November 27, 2024 • 50 mins
From antibodies to killer T cells, there isn't a part of the immune system Brigitte didn't study. Aarati tells the story of a true pioneer in immunology.
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Episode Transcript
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Arpita (00:11):
Hi everyone, and welcome back to the Smart Tea Podcast,
where we talk about the lives ofscientists and innovators who
shape the world.
How are you doing, Aarati?
Aarati (00:19):
I'm doing pretty well, Arpita.
How are you?
Arpita (00:23):
I'm okay.
I feel like we're having somecozy vibes with the weather
right now.
Aarati (00:27):
Yeah.
Arpita (00:28):
It's been just like nonstop rain, and so we have
candles going, we have theheater running, and it feels
like kind of cozy vibes.
Yeah.
What about you guys?
Aarati (00:37):
Yeah, same.
I feel like fall really snuck upon me for some reason.
I don't know why, but I'm justlike, why am I so cold?
All right, it's not summeranymore.
I should probably pull out myheavy jacket and my heavy
sweaters.
And for some reason in my mind,I'm really resisting that.
And then I regret it
Arpita (00:56):
Well, you like the warm weather.
Aarati (00:57):
I do like the warm weather.
And I think part of me is indenial that it's over.
And I'm like, that wasn'tenough.
Where's, you know, where's myother 90 degree days.
Arpita (01:08):
Last year, Logan bought a bunch of like, honestly, just
like kind of a little biggerthan a piece of paper heating
pads that are electric.
Aarati (01:16):
Oh my gosh.
Arpita (01:17):
That sometimes people will use for like back pain or
cramps.
Yeah.
And.
We now have three.
One is on my desk chair, so Isit on it, and then we have one
on the couch that the cats siton, but it's honestly so great.
It's kind of like, you know,when you get into your car and
you have heated seats?
Aarati (01:32):
Yes.
Arpita (01:32):
It's like that, but like in your desk chair or like on
the couch, which is...
Aarati (01:36):
Oh my god.
Arpita (01:37):
...perfect, because then you put a blanket over it and
now you've just created thisincubator and you're just
roasting on the couch and itfeels amazing.
So, maybe that'll be yourChristmas present, Aarati.
I'll just Amazon you a heatingpad and you can sit on it for
all of winter.
Aarati (01:53):
Yes, I have a huge, like, hoodie blanket that I use,
like, Like a Snuggie, but like,it's not, it's a knockoff
Snuggie, I guess.
Yeah,
Arpita (02:02):
Like off brand Snuggie.
Aarati (02:03):
Yeah, like from Amazon.
And I just live in that thing.
It's, it's just so amazing.
It keeps me so warm and I'm sohappy in it.
But yeah, this weekend I went tolike a water lantern festival
that was outside and they had towait until it got dark so that
you could see the lit uplanterns on the water and I was
(02:24):
not dressed appropriately.
I was so cold.
I was wearing my sweater, butlike, you know, I was, I was
freezing and I was like, the sunhas set.
The sun has set.
Let's do this and get out ofhere.
I'm so cold.
And I was like, yeah, I reallyneed to just like come to terms
with the fact that it's notfall.
It's winter.
Arpita (02:43):
Does Kyro keep you warm?
Aarati (02:44):
No, he's not a snuggle.
He's not a snuggly dog.
Arpita (02:47):
Oh yeah, he's not a snuggly dog.
Aarati (02:48):
He'll put up with it.
Like, I'll hug him and he'll belike, okay, fine.
But he's very happy in his ownbed and I'm like, okay.
I see how it is.
Arpita (02:56):
The utility is not there for sure.
Aarati (02:58):
Yeah.
And he's also like, he doesn'tlike having blankets on him
either.
Like, I've felt so cold beforeand I'm like, Oh my gosh, Kyro
must be feeling so cold.
Let me put a blanket on him.
And he's like, why have you donethis to me?
And he like crawls out of it assoon as I am not looking.
He's like, okay, enough of that.
Arpita (03:18):
I feel like that's like, probably the shepherd, you know,
he's just like, no, he's like,yeah, this is not, I don't need
this.
Aarati (03:24):
I mean, he does have a fur coat at all times, so I
guess..
Arpita (03:27):
It's true, but yeah.
Well, let's have a little cozystory.
Shall we?
Aarati (03:33):
Yes.
Arpita (03:34):
Who are we talking about today?
Aarati (03:35):
You know, I'm still not really over the election.
And so I felt like I just neededa little bit of girl power.
Arpita (03:42):
Nice.
Aarati (03:42):
Yeah, so today we are going to be talking about
Brigitte Askonas.
And she basically is the motherof immunology.
And she really earns that title.
