm

39:24

sorry, Alan, I didn't mean that. Just pop out

39:26

of my head. That's fine, that's a good one.

39:28

It popped out of my amygdala. So,

39:32

during the pandemic, we talked a lot

39:34

on Twiv on how every time a

39:36

variant emerged and was a bit immune

39:39

evasive with respect to antibodies, the T-cell

39:41

epitopes were unchanged. And Alessandro Sette came

39:43

on a few times and talked about that. You

39:45

can check that, because you can make the peptides

39:47

and you can show that they're not changed

39:50

in the variant and they can still stimulate

39:52

T-cells. So, in

39:55

this paper, we are looking

39:57

at CD8 positive tissue. issue

40:00

resident memory T cells in the

40:02

respiratory tract, TRMs, T standing

40:04

for T cell and then RM is the

40:07

resident memory T cell. It's

40:09

not an effector, it's a memory T cell that

40:11

could be there, it could hang out there,

40:13

it could have coffee, chat,

40:15

catheclatch, all that. And then when

40:18

bad things happen, they

40:21

can start proliferating and make... That old

40:23

T cell sitting in the corner just

40:25

watching things, it jumps up all of

40:27

a sudden and says, I know who

40:29

this is. It's quiet, it's really too

40:31

quiet out there. I remember you

40:33

in 2019. Picture a Western

40:35

bar and it's smoky and there's somebody sitting in

40:37

the corner just with a hat down and then

40:39

someone walks in and wants to make a mess

40:41

and that guy or gal in the hat

40:44

gets up and says, so it's you again.

40:47

So that's what we're talking about here.

40:50

When you get

40:53

infected or vaccinated, these

40:58

tissue resident memory cells go throughout

41:00

the respiratory tract, the nasal cavity,

41:02

the trachea, the airways, the lung

41:04

parenchyma and they're important in limiting

41:06

replication in immunopathology. They can

41:09

prevent the spread of infection throughout

41:12

the lung and they say here,

41:14

reverting severe disease that can result

41:16

from viral pneumonia. You know, it's

41:19

interesting when you get influenza, it's

41:21

mainly focused in the trachea and

41:24

many people have sub-sternal pain for

41:26

a couple of weeks, which is actually

41:28

destruction of the respiratory

41:30

epithelium by CD8 T cells,

41:33

cytotoxic T cells. So

41:35

it's not zero

41:38

cost of having these lovely T

41:40

cells. That's an innocent bystander effect. Yeah,

41:42

they take a scorcher of the policy

41:44

once they get going. Yeah. And

41:48

one piece to sort of mention about this

41:50

is that in the past,

41:53

when we thought about memory T cells,

41:55

we usually thought about them

41:57

as being maybe present.

42:00

in the blood or maybe going back and

42:02

living in the bone marrow after

42:04

they've been activated and

42:06

differentiated into memory cells with

42:09

the idea that they would find the microbe

42:11

again if the microbe came around the lymph

42:13

node. But they wouldn't

42:16

be specialized to the tissue of

42:18

interest where you were first infected.

42:22

And some of the idea was that you needed

42:24

some cytokines from the bone

42:26

marrow to keep those cells alive as

42:28

memory cells. More

42:32

and more often we're realizing that there

42:34

are memory cells that are

42:36

not just in the bone marrow, not

42:38

circulating around the blood, but that are

42:40

staying in the original tissue

42:42

that was infected. And

42:46

so questions about how they

42:48

stay as memory cells and persist are

42:50

really interesting. But it

42:52

also becomes really important because we as

42:56

immunologists often, at least in

42:58

the past, like when I was doing some of this

43:00

kind of stuff in grad school, would do our measurements

43:02

on things like the blood and the spleen. And

43:05

the only way you're going to measure

43:07

a resident memory T cell that

43:10

is in the respiratory

43:12

tract is to actually sample the respiratory

43:14

tract because these cells are

43:16

not circulating. They're just staying resident

43:18

to the respiratory tract. And

43:21

so only when we've started to

43:23

measure immune responses and figure out

43:25

ways to actually look at different

43:27

tissues have we started to appreciate

43:29

the understanding of these. They would

43:31

be particularly important because you might

43:33

imagine if you got SARS-CoV-2, you

43:37

don't want to wait around for a T cell

43:39

to come out of the bone marrow and go

43:41

to the lymph node and find the tissue and

43:43

then go to the lung. That takes

43:45

a bunch of work. Whereas if you had a memory

43:47

cell that was already in the lung residing

43:50

there, being able to be that person in

43:52

the smoky bar that we've talked about, the

43:54

person lives in the smoky bar,

43:56

it's not like they had to be, you had

43:58

to call him up and tell him to come out. It can

44:01

be really important, but we hadn't been looking for them

44:03

for a really long time. So their

44:06

biology in some cases can be a

44:08

little bit behind our

44:11

understanding of kind of the bulk cells. There also

44:13

may not be as many of them or it

44:15

might be really hard to get them. So

44:17

people have a harder time studying them than

44:21

sort of general memory cells that you

44:23

might find in the blood. Do you

44:25

think these limitations

44:28

that Brienne is

44:30

pointing out are all reasons why

44:33

it's been difficult to assess

44:35

the ability of T cells

44:38

to have an effect on reducing

44:41

viral loads, preventing transmission even in

44:43

another one which

44:46

Brienne mentioned so this is called destructive sampling,

44:48

right? If you got to kill the animal

44:50

to take the T cells or the virus

44:52

to measure virus loads, it's no good and

44:54

Brienne says now we have ways to measure

44:57

the cells. You can measure virus too

44:59

without killing the animal. You can make

45:01

a fluorescent virus or a virus

45:03

with luciferase and then you can

45:05

image the animals. That one they had when

45:07

I was a grad student because I've done that one. But you were

45:09

only a grad student last year, you know. I

45:12

wish. I

45:16

have a question about why

45:19

the T cells would remain in the tissue

45:21

that they were generated in and are

45:24

you of the opinion, it's an

45:26

opinion now, that they

45:28

have receptors on their surface which

45:31

match that tissue only? And

45:34

they lock onto the cells as a result? The

45:37

idea is less that maybe that

45:39

they are locked in in that

45:41

way but that they have things

45:43

like chemokine receptors and other trafficking

45:45

molecules that make them sort

45:50

of do best or always end

45:52

up back in the... They

45:56

stay there because no place else feels like

45:59

home. Yes. Well,

46:01

if they came from the bone marrow, then for

46:03

sure they're out of their element. They

46:06

migrated through the thymus and then

46:08

stuck in the lungs or something.

46:11

Well, no. So the idea

46:13

is that sometimes maybe after they got stuck in the lungs,

46:15

originally we thought then they would go back to the bone

46:17

marrow just because the bone marrow was a nice place to

46:19

hang out. They wouldn't have to go back

46:21

through the thymus again. They're hanging

46:23

out with like the young developing

46:25

cells back in the bone

46:27

marrow. There's an energy cost to that and if

46:30

every T cell variety of every tissue did that,

46:32

I think that would not make

46:34

sense biologically. I think this makes much more sense.

46:37

Sure, but then the question is how many

46:39

T cells do

46:41

you keep in the lung before the lung

46:44

stops being good for breathing and

46:46

it's just T cells? As we

46:48

learned on Twiv, the lung is an important

46:50

organ. I say the important thing. T

46:55

cells offer a breath of fresh air basically. These

46:58

are for future shows.

47:02

These are T cells that have been

47:05

generated in response to an infection.

47:10

And then after that they hang

47:12

out in a tissue where they

47:14

presumably were left over. Exactly.

47:17

Which also makes sense because it's most

47:19

likely that you're going to see

47:21

that same microbe in that

47:24

same anatomic location. It's probably

47:26

not going to show up in a

47:28

completely different anatomic location. In

47:30

that vein, and still pursuing

47:32

the biology of this, how

47:34

many viruses

47:36

do you know that are

47:39

absolutely tissue specific and not

47:41

generalists? That's

47:43

an instant question. It is. Yeah,

47:46

I can... Well, they are both, right? They

47:48

are generalists and then there

47:50

are... I understand that. ...one

47:52

of the very specific tropisms.

47:54

And I would say the

47:56

generalists are more rare, right?

48:00

smallpox, but polio

48:03

virus, quite specific

48:05

intestinal tract and CNS rabies

48:07

virus. We were just talking

48:09

about hep C. Hep

48:11

C liver, influenza virus.

48:14

Human influenza A viruses, lung,

48:17

respiratory tract, right? Epithelial cells. Sure,

48:19

sure. So should we start looking

48:22

for those T cells in those

48:24

places for intractable diseases like AIDS?