She's just crazy smart and justbasically everything we know,
like the foundations ofimmunology, it's thanks to her.
Arpita (04:05):
That's amazing.
Okay, I'm super excited to hear.
Aarati (04:08):
Yeah, this is a little scary for me because I feel like
I have a mental block when itcomes to immunology for some
reason.
Arpita (04:14):
Don't we all a little bit though?
Like I see the T cells and I seethe B cells, the cytokines.
I'm just like...
Aarati (04:21):
Like what is happening?
Why are there so many cellsinvolved in keeping us safe and
healthy?
Yeah, but she was all over it.
She was all over it.
So I'm going to do my best andreally try to explain the immune
system So Brigitte, who went byIta, was born in Vienna, Austria
(04:42):
on April 1st, 1923.
Her parents, Carl, Frederick,and Rose, immigrated to Vienna
from Czechoslovakia.
And they were part of aprominent Jewish community
there.
There isn't a ton of informationabout Ita's childhood.
We know that she had an olderbrother, Fred, and her father
and uncle owned a chain ofknitting mills across Europe.
(05:05):
And her mother had studied fineart, and she passed down her
love of art and music to Ita.
So it sounds like the family waspretty well off in general if
they owned this, you know, chainof knitting mills.
The mothers into fine art, theybuilt up a collection of art as
well, and both parents were verysupportive of their children.
So it just kind of sounds like avery happy childhood.
Arpita (05:27):
Uh huh.
Aarati (05:29):
However, when Ita was 15, Austria was annexed by
Germany just before World WarII, and so Ida and her family
had to flee, and they had toleave behind their house and
most of their art collection.
They hopped around Europe for abit, and then they fled to New
York, but they didn't have avisa to stay in the U.
(05:49):
S., so they ended up settling inCanada in 1940.
And so by this time, Ita is 17.
So she's starting to think aboutcollege and, um, what she wants
to do in life, but she wasn'treally drawn to any one field of
study because her mom was likeinto art and music.
(06:09):
And she loved that.
She loved languages.
She loved literature.
She liked nature.
She liked biology, but shewasn't really like sure what she
wanted to major in.
So she spent 2 years atWellesley College in
Massachusetts beforetransferring to McGill
University.
Arpita (06:27):
Oh nice.
Aarati (06:27):
And even at McGill she kind of spent some time
undecided about what she wantedto study.
Until she started taking classesfrom a biochemistry professor,
who was also the Dean ofScience, Dr.
David Thompson.
And Ita thought he was, quote,"The most brilliant lecturer
I've ever heard speak with amarvelous sense of humor."
Arpita (06:47):
Oh, love that.
Aarati (06:48):
Yeah.
And so solely because of hisinfluence, she decided to pursue
her degree in biochemistry.
Arpita (06:55):
Honestly, I can't relate.
I had a terrible biochemistryteacher in college.
Aarati (06:59):
Yeah.
Arpita (07:00):
Cannot relate.
That class was so hard for me.
And then I did take organicchemistry also for like a short
bit there.
And I was like, get me out ofhere.
That was actually, no, I almostfailed two classes in college.
One was organic chemistry 2.
Then the other was physics.
It was like optics and waves.
Aarati (07:20):
Oh, yeah.
Arpita (07:21):
Like there's like kinematics.
There's like, whatever.
There's like different likesection.
It was like the optics andweight.
Those were the two classes Ialmost failed in college.
Aarati (07:28):
Yeah.
Organic chemistry.
Man, that's, that's like theclass that, you know, everyone
drops out and it's like, I canno longer be a science major.
Organic chemistry is crazy.
Arpita (07:39):
I feel like they did it on purpose.
Like, they must have done it onpurpose.
Like, I think about it now andlike, sometimes it'll like, pop
up, you know, every now andthen, like principles of organic
chemistry.
But I'm like, this makes a lotof sense.
Like, I feel like if someone hadexplained it to me properly, I
would have been fine with it.
But there's also this, like,intimidation factor around it.
Aarati (07:56):
Yes.
Arpita (07:56):
And I feel like the tests were, like, unnecessarily
hard on purpose.
Aarati (07:59):
Yeah.
They definitely made it harderthan it needed to be.
Yeah.
Arpita (08:02):
They made it way harder than it needed to be.
I feel like it was actually notthat bad.
Aarati (08:06):
Yeah, no, it wasn't.
Like I remember, I was taking anorganic chemistry class once and
I was studying for an exam withmy friend and so I was reading
the textbook like tryingdesperately to understand what
was going on.
Arpita (08:19):
That's when you know, it's bad, but yeah.
Aarati (08:20):
Yeah.
And she's like memorizingwhatever was taught to us and
and they had given us some likecrazy mnemonic device that had
15 exceptions to the rule, youknow, and she was like trying to
memorize all those exceptions.