48:26

That's a good question. And I

48:29

would say to Brienne, let me

48:31

modify it slightly. Are there any

48:33

tissues without tissue resident CD8 positive

48:36

T cells? I

48:38

don't know of any tissues without

48:40

resident memory CD8 positive T cells.

48:43

If people have actually done the work

48:45

of extracting them.

48:49

Different tissue. So I know that there's

48:51

some really interesting data on resident

48:54

immune cells, including resident memory T

48:56

cells in the GI tract and

48:59

also in the respiratory

49:02

tract or in the GI,

49:05

sorry, the genital udrogen, you

49:07

know what I mean. Eurogeogenergental tract. That's the one.

49:09

The UG tract. Yes. So,

49:14

but it's, again, you generally are going to

49:16

have to do things like using

49:19

protease to disrupt the

49:21

extracellular matrix and do

49:23

a lot of work to get the cells out from

49:25

tissue layers, which

49:29

can be, you know, really challenging. So I don't

49:31

know of an organ where we have not found

49:33

them, though they may be harder

49:35

to work with and harder

49:38

to really experiment on in some

49:40

organs. Well, can't you light them

49:42

up in sections without having to

49:44

remove them? I

49:47

think that you probably can.

49:50

I haven't done it myself, but I think that you probably

49:52

can. There must be some markers A for the T cell

49:54

and B for the tissue of the T cell. Well,

49:57

you'd have, I think you'd have to do that based on

49:59

the... just what tissue you have

50:01

and do you find T cells there. Right

50:04

and then do they stay or do

50:06

they stay or would you

50:08

go? But if you have a tissue

50:10

you've done destructive sampling so you can't

50:13

then check again later to see if the

50:15

T cell is still in that location. So

50:17

you're in the Heisenberg Virology System.

50:19

Exactly and I think that based on

50:22

your question about generalists and specialists, this

50:25

is probably why the immune system has

50:27

evolved both central memory and resident memory

50:29

T cells. Right because I,

50:31

you know, my list of

50:34

eukaryotic parasites does

50:36

have a tissue specificity to them in

50:39

a lot of cases, not in all of the cases, but in a

50:41

lot of cases they do. And

50:43

you could then use them as your

50:46

experimental model for T cell residents or

50:48

not. Do

50:53

very well with the NIH applying for a grant on

50:55

that subject. Because

50:58

we want to know. Right.

51:02

Let's do some experiments, Dixon. You got

51:04

it. All right. So

51:06

the question here, can

51:09

we see

51:11

the CD8 TRM

51:14

T cells, can they affect transmission?

51:16

And so they use, as

51:19

a model, they use sendivirus infection of

51:21

laboratory mice. So that's a

51:23

parainfluenza virus that is a natural

51:26

virus of mice. It infects mice

51:29

in the wild. It was

51:32

discovered in Sendai, Japan. Hey,

51:36

talk about naming a virus after a locale.

51:39

Here you go. And remember Sendai

51:41

got trashed by the tsunami. The

51:47

tsunami, yes it did. The

51:51

virus is transmitted through

51:54

aerosols and direct contact among

51:56

mice. The mice don't get

51:58

very sick. And

52:00

so they can use that as a model

52:02

for transmission. It's been studied quite

52:04

extensively in all kinds of ways. So...

52:07

Vincent, sorry, I was something I was a little

52:09

bit confused about, and then you sort of mentioned

52:12

it so I wanted to be clear. So they're

52:14

not actually using Sendai here in the mice. They're

52:16

using influenza that has

52:18

Sendai epitopes. They

52:20

talk a lot about PR8. Right.

52:23

And so it's influenza with

52:25

the Sendai epitope. It's not

52:27

full on Sendai. Yeah.

52:32

I know this is... Most of

52:35

the experiments are using that... I'm

52:37

wondering if there's some later experiments

52:39

that actually use Sendai. So I don't know

52:41

why they're making this statement

52:43

in the introduction that Sendai is a

52:46

great virus that's transmitted, blah, blah, blah.

52:48

Let's go through the experiments and see if there are

52:51

any with actual Sendai virus. Sendai virus is a great

52:53

model. So we use something else. So

52:55

we have... So what they want to do

52:57

is... That confused me. What they want to do is generate

53:01

T-resident memory cells in

53:04

the respiratory tract. So they take an

53:06

immunodominant T-cell epitope from Sendai virus. It's

53:08

from the nuclear protein. And

53:11

they put it into influenza virus.

53:14

Right. Yeah, but maybe they do that

53:16

because Sendai virus immunosuppresses. And

53:19

I remember outbreaks of Sendai virus in

53:22

animal colonies and it trashed the

53:24

entire mouse colony and you had to start all over.

53:27

So maybe they don't do that because they

53:29

want to keep the immune system intact. Anyway,

53:34

they take this immunodominant

53:36

T-cell epitope from Sendai virus nuclear

53:39

protein. They put it into PRA.

53:41

So that's now PRH-sen-NP. And

53:44

then they give this to mice intranasally

53:48

and they infect with influenza

53:50

virus intranasally and they get

53:52

T... They get

53:54

effector memory T-cells, TEM in

53:57

the circulation. And then they get

53:59

T-residant T-cells. resident memory cells into

54:02

the respiratory tract. And

54:04

what's cool is that they do not get Sendai-specific

54:08

CD4T cells or

54:11

Sendai-specific antibodies. That

54:13

might be why they do the prominence. Yeah, yeah,

54:15

yeah. I don't want to get it confused.

54:18

Yeah, but you say infected with Sendai, you

54:20

get everything, right? Exactly. However, they

54:22

do talk about using Sendai as a great

54:25

transmission model. Right, exactly. Yeah,

54:27

yeah. It is. But it's

54:29

not in this paper. Okay,

54:33

so if you do that intranasal,

54:35

you get nice TEMs

54:38

in the circulation and TRMs

54:40

in the respiratory tract. But

54:42

if you do intraperitoneal inoculation

54:44

of influenza virus carrying

54:47

the NP of the peptide, you

54:50

get similar TEM in

54:52

the circulation, but less

54:55

TRM in the lung

54:58

and nasal cavity. So that's

55:00

actually experimentally going to be useful for them. It

55:03

also makes some sense. The cells are

55:05

not going to preferentially want to go to the lung

55:07

if they did not first see the antigen in the

55:09

lung. So do they go back to the peritoneal?

55:13

They need an elementary education.

55:15

Yes. Oh,

55:19

my gosh, so many arcs here.

55:21

Okay, so this works

55:23

in a way that they

55:26

want it to work. So

55:28

then they're going to do their

55:30

challenge experiment. So here

55:32

we go. Here's the Sendai part. They

55:35

immunize with this PR8NP, and

55:37

then they challenge 35 days

55:40

later with Sendai virus encoding

55:42

luciferase. Right, right. And

55:45

then they use that luciferase as a measure of

55:48

viral load, and then you can see

55:50

it transmitted to other animals. So your

55:53

vaccine is not Sendai, but your infection

55:55

is Sendai. And Sendai is

55:57

good because it transmits easily between...

56:00

between the mice and then you can

56:02

look at transmission dynamics and they put

56:04

a luciferase in there so you can

56:06

get these glowing pictures that are printed

56:08

really, really tiny. They're so small. It

56:12

send eyes a big message though to the immune system.

56:15

Yeah. All

56:17

right. And so these bioluminescence as

56:20

a surrogate for virus titrate, so they say

56:22

there's a good correlation and that makes it

56:24

easy. It makes them not have to kill

56:26

the mice, right, so they

56:28

can do these long-term experiments, right?

56:31

Yep. Mice

56:33

immunized with PRH-SEN-NP

56:36

had the greatest reduction in viral load in

56:38

the nasal, lavage samples,

56:41

and they had a reduction in

56:44

the duration of infection. So shorter times,

56:46

shorter number of days that

56:48

they're actually shedding. If

56:51

you immunize intraperitoneal, so

56:53

that's immunization intranasally with

56:55

the T-cell peptide. If

56:57

you immunize intraperitoneally, you

57:00

get a more modest reduction of viral load

57:03

and you get a more modest reduction of duration

57:05

of infection because as we said, the cells are

57:08

not – you don't make as many TRMs

57:11

in the lung when you do

57:13

that. Yeah. And so that kind

57:15

of implies that the TRMs are

57:17

the ones that are responsible for

57:19

that clearance and that initial protection

57:22

because this only is seen in the

57:24

immunization type that gives

57:26

you good TRMs. It

57:28

would be interesting though to see if instead

57:31

of being in the respiratory tract, they were in

57:33

the peritoneal cavity, just waiting for the viral

57:36

– come on, where the hell is this

57:38

stuff and it's never going to come because

57:40

it's a long voice. Yeah, no, it's totally

57:42

true. So that's a switcheroo. So

57:45

they want to know now if there's

57:47

any impact on transmission because

57:50

none of these immunization protocols

57:53

actually completely eliminates virus. It's

57:55

not sterilizing, send a virus, right? So

57:57

maybe it would still eliminate or reduce

57:59

– translation, so they do a transmission

58:02

experiment, okay? So they give

58:05

mice intranasally, intraparatinially the

58:08

PR8 and SendiNP, or just

58:10

PR8 alone, and then they infect

58:13

them with Sendi luciferase on

58:20

days 1, 3, 5, or

58:22

7 after the intranasal immunization, okay?