And I was just like, you know,I'm, I'm not good at that.
I'm not good at memorizingthings.
And so I was like trying tounderstand like what's going on.
(08:41):
I read the textbook and it tookme a while, but I finally
understood what the textbook wassaying.
And I'm like, Oh my God, if youjust go through like these five
steps and you answer these fivequestions about the reaction
that you're studying, you getthe answer right every single
time.
There are no exceptions.
Like this is how it worksbecause that's how nature works.
Because...
Arpita (09:00):
Rather than like going the long way around.
Yeah.
Aarati (09:03):
And creating some weird mnemonic devices that has 15
exceptions, why don't you justteach us how it actually works?
Yeah.
And I was just like, Oh, thismakes so much more sense.
But then I told my friend aboutit, who I was studying with.
And she was like, I'm just goingto memorize it.
And I'm just like, why though?
This is so much easier.
And it makes so much more sense.
(09:24):
Yeah, but I don't know whatthey're doing with, with O chem,
but I actually majored inbiochemistry because my dad was
a biochemistry major also and Iwas just like, I'll just do that
and then I'm like, what have Igotten myself into?
Oh no! But Ita decided to pursueher degree in biochemistry.
And after five years at McGill,she graduated with a masters.
(09:47):
So at the time she graduated.
There was another professor, Dr.
Karl Stern, who had just beenappointed to the Allen Memorial
Institute of Psychiatry and wasconducting job interviews
looking for someone inbiochemistry to join his lab.
So Ita went to this interviewand that was being held in Dean
Thompson's office.
(10:08):
And during the interview, shestarts laughing uncontrollably
at a cartoon that Dean Thomashad on his wall.
The cartoon was by this guynamed James Thurber, and it
showed a psychiatrist that wassitting at his desk, but instead
of a normal human head, thepsychiatrist had a rabbit's head
and there's a woman sittingacross from him and the
(10:30):
psychiatrist rabbit guy issaying,"You said a moment ago
that everybody you look at seemsto be a rabbit.
Now what did you mean by that,Mrs.
Sprague?" And apparently Itafound this so hilarious.
That she couldn't stop laughing.
I didn't get it either.
I was just like, I looked at thecartoon, like, I looked it up
and I'm just like, what?
(10:52):
I'm like, maybe this is like1940s humor or something.
Arpita (10:56):
Like, he's supposed to, like, he is a rabbit and he's
saying, you think everyone lookslike a rabbit?
So he's, like, she's nothallucinating.
It's real.
Aarati (11:05):
Or maybe she is hallucinating, and we're seeing
her perspective, and it's likeliterally everyone's a rabbit?
I don't know.
I didn't understand it either,but she found it hilarious.
She was just like
Arpita (11:17):
And then also started laughing during an interview.
Aarati (11:19):
During an interview, she was like laughing so hard, she
couldn't stop laughing at thiscartoon.
Arpita (11:24):
Interesting tactic, but okay.
Aarati (11:26):
Yeah, but it worked.
Dr.
Stern was like, I like yoursense of humor, I will hire you.
And so, I mean, that's how Itatells the story of how she got
her first job.
But, you know, I'm sure Dr.
Stern was very impressed withher knowledge and passion for
science and her, like, you know,biochemistry acumen.
Arpita (11:46):
Speaking of sense of humor, I one time during a grad
school interview had someonestraight up ask me, tell me a
joke.
And I was like, what?
Aarati (11:55):
What?
Arpita (11:56):
Yeah,
Aarati (11:57):
That's so random.
Arpita (11:59):
Isn't that terrifying?
And then like also, I was like21 or 22, you know, like I was,
Aarati (12:05):
oh my God.
Arpita (12:05):
Like already petrified to be in this room, you know?
Like, I was like, I shouldn't bein this room to begin with.
Aarati (12:10):
Yeah.
Arpita (12:10):
Like I'm already feeling horrendous things.
And I was just like, how do youwant me to answer that question?
Aarati (12:18):
Yeah.
Did you tell them a joke?
Arpita (12:20):
I don't even remember what I said.
I honestly, I think I blackedout.
I don't even know what I said.
But I have, now I have two backpocket jokes.
Aarati (12:29):
Are they science jokes?
No, not really.
Arpita (12:35):
One is inappropriate and one is very G rated.
Aarati (12:38):
Okay.
Arpita (12:39):
So, you know, it's audience specific.
Aarati (12:41):
Yes, it depends on who you're talking to.
That's a good tactic though.
Arpita (12:45):
Thank you.
Aarati (12:46):
So, yeah, so she got this job and she starts working
on the biochemistry of dementiawith Dr.
Stern.
Dr.
Stern thought there must be somechemical imbalances in the brain
that were leading to dementia,but since it's the 1940s, they
didn't really have good enoughtools to properly test these
theories.
And pretty soon, Ita alsorealized that her master's
(13:09):
degree just wasn't gonna cut itin addition to not having the
tools to study dementia, shejust didn't have enough training
in science.
And so if she wanted to work asa scientist, she needed more
education.
So she talked to Dean Thompsonabout it.
And he helped her get into theSchool of Biochemistry at
Cambridge to do her PhD.
(13:30):
Uh, she had a wonderful time atCambridge.
Here she met two scientists,Drs.
Margaret Stephenson and DorothyNeedham, who were some of the
very first women to be electedinto the Royal Society, which
was very encouraging to Ita as ayoung woman scientist.
Arpita (13:45):
That's super cool.
I was gonna say two women.
That's really like, I guess, notexpected.
Aarati (13:52):
Yeah.
She said they made her realizethat quote,"Good science gets
recognition regardless of thesex of the scientist." End
quote, which I thought was verynice.
Arpita (14:00):
I feel like we've maybe had some episodes to the
contrary, but...
Aarati (14:04):
Yes, I was thinking of Svetlana Mosjov.
Yeah, I was.
Yes, I was thinking of her.
Arpita (14:10):
I do appreciate the sentiment.
I do.
But yes.
Aarati (14:12):
Yeah.
I'm glad that that was hertakeaway and that she was
inspired.
Arpita (14:17):
Agree.
Aarati (14:18):
Uh, her PhD supervisor was Dr.
Malcolm Dixon and Ita reallyappreciated him because he
basically gave her a project andlet her go at it and let her
figure it out herself.
And that really gave her theconfidence to believe that she
could pursue independentresearch.
So after completing her PhD, shegot a staff position at the
(14:38):
National Institute for MedicalResearch or NIMR in Mill Hill,
London, studying proteinsynthesis.
And the question Ita was reallyinterested in was whether
proteins were translated fromRNA in one long continuous
strand or whether multiple smallsegments were translated and
then they all came togetherafterwards.
Arpita (15:00):
Mm-hmm.
Aarati (15:00):
Because remember, like we don't really know, this is
like basic biology.
We don't know the answer to thisvery basic question.
Um, and so to look at this, theywere working with lactating
goats and studying their milkproteins.
Arpita (15:16):
Interesting.
Okay.
Aarati (15:17):
Yeah.
So Ita would give the goatsshort pulses of radio labeled
amino acids, which are thebuilding blocks for proteins.
And then she would collect themilk, purify the milk protein
that she was studying, which wascalled lactoglobulin.
And the theory was that if shehad seen certain segments of the
protein were made withradiolabeled amino acids and
(15:40):
other segments were not, thenthat would have indicated that
the proteins were translated insmall pieces and then came
together into a long chainlater.
But that's not what she saw.
Instead, she observed that thewhole lactoglobulin protein was
made with radiolabeled aminoacids, so that meant that the
proteins were being translatedrapidly in one long, continuous
(16:01):
piece.
Arpita (16:01):
One long chunk.
Aarati (16:02):
Yeah.
Arpita (16:02):
Yeah.
Aarati (16:03):
And this was later confirmed, in, various other
ways by other scientists.
And ultimately we got the doublehelix model of DNA, which, you
know, that all fit together.
So that was a successfulproject, but Ita had a few
issues.
One was that she really didn'tlike working with the goats.
Especially there was one namedUrsula who she found nearly
(16:26):
impossible to catch and milk.
Arpita (16:28):
Okay.
What are all of these modelorganisms?
Like, I'm just like, what ishappening?
Like, there's just like.
Whatever animal they could gettheir hands on, like, I just
feel like this range of modelorganisms that we've discussed,
I don't even know, this doesn'teven count as a model organism,
but like.
Aarati (16:42):
Yeah, I don't know why goats.
I don't know what they weredoing, but...
Arpita (16:45):
Like, why was it goat milk, like lactating goats,
like,
Aarati (16:49):
I don't know.
I have no idea.
Arpita (16:51):
Why are we milking goats?
There's no other way to findprotein?
Aarati (16:56):
Yeah.
So that was her problem exactly.
She was just like, why are, whyam I, these, these goats are so
annoying.
They don't wanna be milked.
I have to chase them around thepen and I have to like try and
catch them.
And they're so like...
ugh, irritating.
And I actually watched thisYouTube video where one of Ita's
friends was talking about herand she said that Ita was a big
(17:17):
fan of flora but not of fauna.
She really didn't like dogs,cats, babies.