58:25

And then they put them in

58:29

a cage with other mice, and

58:32

they see if the other mice glow, because the virus

58:35

has a bioluminescent marker in

58:37

it, so you can easily check

58:40

that out. All right, so this is kind of

58:42

interesting. When you co-house mice with naive contact mice one

58:45

day after infection,

58:48

transmission is observed

58:52

in all groups, but at different

58:54

levels. This is cool. 75% of contact mice,

58:56

all the contact mice became infected when they're co-housed with

59:02

an index mouse that

59:04

got PR8 wild type, no NP from Sendi. 75%

59:06

of the mice got infected when,

59:10

so fewer, when they're housed with

59:12

a mice immunized with PR8 SendiNP

59:14

intraparatinially, and

59:16

then finally if you give them

59:18

intranasally the PR8 SendiNP, only 33%

59:20

of the contact mice get

59:25

infected. I definitely want to be in cage 3. Yeah.

59:27

In cage 3. Okay, so the first thing I want to

59:29

do is I want to be in the case where I

59:31

have a mouse that's

59:40

pretty cool. Day 3 and day 7? Day

59:43

1, that's all day 1. Oh no, day 1 of

59:46

course, so we have more days to discuss. Yeah, now

59:48

we have day 3, no

59:50

transmission in contact

59:52

when you give them the

59:54

Sendi virus, the Sendi influenza

59:56

peptide, PR8 SendNP, let

59:58

me be consistent. All right. So

1:00:01

now if you wait three days, which presumably is you

1:00:03

generating more T cells, right? Now

1:00:05

you don't get any transmission, but there's still

1:00:08

virus there, okay? So you don't need to

1:00:10

completely get rid of virus to stop transmission.

1:00:13

So day three, and

1:00:15

then you get transmission in

1:00:18

mice that either got intraperitoneally

1:00:21

inoculated or the wild

1:00:24

type influenza virus intranasally.

1:00:27

Day five, again,

1:00:29

no transmission when

1:00:32

you get, there's

1:00:34

still no transmission with the intranasal PR8,

1:00:38

SNNP, but now there's also no

1:00:41

transmission with the intraperitoneally inoculated animals.

1:00:43

So that by day five, they

1:00:45

have produced enough T cells

1:00:48

in the lung, I guess, to take care of that. The

1:00:50

T cells finally made it there. Yeah. I

1:00:53

mean, they also say this trip. Well, but remember the

1:00:57

intraperitoneal inoculation makes normal levels

1:01:00

of circulating TEM. Right. The

1:01:02

effector memory. So some of them have finally

1:01:04

made it to the lung. Yeah. So that,

1:01:06

well, yeah. And what we're really looking at

1:01:08

here is, I think, the length

1:01:10

of infection in the vaccinated mice, right?

1:01:13

So with the, with

1:01:16

the PR8, SNNP, intranasally, the

1:01:18

proper route, you

1:01:21

get after, after day,

1:01:25

well, by day three, certainly, there's

1:01:28

just no transmission happening because if

1:01:30

you look previously at how long

1:01:32

the virus is actually in the

1:01:34

lung, it's pretty much gone

1:01:36

by day three, right? Yeah. So,

1:01:39

and then the others, the

1:01:42

virus is still around for longer. And so

1:01:44

you see it. Day five. Yeah.

1:01:47

You see it transmitting. So you still see virus

1:01:49

at day five, actually. Yeah. A little bit. But

1:01:51

then it's a matter of now. We don't know

1:01:53

how much. I can just hear the T cells.

1:01:55

So at that point, the

1:01:57

swinging doors open, they shout.

1:02:00

out boys there's a new sheriff

1:02:02

in town we're

1:02:04

gonna ride this metaphor all the way

1:02:06

through the show all the way into

1:02:09

the sunset thank you it's

1:02:12

boys and girls oh

1:02:16

the boys and girls there's a new girls

1:02:18

it did the guy that gets a T-cell

1:02:21

stands up as a boys and girls we're

1:02:23

gonna do boys and girls I see what

1:02:25

you're saying now okay so basically what we

1:02:27

found so far is that these t rms

1:02:30

in the lung can reduce the amount

1:02:32

of virus made and shorten the window

1:02:34

and also reduce transmission pretty cool yeah

1:02:38

I like so the experimental setup

1:02:40

is beautiful right because you'd have

1:02:42

no antibodies you have no CD4s

1:02:45

to help make antibodies you just

1:02:47

have these CD8s it's cool

1:02:49

it is very good all

1:02:52

right so what's the mechanism

1:02:54

it's not just CD8s

1:02:56

you're right

1:02:59

you're absolutely right you are not just you are

1:03:01

what you are thank God they

1:03:04

came I mean a PhD

1:03:06

student people say no you

1:03:08

are a PhD student that's

1:03:10

right you are what you

1:03:12

are you're not just Dixon de Palmier no

1:03:14

are Dixon de Palmier yeah I guess so

1:03:17

we said that so long ago in the

1:03:19

middle of the pandemic people would

1:03:21

write and say I'm just a economist

1:03:23

I'm just a teacher and we would always

1:03:28

say no take out the

1:03:30

just all right so I was

1:03:32

on a trip I have to I have to tell

1:03:34

you this story very brief I want to trip my

1:03:36

wife in Africa and we're all telling each other what

1:03:38

we did for a living to be able to afford

1:03:40

this trip and we get to

1:03:42

this one guy and he says I'm a

1:03:45

plumber I

1:03:47

said really you're a plumber I said where

1:03:50

did you plumb said

1:03:52

Los Alamos not

1:03:56

just a plumber they

1:03:59

worked on Sun's incredible instruments and he

1:04:01

was the only one that could save the

1:04:03

day basically in several cases. Although

1:04:05

having hired plumbers I would say that if

1:04:07

you're a plumber pretty much anywhere you could

1:04:09

probably afford a safari to Africa. This is

1:04:12

all true, this is all true. He

1:04:14

sold himself so timidly

1:04:17

he was expecting your reaction, I'm

1:04:19

sure he was. Alright, what's

1:04:21

the mechanism of this protection? Okay,

1:04:25

so they took these

1:04:28

peptide specific TRMs

1:04:30

and TEMs and

1:04:33

did RNA-seq to

1:04:35

see what's turned up and

1:04:38

they say unsurprisingly there's

1:04:40

an upregulation of pro-inflammatory

1:04:43

cytokine genes associated

1:04:45

with cell killing activity and they

1:04:48

list a bunch of those and

1:04:51

included among those are interferon gamma

1:04:53

and perforin which are induced

1:04:56

in TRM cells, the ones in the

1:04:58

lung, the tissue resident memory cells on

1:05:00

day three post challenge. We know though

1:05:03

those are important for T cell function.

1:05:05

So then they took knockout

1:05:07

mice. What I love

1:05:09

about this paper they didn't say we're going

1:05:11

to take perforin knockout mice and

1:05:14

we're going to take interferon

1:05:16

gamma receptor knockout mice. So

1:05:18

there's one other part of A and B that

1:05:20

I think is important that we should mention. Sure.

1:05:23

So here they're looking at

1:05:27

different anatomic locations.

1:05:29

So they look at bronchial diololivage,

1:05:31

lung, or spleen and in

1:05:35

lung they look at both effector

1:05:37

memory and the resident memory cells and you kind

1:05:39

of assume the spleen would only have the effector

1:05:42

memory cells because why would it? They can't have

1:05:44

the lung resident memory cells because it's not the

1:05:46

lung. And

1:05:48

they look at them sort of at

1:05:50

day 30 after vaccination.