Arpita (17:23):
I was about to be like, relatable, but then I was like,
wait, wait, wait, wait, wait,wait.
Aarati (17:26):
No, no, no.
She just didn't like anyanimals.
Arpita (17:29):
What I don't like is animals in the lab.
Aarati (17:31):
Yes.
Yeah.
Arpita (17:32):
Yeah.
Aarati (17:32):
Like she just didn't like animals in general, so this
was probably even worse for her.
Arpita (17:36):
Yeah.
Okay.
Yeah.
Aarati (17:37):
But the second problem was that purifying lactoglobulin
or really any milk protein wasdifficult because milk contains
something called casein.
And we talked about this brieflyin the Wilbur Scoville episode
about how when you eat somethingspicy, drinking dairy products
is a great remedy because itcontains casein, which is a
really sticky molecule and itwill surround the capsaicin and
(18:01):
wash it away.
But because it's so sticky, Itahad a really hard time getting
rid of it in order to study thelactoglobulin.
Arpita (18:07):
To purify it.
Yeah, that makes sense.
Aarati (18:10):
So Ita, like you said, was like, there has to be a
better way to study proteinsynthesis than chasing around
goats and crystallizing tinyamounts of protein.
Arpita (18:19):
Hard agree.
Aarati (18:20):
So around this time, she attended a lecture at the NIMR
given by an immunologist, Dr.
John Humphrey.
And his lecture was aboutantibodies, which Ita knew
nothing about at all.
So, I know you know this,Arpita, but maybe just for our
listeners who kind of needsomething to form an image in
(18:40):
their head like I do, um,Antibodies are proteins that are
shaped kind of like the letterY, and that top part of the Y
can detect and bind to otherproteins called antigens.
And antibodies are naturallyprogrammed to detect foreign
invaders like viruses orbacteria that do not belong in
our bodies.
(19:00):
And once they detect somethinglike that, they can trigger an
immune response, which basicallytells our body to destroy that
invader.
So Dr.
John Humphrey was giving hislecture and he gave a
demonstration of how thisworked.
He had two clear solutions.
One was a solution of purifiedantibodies, which are the Y
shaped proteins.
(19:21):
And one was the antigen, whichis what the antibodies detect
and bind to.
And when he mixed the twosolutions together, all of the
antibodies glommed onto theantigens and formed a
precipitate that settled to thebottom of the mixture.
Arpita (19:36):
That's cool.
Aarati (19:37):
And so when Ita saw this, she's like, that's
brilliant.
That's such an elegant answer tomy protein purification problem
because that precipitate that'sforming in Dr.
Humphrey's flask is mostlyantibody.
So, if she studied proteinsynthesis using antibodies
instead of lactoglobulin, firstof all, she could use any small
(19:58):
animal.
She didn't have to use goats.
She could use rabbits or micethat she didn't have to chase
all over the place.
And instead of collecting milk,she could instead trigger an
immune response so that theanimal created antibodies and
then she would just have tocollect some blood or some serum
and then use that same methodthat Dr.
Humphrey just used toprecipitate out the antibodies
(20:20):
and then you've got pretty muchpurified antibody protein that
she could study.
Arpita (20:25):
Oh, interesting.
I see.
So her protein of choice is nowjust antibodies.
Aarati (20:30):
Yeah, exactly.
Arpita (20:31):
Got it.
And like a particular antibodyor she's just casting a wide net
here?
Aarati (20:36):
Um, at this point, not yet.
Arpita (20:38):
Okay.
Aarati (20:38):
I mean, actually throughout her life she kind of
hops around differentantibodies, but right now she's
just like, what antibody canI...
Arpita (20:45):
yeah.
Aarati (20:45):
Use to study protein synthesis and antibody
synthesis.
Yeah.
So she ran this idea by Dr.
Humphrey and he was all for it.
He's like, I'll help you howeverI can.
So, Ita asked him, well, since Iwant to study antibody
synthesis, it would be reallyhelpful to know which tissue or
organ they're made in.
Arpita (21:04):
Right.
Aarati (21:04):
And, Dr.
Humphrey's like, well, that's agreat question.
Um, the antibodies aredefinitely made in a type of
white blood cell called plasmacells.
And they didn't have the namefor it at the time, but today we
call them plasma B cells.
Um, But as for which tissuethey're made in, he didn't know.
And so Ita's like, great, let'sstart there.
Arpita (21:27):
Yeah.
Aarati (21:27):
So Ita and another scientist Bob White start using
guinea pigs to systematicallyfigure out which tissue the
antibodies are coming from.
They would inject the guinea pigwith ovalbumin, which is a
protein found in egg whites.
And actually, if you have an eggallergy, you're probably
allergic to ovalbumin.