1:05:52

So basically at this point

1:05:54

the resident memory cells are just

1:05:57

sitting in the corner. not

1:06:00

responding to anything. They

1:06:03

have become resonant memory cells, but

1:06:06

they are actually responding

1:06:08

to anything. And

1:06:11

then they also look at day 30 resonant

1:06:14

memory cells three days after challenge. So

1:06:16

it's sort of like, can those resonant

1:06:18

memory cells actually

1:06:21

recognize that and do

1:06:23

something early after seeing

1:06:25

the re-challenge? And

1:06:28

so they note that in the

1:06:30

Bronchialviale de Ollivage and in the

1:06:32

lung, they see at three

1:06:35

days after challenge, these

1:06:37

resonant memory cells have now kind of

1:06:39

woken up and are starting to do

1:06:41

this and are making the inflammatory cytokines

1:06:44

that Vincent mentioned and have a particular

1:06:46

gene expression profile by PCA. But

1:06:48

the effector memory cells at

1:06:50

day 30 post challenge or day 3

1:06:53

post challenge have not yet started to

1:06:55

do something, whether they're in the

1:06:57

lung, so they're there or in the spleen.

1:06:59

And so again, this is kind of saying

1:07:01

the resident memory cells are the ones that

1:07:03

are reacting really quickly in that first

1:07:05

three days. They're the ones that are quick

1:07:07

on the draw. Yeah, exactly. There you

1:07:10

go. That's right. So

1:07:13

they do a series of experiments similar

1:07:15

to the ones we've described using these

1:07:17

knockout mice. So let me just summarize

1:07:19

them. So they do

1:07:21

the co-housing, right? They do the immunization,

1:07:24

they do the challenge

1:07:27

with send a virus and then they do

1:07:29

co-housing. So

1:07:31

day 3 post challenge, they get

1:07:34

good transmission in

1:07:36

the contact mice

1:07:39

housed with the interferon

1:07:41

gamma receptor knockout mice. So

1:07:45

that's needed, interferon gamma receptors needed

1:07:47

to reduce the transmission that they

1:07:49

see, right? Perferon

1:07:53

makes less of a difference. When

1:07:57

perferon is important for cytotoxic T cell killing.

1:08:00

us now, maybe that's not part of

1:08:02

it, right? Not cytotoxic

1:08:04

T-cell killing of cells. So it's the

1:08:06

interferon gamma receptor

1:08:08

interaction that's critical for the mechanism

1:08:11

by which the T resident memories

1:08:13

are limiting the

1:08:16

virus reproduction. So

1:08:20

the next experiment is they say is couldn't we – these

1:08:23

are all pretty close challenges

1:08:27

to the immunization, so they want to know

1:08:30

if we have pre-existing T

1:08:33

resident memory cells, can they

1:08:35

also work to protect the

1:08:38

respiratory tract and limit transmission?

1:08:42

So they immunize the mice, the

1:08:45

contact mice now in

1:08:48

the different ways to generate T cells.

1:08:50

They can make TRMs

1:08:52

or TEMs or

1:08:54

just TEMs by intranasal

1:08:57

or intraparitoneal, and

1:08:59

then they look at sendi transmission

1:09:01

from index mice to contact mice.

1:09:05

Remember, before they didn't do anything to the contact

1:09:07

mice, they were just naive contact mice. Now they

1:09:10

want to know if you

1:09:12

immunize the contact mice with the peptide,

1:09:15

can that protect you? And

1:09:17

they wait, I don't know how many

1:09:19

days, 35 days after

1:09:21

immunization before they introduce someone into their

1:09:23

cage. I'm

1:09:26

having this of a classroom, right? So there's one

1:09:28

student in there and they're immunized and you wait

1:09:30

35 days before a stranger comes down. In

1:09:34

the previous figure, we were looking to see

1:09:37

if I care – if

1:09:39

my neighbor was vaccinated, if my neighbor

1:09:41

is being vaccinated, protected me. Now I'm

1:09:43

looking to see if me being vaccinated

1:09:46

protects me from my neighbor. Now

1:09:48

one student in a classroom, all

1:09:50

by themselves for 35 days, does

1:09:52

not constitute herd immunity. No,

1:09:55

I just – I was just – you need 35 days to make the immune response.

1:10:00

response. Okay, so what happens?

1:10:08

I have everything highlighted here.

1:10:10

It's not useful. The

1:10:14

mice that got

1:10:17

immunized with PRH-SEN-NP intranasally, they

1:10:19

got big reductions in viral

1:10:21

burden and the probability of infecting only 4

1:10:23

out of 15 mice got

1:10:26

infected compared to

1:10:28

12 out of 13

1:10:30

when they just got the PRH-A without

1:10:32

the NP peptide or

1:10:35

the PRH-SEN-NP peptide

1:10:38

intraparatinally. That didn't

1:10:40

do very well either as we saw in the

1:10:43

donors before. So

1:10:45

basically, if you're immunized and

1:10:47

you're immunized intranasally with a

1:10:51

NP peptide, that can help you

1:10:53

not get infected. Yep,

1:10:56

so it's going to help you both not

1:10:58

infect others and not get infected yourself. Yeah,

1:11:00

and they do the same experiment and knock

1:11:02

out mice and they show the same mechanisms

1:11:04

are at play. In other words, interferon gamma

1:11:07

is really important and perferent doesn't matter all

1:11:11

that much. And

1:11:13

interferon gamma signaling, so it's a big deal here.

1:11:16

So what does interferon gamma do? So

1:11:22

they said, well, maybe this

1:11:25

results in recruitment of it.

1:11:28

So maybe the TRM recruit

1:11:31

innate immune cells into tissues. But

1:11:35

they say, well, we looked and we don't see any

1:11:38

more NK cells or monocytes recruited

1:11:40

in on day two, so maybe

1:11:43

that's not what's going on here. So

1:11:45

then they said, let's

1:11:47

look at what kinds of cytokines

1:11:50

and chemokines are

1:11:53

being made. And

1:11:56

these mice that get

1:11:58

the peptide have a distinct proteome

1:12:02

that is made compared to

1:12:04

say mice that don't get a

1:12:06

peptide or that get the peptide

1:12:08

intraperitoneally. They have

1:12:11

upregulation of genes, not just

1:12:14

general inflammatory genes, but genes

1:12:16

associated with antiviral responses and

1:12:18

antigen presentation basically. Yeah, and

1:12:20

this isn't just in the

1:12:23

immune cells. This is actually

1:12:25

in the airway epithelial cells.

1:12:28

And so the presence of

1:12:30

perhaps interferon gamma is

1:12:32

changing other parts of the lung

1:12:34

to make the lung better at

1:12:36

presenting antigen. Right,

1:12:39

right. Right,

1:12:41

so and then if you knock

1:12:44

out interferon gamma receptor or interferon

1:12:46

gamma gene, you

1:12:50

do get inflammatory responses, but

1:12:52

you don't get this increase

1:12:54

in antiviral immune associated genes.

1:12:57

And so that's what the

1:12:59

TRM cells are doing. So they're,

1:13:01

it's via interferon gamma, they're making

1:13:04

interferon gamma and that gamma is

1:13:06

somehow turning on an antiviral program

1:13:10

in the lung. Is

1:13:12

this information useful in understanding

1:13:15

something about the cytokine storm

1:13:17

in SARS-CoV-2? He

1:13:25

asked innocently. I hadn't

1:13:28

thought about that. So I'm

1:13:30

trying to think it through now and I don't know. Okay,

1:13:36

maybe. That's a good answer.

1:13:40

Let's find out. I

1:13:42

do, but where I thought you were going

1:13:45

is slightly different. Does this help us understand

1:13:48

more about the role

1:13:51

of T-resonant memory? And I think it

1:13:53

does, right? I think it tells us

1:13:55

we should be trying to get those

1:13:58

immunized in our vaccines, right? Yeah, well,

1:14:00

I think it also tells us, you know, because

1:14:03

normally we would think about the

1:14:05

point of having a resident memory

1:14:07

T cell is to kill the

1:14:09

infected cell. And it's not just

1:14:11

about killing the infected cell. It's

1:14:13

actually about changing the immune environment

1:14:15

as quickly as you possibly can.

1:14:18

And so it's not about can this cell

1:14:21

kill the virus infected cell, it's can this

1:14:23

cell turn on

1:14:26

other immune responses by

1:14:28

its early quick presence

1:14:30

and early quick action. So

1:14:33

it doesn't really shoot, it organizes a posse.

1:14:35

Yeah, but no,

1:14:37

that's exactly right. And we should think about, you

1:14:41

know, we shouldn't be trying to imagine

1:14:43

strategies to make things shoot. We

1:14:46

should be trying to come up with strategies

1:14:48

to get that posse organization back in

1:14:50

jail would be fine. So

1:14:54

the next question is, is

1:14:56

this durable? Does it last? So

1:14:59

they wait six months after

1:15:02

immunizing with the peptide. Which

1:15:04

is a very long time in a mouse

1:15:06

life. It's a quarter of this lifespan, right?

1:15:09

Absolutely. Let's

1:15:12

see, six months after immunization,

1:15:16

contact my immunized with

1:15:18

the influenza with

1:15:20

the Sendai. So

1:15:24

where did I see this? Wait, where is it? You

1:15:27

should have highlighted it. Hey,

1:15:30

you're making fun of my highlighting. All right.

1:15:34

They're using fluorescent green to highlight

1:15:36

with. Okay, that's a separate experiment

1:15:39

that it was just thinking about. Okay, so

1:15:41

this one, six months after immunization, the

1:15:43

contact mice that were immunized

1:15:45

with the Sendai peptide have

1:15:47

no protection against infection compared

1:15:51

with control mice immunized with just

1:15:54

the wild type virus. But

1:15:56

they did have much less virus.

1:15:59

in them. So six months after,

1:16:02

you still get infected, but

1:16:06

from a mouse put in the

1:16:08

same cage by transmission, but they make less virus,

1:16:11

right? So while

1:16:13

we cannot ask the mice how they are feeling,

1:16:17

we may be seeing a situation of protection from

1:16:20

more severe disease, even if we don't

1:16:22

see protection from infection. Right.

1:16:24

Yes. And also with lower viral titers,

1:16:27

they may be less likely to spread.

1:16:29

Yeah. Is there weight loss with this?

1:16:34

There would be an easy parameter to measure without

1:16:36

having to. Yeah, it's a common one, but they

1:16:38

don't do that. No. So one

1:16:42

month, so that was six months, but one month post

1:16:45

immunization, there is protection.

1:16:49

Now look at this. They use a different

1:16:51

vector to deliver the nuclear

1:16:53

protein. They use an adenovirus vector.

1:16:57

Six months, they get

1:16:59

really good protection against transmission

1:17:03

and they get PRM cells in the

1:17:05

lung. And

1:17:07

so you just change the vector and you get

1:17:10

a different result. It's very interesting. So

1:17:12

you cannot assume that just

1:17:14

giving the peptide is going

1:17:16

to be the same no matter what, right? You

1:17:19

can't just not replicating adenovirus. This is not a replicating adenovirus.

1:17:21

It's entirely neutral in the process. Just the

1:17:24

adenovirus does not replicate. Is that correct?

1:17:26

It's a non-replicating adenovirus. Right. So it's

1:17:28

just the sendine protein peptide, but they

1:17:30

get six months. It's durable for six

1:17:33

months. Very cool. So then

1:17:35

they put all their data together and they see there's

1:17:37

a negative correlation between total

1:17:39

viral burden and the number of TRM

1:17:41

cells in the bronchial,

1:17:43

alveolar, lavage, the lung, and the nasal

1:17:46

cavity with the strongest correlation in the

1:17:48

nasal cavity. Not surprising, right? That's

1:17:50

where the virus comes in. Yeah.

1:17:53

Interesting. And a negative

1:17:56

correlation. How much can you get out of

1:17:58

a mouse nose? Good question. You

1:18:01

know how many brain cells there are in an ant?

1:18:05

I don't. I had to look

1:18:07

it up the other day, 250,000. That's...

1:18:11

And there's a worm that goes in there, Dixon.

1:18:15

Yes, there is. Also

1:18:19

negative correlation between the number of TRM

1:18:21

cells in the same place and probability

1:18:23

of infection. So the other was probability,

1:18:25

it was total viral burden, this is

1:18:27

probability infection. In this case, the

1:18:30

correlation is in the lung. It

1:18:33

makes sense, right? So probability

1:18:35

of infection getting established, it's in the lung

1:18:37

and that's where the protection is but just

1:18:40

viral burden is in the upper tract.

1:18:43

The protection from infections in the

1:18:45

nose, the protection from severe diseases

1:18:47

in the lung. That's right.

1:18:50

That's right. All the other macrophages play no role

1:18:52

in this whatsoever, is that right? No,

1:18:56

they looked and they weren't seeing differences

1:18:58

in the vaccine groups and macrophages and

1:19:00

K-cells. Yeah,

1:19:03

no role in this. All right, so this is

1:19:05

what I was thinking of before. So they

1:19:07

say, you know, we have some

1:19:09

vaccines, we have two doses, there's a prime and a boost.

1:19:12

And maybe the boost never

1:19:15

gives rise to T-cells because there's

1:19:17

a... The antigen's

1:19:19

cleared because you already have some kind of

1:19:21

memory, right? So let's look at this. Does

1:19:24

pre-existing TRM

1:19:26

mediated immunity

1:19:29

limit... Sorry, does pre-existing immunity

1:19:31

limit TRM mediated protection against

1:19:34

infection? All right, so niacin

1:19:36

immunized with either

1:19:40

wild type influenza virus or mock

1:19:44

immunized and then they're given

1:19:46

influenza virus, Sendi-NP or

1:19:49

adenovirus, Sendi-NP. So

1:19:51

that's like a prime boost, but it's a

1:19:53

heterologous prime boost, right? The first is... There

1:19:56

are two different virus vectors carrying the NP. Okay.

1:20:00

The mice that got preexisting

1:20:02

influenza virus immunity were

1:20:05

not protected against Sendi virus

1:20:08

infection after they got the peptide. Remember,

1:20:12

in the previous experiments, they were, had

1:20:14

much reduced virus loads and transmission and

1:20:17

so forth. But

1:20:20

adenovirus, on the other hand,

1:20:23

gave them protection mediated by TRM.

1:20:25

So using a different virus for

1:20:27

the boost makes a big

1:20:30

difference. And the idea would be

1:20:32

that if you use influenza virus twice, the second time

1:20:34

is being cleared before it can do anything, right? Right.

1:20:37

Because of all of those evil antibodies in

1:20:39

CD4 cells being a

1:20:41

problem. Evil

1:20:44

antibodies. That's right. Now

1:20:48

people can realize I'm a T cell immunologist. So

1:20:50

they also asked, they

1:20:53

also asked, does

1:20:56

this heterologous prime boosting affect

1:20:59

the longevity of protection? Remember

1:21:02

the influenza only gave us one

1:21:04

month of protection. So

1:21:07

they did the same experiment. And

1:21:12

again, if

1:21:15

you do the heterologous prime boost, you

1:21:18

get three months

1:21:20

of protection. They didn't

1:21:22

look so far out. So

1:21:27

basically the number of virus specific TRM

1:21:29

cells in the respiratory tract dictate the

1:21:31

ability of cell

1:21:33

mediated immunity to protect against, well,

1:21:37

I wouldn't say protect against infection. But

1:21:39

they do modulate infection because it's not sterilizing

1:21:41

as they say. No, right. They

1:21:44

say later, these protective

1:21:46

immunity provided by the CD8

1:21:48

TRMs is not sterilizing as

1:21:51

the cells must first encounter their antigen

1:21:53

presented by a virus infected cell. So

1:21:55

it's not sterilizing. It's a virus infected

1:21:57

cell, right? And I don't think you

1:21:59

can ever make it. is sterilizing vaccine,

1:22:01

but that's another story. So

1:22:05

that's the story here. But you did

1:22:07

prevent transmission. Oh, here's the other thing.

1:22:10

They reduced it. Although at

1:22:12

some points they prevented transmission also. Yes,

1:22:14

like days three and five with the

1:22:19

influenza and P. Yeah,

1:22:21

they did prevent transmission. But

1:22:25

they say, now we're not going to use a

1:22:27

peptide, one peptide in humans because the MHC

1:22:31

is diverse. So one peptide is not

1:22:33

going to suffice for all. One peptide

1:22:36

cannot rule them all, right? No.

1:22:40

No. So they said, what

1:22:42

the hell? Just put the whole protein in. Put the

1:22:44

whole nuclear protein in. And while

1:22:46

you're at it, put in other proteins

1:22:48

that don't give rise to neutralizing antibodies. So

1:22:51

this is a proof of concept here with

1:22:53

using a single peptide because the mice are

1:22:55

all inbred and they'll have the same MHC,

1:22:57

right? Mm-hmm. Let's

1:23:02

see, what else? Oh, so the other question I

1:23:04

think is very interesting. So

1:23:07

they say, an

1:23:09

interesting question is, what's the

1:23:11

importance of TRMs in

1:23:14

different locations in

1:23:16

the respiratory tract? And they say, we

1:23:18

didn't address upper versus lower, but

1:23:21

probably the upper tract TRMs have a

1:23:23

bigger role, right? Because they're right there

1:23:25

at the pool of entry. So

1:23:28

that's where you want to get them. And

1:23:31

again, remember, the CD8

1:23:34

TRMs, they

1:23:38

respond to infection. They make interferon

1:23:40

gamma and that makes the respiratory

1:23:43

epithelium turn on an antiviral program.