Arpita (21:47):
Yeah I,, I'm not allergic to this, but I, I do, I
did know that because that'swhen you get the flu shot.
They always ask you if you havean egg allergy.
Yeah,
Aarati (21:54):
We learn about that in like bio and biochemistry
because it's a really easyprotein or it's, it's really
easy to purify.
And so it's a very commonantigen that's used to create an
immune response in lab animalsall the time so that scientists
can study the immune system.
It's like very common.
Arpita (22:10):
Yeah.
And in vaccine development,which is why they ask you that.
Aarati (22:14):
Yeah, that's why they ask you.
Exactly.
So she uses ovalbumin to triggeran immune response and then
collected a tissue sample fromwhatever tissue they thought
might be producing theantibodies.
She chopped up the tissue, addedradiolabeled amino acids and
then collected the antibodies,which if they were being made in
that tissue would now beradiolabeled and she could
(22:37):
detect that.
So if they thought like, hey,maybe the antibodies are being
made in the liver, they choppedit up, added radio labeled amino
acids, and then look to see ifany radio labeled antibodies
were made.
And in the case of the liver,not many radio labeled
antibodies were detected,indicating that they're not
being made there.
The tissues where she did findthe highest amount of radio
(22:58):
labeled antibodies were in thelymph nodes, bone marrow, and in
the lungs.
Arpita (23:04):
Oh, the lungs.
Interesting.
Aarati (23:05):
Yeah.
But they also discoveredsomething called the bystander
effect, which is that it wasn'tjust antibodies that was
specific to ovalbumin beingformed, but generic antibodies
as well.
And that was pretty surprisingto them at the time.
But now we know that when theimmune system is highly
activated, non specificantibodies are created to help
(23:25):
drive the overall immuneresponse.
So that's kind of what washappening there.
Arpita (23:29):
Right.
Aarati (23:30):
And I think that maybe explains why they were seeing
antibody synthesis in the lungs.
Cuz that's...
Arpita (23:36):
That is interesting.
I did not know that.
Lymph and bone marrow make a lotof sense.
That's what we typically thinkof as like, kind of like hubs
for the immune system, butinteresting about the lungs.
Aarati (23:50):
Yeah, so under Dr.
Humphrey, Ita is really makingsome huge contributions to the
field of immunology already.
In 1957, a new immunologydivision was created at NIMR,
and Dr.
Humphrey was asked to lead it.
And so Ita joined him, and they,along with a core group of
scientists, became really thefounding team for this division.
(24:13):
But Ita's still not happy aboutthe fact that she has to do
these experiments in animalsbecause she couldn't isolate the
specific cells that created theantibodies to ovalbumin and then
create a cell line from them.
So she couldn't study this invitro, or in a petri dish.
And that's because the lymphnodes contain a whole bunch of
(24:34):
different cells, So the cellsthat Ita is interested in are
the B cells.
And there are two types of Bcells.
There's the plasma B cells,which I mentioned are the ones
that make and secrete theantibodies, and there are memory
B cells that can live for yearsjust hanging out, and their job
is to remember a specificpathogen and trigger an immune
(24:56):
response if it ever enters yourbody.
So, there will be a memory Bcell for ovalbumin, which was
what Ita was triggering to startmultiplying and create a bunch
of plasma B cells, which wouldthen create the ovalbumin
specific antibodies.
But there are also other memoryB cells for like flu virus or
(25:17):
bacterial pathogens that wouldall just kind of be hanging out
together in the lymph node.
And so if you only wanted tocollect the B cells that are
responsible for creating, like,one type of antibody, it's
really hard to separate.
them out from the lymph nodefrom all the other cells.
Arpita (25:32):
Like if you're doing this in the animal, in vivo,
that's really hard to do.
Yeah, that makes sense.
Aarati (25:36):
And then if you wanted to take those cells and put them
like in a petri dish and thenkind of create a line that you
could study and just take theseexperiments out of animals and
not have to deal with animals atall, it's really hard to do
that.
Fortunately, around this time atthe NIH, A group led by Dr.
Mike Potter had discovered acancerous cell line in which the
(25:58):
plasma cells were secretingantibodies out of control.
So cancerous, right?
Arpita (26:03):
Wow.
Okay, great.
Love that serendipity.
Aarati (26:06):
Yes, exactly.
And so these plasma cells wouldproduce antibodies, both in
vivo, in mice, and in vitro.
Arpita (26:15):
Oh, great.
Aarati (26:16):
Yeah.
Ita's like, perfect.
Exactly what I needed.
Yeah.
That's what I need to studyantibody synthesis and how these
proteins are being synthesized.
That's great.
And this became a reallyvaluable tool for her for
studying antibody formation.