1:23:47

And they say, maybe you don't even

1:23:49

need contact of the TRM with

1:23:51

the epithelial cells. I guess not

1:23:53

because, you know, one

1:23:56

TRM cannot contact so many

1:23:58

epithelial cells, right? Well,

1:24:00

and I think that that's a

1:24:02

really interesting thing to really

1:24:04

be thinking about is if the

1:24:06

goal is to get

1:24:09

a diffusible protein that's inducing this antiviral

1:24:11

response, that might be something you could

1:24:13

do in a

1:24:15

different way than if you have to get a T cell

1:24:17

to be able to contact the viral infected cell.

1:24:21

And I just want to end by reminding everyone,

1:24:25

there's no antiviral antibody in

1:24:27

any of these experiments. No

1:24:30

antibodies were harmed in these work.

1:24:35

So this, please believe in

1:24:37

T cells. You have to believe in

1:24:39

them. So those science is not

1:24:42

a belief system. So we have data here that shows.

1:24:44

That's right. That's right. You have to

1:24:47

believe the data. So you have to make

1:24:49

vaccines. Well it probably would be good to

1:24:51

make vaccines that make both antibodies. Yes.

1:24:55

Not just one. And

1:24:57

more evidence for T cells. I like that. Really

1:25:00

cool stuff. Yeah. Yeah, no, it's really good.

1:25:03

And the T cell blows the smoke off its

1:25:05

pseudopod and sits back down to its drink. Exactly

1:25:08

right. You

1:25:10

got the voice tune. That's right. That's

1:25:14

right. Hi. I

1:25:17

just want to

1:25:20

read one email because it is

1:25:22

a passing, right? Does

1:25:27

that sound like a plan? Sure. That

1:25:29

sounds like a plan. Sure. Alan,

1:25:32

can you read that one from Steve? Yes,

1:25:35

this is from Steve, right? Yeah. Dear

1:25:38

Microbe, I thought you might be interested in

1:25:40

a notable passing. Steve

1:25:43

sends this from Wolfson

1:25:45

College in memoriam Sir

1:25:47

Anthony Epstein. It is

1:25:49

with great sadness that the college has been informed of

1:25:51

the death of Sir Anthony Epstein, 1921 to 2024, who

1:25:53

died after a very short illness in the early hours

1:25:55

of Tuesday mornings.

1:25:59

6 February 2024 at the age of 102. Sir Anthony was

1:26:02

an extraordinary fellow, 1986 to 2001, and

1:26:09

later honorary fellow, 2001 to 2024, and his obituary is

1:26:11

expected to appear in the times

1:26:14

in the next few days. The College

1:26:16

understands that there will be a small family funeral,

1:26:18

perhaps followed by a memorial event for which the

1:26:21

details are not yet known. Further

1:26:23

details, including arrangements for any messages of condolence,

1:26:25

will follow in due course. And

1:26:28

that's from Luke Jackson Ross, the college secretary

1:26:30

at Wolfson College, which is at the University

1:26:33

of Oxford. And yes,

1:26:35

Epstein-Barr virus. Yes. That

1:26:39

Epstein. Yeah, that Epstein.

1:26:43

Sir Epstein. Sir

1:26:45

Anthony. Sir Anthony Epstein, yes. And

1:26:47

indeed, he was an extraordinary fellow, whether

1:26:49

he was an extraordinary fellow or not.

1:26:53

Yeah, I caught that when Alan was reading as

1:26:55

well. I think he

1:26:57

was probably an extraordinary fellow for more

1:26:59

than just 1960. For more than just

1:27:01

that period of time. I think you don't

1:27:03

stop being extraordinary at the time when you

1:27:06

become an honorary. Yeah. Right.

1:27:09

And I don't think that's the same as the League of

1:27:11

Extraordinary Gentlemen, although it's not possible

1:27:13

that he had superpowers. We can't exclude that.

1:27:18

We didn't do the experiment. Yeah. A

1:27:20

giant in the field. Does anyone

1:27:22

else know who has

1:27:25

been given knighthood or damehood

1:27:27

as a scientist? Anybody.

1:27:31

Stephen Hawking. Yeah, he was. He was?

1:27:34

I think so. I think so. I

1:27:37

think Darwin was. Let's

1:27:40

see. I

1:27:45

don't see name. I don't recognize names here.

1:27:47

That's funny. So

1:27:50

I just googled Order of the

1:27:52

British Empire Scientists. Yeah. And

1:27:54

I get Stephen Hawking, John Bell and

1:27:57

Jane Haley. Okay.

1:28:00

Oh, actually I've got a longer list. Isaac

1:28:02

Newton, Tim

1:28:04

Berners-Lee, Jane Goodall,

1:28:07

Colin Blakemore, Maryse Wilkins,

1:28:09

Maryse Wilkins, Maryse Wilkins, Sir

1:28:13

Alec Jeffries, Darwin

1:28:15

Knapp, Stephen

1:28:17

Hawking, right. Peter

1:28:19

Medawar, right. Also I saw

1:28:22

Tim Berners- Alexander Fleming. Tim

1:28:24

Berners-Lee. Goodness.

1:28:28

You got to do big stuff to get that. You

1:28:30

do. You get knighted. Or

1:28:32

named- Paul Nurse. Paul Nurse. Paul

1:28:35

Nurse. And then

1:28:37

you can be called Sir or

1:28:40

with name, right? Eldon- Eldon-

1:28:43

Eldon-John. Paul McCartney,

1:28:45

right? Right. Yeah, that's

1:28:47

right. Terry

1:28:51

Pratchett. Keep

1:28:53

going. Anyway, Sir Anthony Epstein,

1:28:55

102, not bad. No,

1:28:58

not bad. I don't think you can complain about that, Dixon. No,

1:29:00

no, that's a good one. No, no, I wouldn't have. I

1:29:05

would have a smile on my face. I think you're going to make

1:29:07

it 102, Dixon. I

1:29:09

hope so. I would like to. I'd like to know

1:29:11

who I was in 102. Because

1:29:13

if I don't, I don't want to live to 102. You're

1:29:17

Dixon Dicomier. Well,

1:29:19

I know, I know, but- Hold

1:29:27

on, I got somebody knocking at the door. I'll

1:29:29

be right back. Uh-oh. So

1:29:31

the title of this show, Alan, I

1:29:33

think we should come up with something like Blazing

1:29:35

Sendai. He

1:29:41

sells at the OK Corral. That's right.

1:29:44

Matt, listen. You

1:29:46

know, when you leave Dodge, in this

1:29:48

case you're actually dodging something. Get

1:29:52

out of town, right? No,

1:29:55

I think a lot of good analogies, western analogies, would be

1:29:57

good. It's just the Amazon

1:29:59

guy. You need to get up to get

1:30:01

that. Amazon. No. Prime

1:30:03

or regular? What? Prime

1:30:07

or regular? I don't

1:30:09

know. It's just bag. It's

1:30:12

a... Well, we have a prime account here

1:30:14

at the incubator. Yeah. It saves shipping. Right.

1:30:18

And we order so much stuff that pays. Pays.

1:30:21

Pays. Indeed. Like...

1:30:24

All right. Back to the show.

1:30:26

Stuff we need. All right. So

1:30:28

we read that email. Let's do some pick sticks

1:30:30

and you're up first. Yes, sir.

1:30:32

Okay. So I've been neglect

1:30:35

with regards to my interest in the crossover

1:30:38

between science and art

1:30:40

and art and science. And

1:30:43

we've all agreed in the past that

1:30:46

there is a tremendous crossover. Without

1:30:49

being able to envision data in

1:30:51

a way that your optic lobes can

1:30:53

process it, a table

1:30:56

of numbers leaves me cold. But

1:30:59

a picture of that table of numbers that you

1:31:01

can actually visualize

1:31:04

is something of beauty

1:31:07

that is rare. So

1:31:09

I have located this

1:31:12

website by Scientific American that

1:31:14

actually has a very extensive

1:31:16

list of ways in

1:31:19

which art has

1:31:21

aided science in visualizing

1:31:23

information. And it's really a wonderful

1:31:26

thing to look through because you look

1:31:28

through it. You don't have

1:31:30

to read it necessarily, although you probably

1:31:32

do eventually. But just to look

1:31:34

to see the way data is presented, you

1:31:37

can see the history of the development

1:31:39

of and then, you know, the

1:31:41

circular charts showing how all

1:31:43

life on Earth is related. And

1:31:46

the more you expand that, of course, the more you

1:31:48

see. There had to be

1:31:50

a first person that could do that.

1:31:52

And my first person pick, although

1:31:54

we can start a contest, to

1:31:57

see who's the

1:31:59

very first It's just genius

1:32:02

at expressing scientific

1:32:04

data in an artistic way that

1:32:06

lets everybody get it. There's

1:32:09

no way to miss it because when you see it, you

1:32:12

believe it. And so that's why I say seeing

1:32:14

is believing. Ernst

1:32:17

Haeckel was

1:32:19

an amazing science

1:32:22

illustrator and a scientist. And

1:32:26

if you didn't know that, and I know

1:32:28

that everybody listening here at the podcast did,

1:32:31

but if you listening out there

1:32:33

had never experienced an Ernst Haeckel

1:32:35

poster, just go on

1:32:38

Google images and type his name out

1:32:41

and illustrations next to it and you

1:32:43

will be astounded at the

1:32:45

beauty and the intricacy and the amount

1:32:47

of time it took to

1:32:50

just create those wonderful pictures

1:32:53

of real life objects. And

1:32:56

they're elevated to something else

1:32:58

because they're not just depicted,

1:33:00

they are arranged. They

1:33:02

fit together like a puzzle. And

1:33:05

he envisioned this puzzle prior

1:33:08

to making the drawing. So he had to spend

1:33:10

hours drafting and getting examples of the

1:33:13

same specimen to make sure he had

1:33:15

all the parts spoken for. It's

1:33:18

a very difficult chosen

1:33:22

lifestyle to develop into

1:33:24

a very picky,

1:33:30

I would say, medical illustrator that refuses to

1:33:32

leave anything out of the picture that isn't

1:33:34

there or refuses

1:33:37

to put something in that's not there.

1:33:40

So Haeckel was the

1:33:43

amazing first in my book. I don't know

1:33:45

who preceded him. I have no data on

1:33:47

that whatsoever. I

1:33:50

could say that Leonardo da Vinci was a wonderful

1:33:52

illustrator, but he actually drew the heart wrong.

1:33:56

And I learned that

1:33:58

from a good friend of mine. I'm going to

1:34:00

like. illustrator who said although Da Vinci was a

1:34:02

fabulous draftsman, he

1:34:05

was not such a great

1:34:07

anatomical person. And neither was anybody else for that

1:34:09

matter. He was like one of the first,

1:34:12

right? And so

1:34:16

I don't know, I'm just so struck

1:34:18

by the absolute beauty,

1:34:20

intricacy, and detail of

1:34:23

Hegel's drawings and charts.

1:34:26

So that's my pickle. It's pretty cool. I

1:34:28

like how they just put

1:34:32

the animals first and then they start to fill

1:34:34

in the chart, right? It's

1:34:36

very cool. Nice.

1:34:40

And also I noticed on the sidebar, some

1:34:43

other articles, and it is one

1:34:45

about these obelisks that have been

1:34:47

found. And that's a preprint. I'm waiting for it to be

1:34:49

reviewed and then we'll do it. Good,

1:34:53

because I'm excited to think about it

1:34:55

and talk. Yeah, it'll be fun. And

1:34:57

have a conversation about it. Brienne,

1:34:59

what do you have for us? Last

1:35:02

week I was part of

1:35:04

a film fest where some

1:35:07

science-related documentary was shown

1:35:09

and then people,

1:35:11

we were talking about it as

1:35:14

experts in the field. In fact, the director was also

1:35:17

on the panel so I got a chance to meet

1:35:19

him too. And the

1:35:21

documentary that was shown is called

1:35:23

Vaccination from the Misinformation Virus. And

1:35:28

so it's really about reasons why

1:35:30

people are vaccine hesitance or are

1:35:32

not getting vaccines and kind of

1:35:34

talking about why vaccines are important.

1:35:38

It involves interviews

1:35:40

with a lot of scientists as

1:35:43

well as pharmacy students,

1:35:46

pharmacists, and sort of people kind

1:35:48

of throughout parts

1:35:51

of science. And it's really sort of meant

1:35:53

to be informing a lot of people.

1:35:55

If you go on the website that I've linked and

1:35:57

you click on the PBS part at the top, You

1:36:00

can actually watch a full version of

1:36:02

the documentary there. There's

1:36:05

also a place where he

1:36:07

lists media resources, and one of the

1:36:09

resources he's made are, I

1:36:11

think he called it link outs

1:36:13

or lift outs. He used

1:36:15

lift outs, which are small

1:36:17

video captures of different pieces of the

1:36:19

documentary that are meant to be shared

1:36:22

on social media. So

1:36:24

you can have a short clip of Betty Korber

1:36:26

talking about the importance of vaccines that

1:36:29

you could share out or things like that.

1:36:31

And so I thought that that was a

1:36:33

really neat approach. And it's a great documentary

1:36:35

for people who are interested in thinking about

1:36:37

reasons people aren't getting vaccinated. That's

1:36:40

the one that I watched and discussed, but

1:36:42

he has another documentary that has come out

1:36:44

much more recently called the Invisible Corpse,

1:36:46

which is about the public

1:36:48

health infrastructure and public health workers in

1:36:50

America. So I thought both of

1:36:53

those might be of interest to our listeners. Is

1:36:55

that Korp's or Kor? Kor. Might

1:36:58

be Kor. I

1:37:00

said the Invisible Corpse. That sounds like

1:37:03

a... No, no, they didn't finally find

1:37:05

the body. The Invisible Corpse, it's about

1:37:07

the public health service. I'm sorry, I

1:37:09

didn't... I was just... Thank

1:37:13

you, Brienne. Alan, what do you have for us?

1:37:16

Well, we didn't plan this, but mine

1:37:18

is slightly linked to Brienne's pick. So

1:37:22

this is just an NPR article, but

1:37:25

the thing that it links to, I thought, is a

1:37:27

really cool effort to try

1:37:29

to reduce or

1:37:32

eliminate the pain and trauma

1:37:34

associated with childhood vaccination and

1:37:38

try and prevent needle phobia. Dip

1:37:40

it in the bud. The

1:37:42

idea is there

1:37:44

is a significant fraction of the population that

1:37:47

is terrified of needles. And

1:37:49

I have to say that I'm not a huge fan

1:37:51

of them. I don't know if I quite have needle

1:37:53

phobia, but I don't look when I'm getting my flu

1:37:55

shot. And

1:37:58

this stems, of course. from one's

1:38:00

earliest childhood experiences, which may include

1:38:02

being held down by a doctor

1:38:04

and getting a painful shot in

1:38:06

your arm. This

1:38:09

also is traumatic for the parents. I

1:38:11

can now say with authority, when

1:38:14

you're holding your child and they're getting a

1:38:16

painful shot in their arm and they're looking

1:38:18

at you like, why are you doing this

1:38:20

to me? That is a pretty terrible experience.

1:38:24

You can't explain to a one-year-old

1:38:26

what this is doing. So

1:38:30

this is an effort led

1:38:33

by a pediatrician,

1:38:36

what is the guy's

1:38:38

name? Stefan Friedrichstorf, who's

1:38:41

at UCSF. And

1:38:44

he has developed a protocol for

1:38:47

dealing with this, for preventing this

1:38:49

kind of traumatic scene in the

1:38:52

pediatrician's office. It's basically a

1:38:54

three-step thing. You apply a numbing cream to

1:38:56

where the shot's going to be delivered. And

1:38:58

then the child is

1:39:02

held ideally on the lap of the parent,

1:39:05

so they feel safe. And

1:39:07

the third part is that they're distracted. You

1:39:10

give them a lollipop or a little toy

1:39:12

or something, or if they're an infant they

1:39:15

could nurse or they could suck on a

1:39:17

pacifier. And

1:39:20

in doing this, the kid is preoccupied

1:39:23

and feels comfortable and the

1:39:25

shot goes in and they

1:39:27

don't know it. And

1:39:29

then you have one less person who's

1:39:32

needle-phobic. So I

1:39:34

thought this was a great idea and a great

1:39:36

effort. That's awesome. And then they

1:39:38

see the needle, then they start to cry. Well,

1:39:40

no, you don't let them see the needle. And

1:39:42

I have to say, I think veterinarians may actually

1:39:44

be a step ahead on this. When

1:39:48

I took Theo, our newest cat,

1:39:50

to the vet for his initial

1:39:52

visit and he needed one more shot then, giving

1:39:54

him all of his shots, just because of

1:39:57

sequencing he hadn't quite gotten all of his shots

1:39:59

at the vet. shelter. So there

1:40:01

was one more he had to get. He

1:40:03

was a great little cat. He's very friendly.