And I'm not.
going to go super into detailabout all of her experiments
here, but once Dr.
Potter sent them the cell line,Eda was really able to pin down
(26:40):
like some of the nitty grittydetails as to what parts of the
antibodies were formed first andhow the different parts of the
antibodies come together to formthat Y structure.
So she really like nailed downantibody synthesis.
Arpita (26:54):
That's super cool.
Aarati (27:00):
Hi everyone.
Aarati here.
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Okay back to the story.
(27:44):
So now Ita's been working onprotein synthesis and
particularly antibody synthesisfor nearly a decade.
She decides to take a bit of astep back and revisit her
biochemistry roots.
So from 1961 to 62, she did asabbatical at Harvard Medical
School, and here she wasreminded about our good friend,
(28:04):
Elie Metchnikoff, who youcovered in Episode 6.
At this point, it's been about ahundred years since he
discovered macrophages, andpeople knew that macrophages
were another type of white bloodcells that were different from
plasma B cells but still relatedto the immune system because
(28:25):
they went around engulfing anddegrading foreign invaders in
the body.
Arpita (28:29):
I also feel like macrophages are conceptually
just so easy to understand.
Like you very much think aboutthem as like Pac- man, you know?
Like it just makes a lot ofsense that you have something
that's just like eating trash.
Aarati (28:40):
Yes.
Arpita (28:41):
And it really is not that much more complicated than
that.
Like that is really the scienceis that it's just kind of
engulfing things and thendegrading them.
Aarati (28:49):
Yes.
Arpita (28:50):
I feel like once you start getting into antibodies
and the rest of immunology, likeeverything hits the fan.
But...
Aarati (28:57):
Yeah, yeah, no, macrophages are simple.
Arpita (29:00):
Macrophages we can do.
We can do macrophages.
Aarati (29:02):
Yeah.
So that's what people knew.
They're like, macrophages goaround and if it runs into like
a foreign bacterial cell orvirus, it'll eat it and degrade
it.
And so Ita was like, huh, goodpoint.
I wonder what a macrophage woulddo if it encountered a foreign
antigen.
So just like a protein that, youknow, didn't belong in the body,
would it just gobble it up orwas there's some way that it
(29:24):
could trigger an immune responseor at least spread the
information that it hadencountered something foreign
to...
Arpita (29:31):
Yeah.
Aarati (29:32):
...the other immune cells, so that the other immune
cells were like aware that thisthing was in your body.
So she and another scientist,Joan Rhodes fed a radio labeled
large antigen protein tomacrophages.
And they were able to observethat it rapidly broke down the
antigen into smaller proteinfragments.
(29:53):
And then a few years later, apostdoc fellow, Emil Unanue
joined Dr.
Humphrey's group and startedworking on the macrophage
experiments with Ita.
And together they discoveredthat they could use macrophages
to jumpstart the immune system.
So if they gave the macrophagesan antigen, and the macrophages
(30:16):
engulfed it and degraded it andthen they took those macrophages
and put them in mice andtriggered an immune response in
the mice, the immune responsehappened a lot faster than mice
that didn't get the macrophages.
So, they were like, huh, that'sinteresting.
They published this finding, butthey didn't know how to explain
(30:36):
it.
They were just like, yeah,somehow these macrophages are
helping facilitate the immuneresponse, but we don't know how.
And so a lot of scientists werereally skeptical about this.
But a few years later, Emil wentback to Harvard.
And he really nailed down thatwhat these macrophages were
doing was they were keepingsmall parts of the antigen so
(30:58):
that they could show it to atype of immune cell called
helper T cells, which, as thename suggests, help trigger the
immune response.
Arpita (31:08):
Yeah, it's actually like kind of cute.
I feel like when macrophagesbreak stuff down and they're
just like, look what I have,like, look what I found.
Aarati (31:14):
Yeah.
Arpita (31:14):
And look what I have.
What do we do now?
Like, what do we do?
I have these little pieces.
I started to break it down, butlike, what do we do now?
Aarati (31:23):
Yeah, I saved this for you.
I thought you might find itinteresting.
Arpita (31:27):
I thought you would like it.
What do we do now?
Aarati (31:31):
I do have to say, immunology diagrams are really
cute.
Arpita (31:34):
They are real cute.
Aarati (31:35):
All the little soldiers, and all the like, little helper
T cells.
Arpita (31:39):
The little cartoons are extremely adorable, I will say.
Immunology itself, real toughfor me.
I won't lie.
But the little cartoons are cute
Aarati (31:49):
Cartoons are great.
Um, but there's another postdocthat eat a mentored Hugh
McDevitt, who figured out thatthere's a specific molecule
called the majorhistocompatibility class two
molecules on the self surface ofthe macrophage, so MHC II
molecules.