1:40:07

And the technician held a squeeze

1:40:09

treat, which is a tube of

1:40:12

basically cat putte. I think it's

1:40:14

utterly disgusting, but cats are mad

1:40:17

for it. So

1:40:19

the technician held the squeeze treat open

1:40:21

and Theo is there like, Oh,

1:40:23

squeeze treat. This is the best. I love squeeze treats.

1:40:25

The vet comes in with a needle and shot and

1:40:28

Oh, yummy. Squeeze treat. You know, the cat had no

1:40:30

idea it was vaccinated. And

1:40:32

not that not that

1:40:35

kids are animals, but well, they kind

1:40:37

of are. They still like treats. Yeah,

1:40:39

they still like treats. Alan, do you

1:40:41

do you mind having an

1:40:43

IV put in? I don't

1:40:45

I don't like any kind of no, I don't like

1:40:48

I bought shoes like when they draw

1:40:50

blood. I want no, no, I want to

1:40:52

see how well when I do when

1:40:54

I give blood, it's like, okay, I'm looking

1:40:56

over here. Yeah, I'd like to watch.

1:40:58

I watched recently and they remember

1:41:02

she like, went in and

1:41:04

went in and then she pushed it all like an inch in.

1:41:07

And I don't have a problem with that. I think

1:41:09

it's cool. I like to talk to them about Hey,

1:41:11

I have really good veins, by the way, look here.

1:41:13

Oh, yeah, you do. You do. And

1:41:16

then I, you know, on your wrist,

1:41:18

if you have visible veins, you

1:41:20

can show where the valves are by

1:41:23

pushing down and then moving your finger forward and

1:41:25

it remains collapsed to the

1:41:27

valve. And then if you

1:41:30

lift and the blood flow resumes, it's very cool. And

1:41:32

I've done that with a number of Vini

1:41:34

punctures. And they're like, Yeah, look at mine. I'll

1:41:36

show you my valve. Let's

1:41:39

compare valves. All

1:41:42

right, it's not that bad. It's okay. You guys don't

1:41:44

like it. Okay,

1:41:46

thank you, Alan. I asked

1:41:49

Alan this week for that website that

1:41:51

shows nice pictures of

1:41:53

kids getting vaccinated because

1:41:56

I wanted a picture of a

1:41:58

kid getting vaccinated for pull

1:42:00

off its latest video and

1:42:03

he gave it to me. I think

1:42:05

I should tell people now what it is since I... Is

1:42:08

that it from like a... It's

1:42:10

from a magazine. Yes, self magazine

1:42:12

got together with... It's

1:42:15

an American Academy of Pediatrics or somebody and...

1:42:19

Because this is a pre-pandemic. The

1:42:21

editors itself, I guess, needed a stock photo

1:42:24

of somebody getting a vaccine and all the

1:42:26

available ones were horrible. And

1:42:29

so they said, okay, let's shoot

1:42:31

some. And they shot a whole gallery and

1:42:33

they're free for download. Right.

1:42:37

Okay. But that's not your pick. That's not

1:42:40

my pick. My pick is... So my

1:42:42

pick are two new DJs that I've

1:42:44

discovered. Now, about two years

1:42:46

ago, during the pandemic, I

1:42:50

got interested in electronic dance

1:42:52

music, EDM, and I

1:42:54

picked a couple of DJs. Two

1:42:56

DJs, I picked Chris

1:42:59

Luno and Miss Monique. And

1:43:02

I've since been listening all the time. We

1:43:04

play music here at the Incubator. We've actually

1:43:07

bought some wireless speakers and we play music

1:43:09

and mostly it's what I pick. So

1:43:11

I've been playing EDM and it's on YouTube.

1:43:14

And you go there, you play, and then

1:43:16

they'll recommend new people. So I'm meeting new

1:43:18

DJs all the time. And I

1:43:20

have two which I think are fabulous. So

1:43:24

one of them is Rosanna

1:43:26

Nune, who is from

1:43:28

Spain. And has

1:43:30

just 41 videos on YouTube, but

1:43:34

really very, really

1:43:36

interesting and different kinds

1:43:39

of DJ. And also she often

1:43:41

does vinyl. She'll have two vinyl

1:43:43

turntables, right? And

1:43:46

mixes between them. And it's

1:43:48

very interesting because she'll have one playing and then

1:43:51

she's looking through her vinyl collection, through the boxes

1:43:53

that she has of all these LPs. And she

1:43:55

pulls one out and she listens and she goes,

1:43:57

no, I don't know how they do that because.

1:44:00

Nowadays you just get electronic libraries,

1:44:02

but she uses vinyl. And

1:44:04

it's very funny because you can hear

1:44:06

the crackling sometimes, right? Because they're scratched.

1:44:08

So I really like her. And she

1:44:10

doesn't always do vinyl, but... The

1:44:14

thing about DJs now on YouTube is that they

1:44:16

go to different places and record in different venues

1:44:18

like outside or next to a beach or in

1:44:20

a park or something. This is the latest thing,

1:44:23

right? In the winter, in the middle of a

1:44:25

snowstorm, they always do different stuff and try and

1:44:27

now do each other. But she's mostly in her

1:44:30

home, I think, where she's got her record collection.

1:44:32

I like her a lot. Rosanna

1:44:34

Nunn. And then the other one

1:44:36

is called Sunset Cartel. This

1:44:38

is a collection of DJs. And

1:44:43

they're all different. They're men and women

1:44:45

and different styles as well. But

1:44:48

they're all very, very cool music.

1:44:50

Very different from your usual electronic

1:44:53

music. So I think you should check them

1:44:55

out. If you like

1:44:57

EDM, I think it's really cool. Nice.

1:45:01

Little non-science pick. Yeah.

1:45:04

We have a listener pick from Mary. Hi,

1:45:07

I've been a dedicated listener watcher

1:45:09

since I discovered Microbe TV. What

1:45:11

a great educational and humanitarian service.

1:45:14

You provide. I'm watching

1:45:17

your virology course episodes. And

1:45:20

although I have a degree in biology,

1:45:22

it was more than 40 years ago. I'm learning a lot.

1:45:25

I have a listener pick from the early

1:45:27

70s for Twiv, if you should happen to

1:45:29

enjoy it. It's a film called Protein Synthesis,

1:45:31

an epic on the cellular level. And

1:45:34

it's a super fun happening from the early 70s to

1:45:37

illustrate what was known about protein

1:45:39

synthesis at the time introduced by Dr.

1:45:41

Paul Berg. You can see a young

1:45:43

Paul Berg at the beginning. T-R-N-A,

1:45:47

T-R-N-A. It's great. We've had

1:45:49

this before. But it's just

1:45:51

wonderful for new people who haven't seen

1:45:53

it. Go check it out. It's just a lot

1:45:55

of fun. All right, speaking

1:45:57

of a lot of fun, the fun is now over,

1:45:59

folks. That's

1:46:02

Twiv1089. You can

1:46:04

find show notes at microbe.tv

1:46:07

slash Twiv. You

1:46:10

can send

1:46:12

us questions, comments, picks to twiv

1:46:14

at microbe.tv. And if you like

1:46:16

our work here, it's not really work to

1:46:18

us. We just love it. It's our passion. You

1:46:21

can help us, support us,

1:46:24

please. Financially, microbe.tv slash contribute

1:46:27

Dixon de Pomie,

1:46:29

trickanella.org, thelivingriver.org. Thank

1:46:32

you, Dixon. A good

1:46:35

comic romp through the

1:46:37

world of viruses. And

1:46:39

immunology. And immunology. Excuse me.

1:46:42

Forget. You know, they are

1:46:44

inextricably entwined. They are, they are, they

1:46:46

are. You cannot really

1:46:48

separate the two. No, nor should we try.

1:46:51

Alan Dove is at

1:46:53

turbidplaque.com and known

1:46:56

allendove.com. Thank you, Alan. Thank

1:46:59

you. It's always a pleasure. Brie

1:47:01

and Barker's at Drew University. Bioprof

1:47:05

Barker on blue sky. Thank you, Brie

1:47:07

Ann. Thank you. I appreciate

1:47:09

the love for immunology and the fact that

1:47:11

the two are fields are so intertwined and

1:47:14

I learned a lot. Pretty

1:47:17

twisted by arm. I just learned. This is

1:47:19

the way it is. I have to say,

1:47:21

the best way

1:47:24

to understand something is to study it.

1:47:26

And that's what we do here on

1:47:28

Twiv, on Immune. I've been having a

1:47:31

long-term course on these subjects and

1:47:33

I really, you begin

1:47:35

to appreciate how they're related. Not

1:47:39

just how they work, but how they're related. I

1:47:41

have to add my two cents on this also. I'm

1:47:43

an old school person and I was a good friend

1:47:45

of Elvin Kabat. So as a leader,

1:47:48