Those are on the cell surface ofthe macrophage, and that's what
(32:12):
it uses to present the antigento the helper T cells.
So it's like the little armholding out the antigen to the
helper T cells to show it tothem.
Arpita (32:23):
Or the little plate with all the little cookies on it.
Aarati (32:26):
Exactly.
Yeah, so this is like a hugebreakthrough for immunology.
Like, this is reallyfoundational work, right?
Like, we learned about MHC class2.
Arpita (32:36):
This is like all very just like Immunology 101, for
sure.
Aarati (32:41):
Exactly.
So it's very foundational workbeing done.
But Ita declined authorship onboth Emil and Hugh's papers
because she didn't think she hadcontributed enough to be an
author.
She was just like, I justmentored you and like pushed you
in the right direction.
I didn't actually do anything.
Arpita (32:57):
I have never met a PI like that in real life, but
continue.
Aarati (33:00):
But both of them have said on numerous occasions that
they would not, they would nothave figured this out without
her, like, they would not bewhere they are today without
her.
So I think because of that, alot of times, like, people don't
know about Ita Askonas You know,she just like, was like, uh, no,
don't put me on that paper.
You really did all the work.
Arpita (33:20):
I've put people on papers for less.
Aarati (33:22):
Yeah, right?
Yeah.
Arpita (33:26):
But, like, the random person who, like, sometimes
shows up in the lab every oncein a while, the fellow who,
like, isn't really part of thelab anymore, they're on the
paper.
Yeah.
Like,
Aarati (33:34):
The person who took your plate out of the incubator when
you were in a meeting, it'slike...
Yeah, but Ita just like helpedso many graduate students and
postdocs and every single one ofthem was like, she could be
really tough on you and verychallenging, but in the end the
people that she helped mentorbecame better scientists because
(33:55):
of it.
So it's like a theme throughouther life that she was just like,
this helping hand, this forcethat mentored people.
Arpita (34:02):
It's best case scenario.
Aarati (34:04):
Yep.
So while she's helping with theproject on macrophages.
She also continued to work on Bcells, and she had another
scientist, Alan Williamson, didexperiments that showed that a
single B cell will only form asingle specific type of
antibody.
So remember, there are two typesof B cells.
(34:25):
There's the memory B cells andeach memory B cell remembers one
specific pathogen, whether it'sa flu virus or a bacterial
pathogen or ovalbumin.
And so when the immune responseis triggered to the specific
thing that that memory B cellremembers, it starts to divide
and it makes more memory Bcells.
(34:46):
But it also makes plasma Bcells, which will produce
antibodies to that specificpathogen, and so because of
that, if you look at a singleplasma B cell, it only makes one
type of antibody.
So they figured that out.
Arpita (35:01):
It is kind of crazy.
And you think of how manyantigens you encounter.
It's constant.
It's like literally anything isan antigen.
Like it could be a virus.
It could be pollen.
It could be dander.
It could be anything that causesany sort of immune reaction.
Aarati (35:19):
Yeah, it could be a little bug that you inhale by
accident.
Arpita (35:22):
Exactly.
Exactly.
It could be anything.
It could be something on adoorknob.
It could be.
And so you think about truly howmany antigens we encounter and
then how many corresponding Bcells you have.
It actually is quite crazy.
And so when you think about yourwhole immune system, it like
incorporates all of these thingsin the memory of all of these
past antigens.
Aarati (35:43):
And I think that's why they had such a hard time like
isolating any specific B cellthat they wanted to study from
the lymph nodes, because thereare just so many things, you
know, that your body isprogrammed to remember.
But actually they kind ofsucceeded.
So Ita and Williamson and athird scientist, Brian Wright,
(36:04):
are also credited withdeveloping a way to clone memory
B cells in mice.
And so, this was huge because noone had been able to do that
before either in vitro or invivo, like she had been working
with the cancerous plasma cellline for that purpose.
Um, but they finally figured outa method to do it and they were
(36:25):
able to clone or create copiesof a single memory B cell.
And because they did that, theyessentially produced the first
monoclonal antibodies.
So mono means one and clonerefers to like identical cells
from a single parent And so,since the cells making the
(36:47):
antibodies are identical, theantibodies that they make are
also identical.
So.
Um, they were doing this reallyas a larger project to figure
out how long a memory B cellwould survive and divide before
dying out.
They didn't really set out tomake monoclonal antibodies, but
they're credited really withmaking the first ones kind of as
(37:08):
a byproduct.
Arpita (37:10):
Yeah.
Aarati (37:10):
But just to like provide some context for how important
monoclonal antibodies are (37:14):
a few years later, two scientists,
Cesar Milstein and George Kohlerwon the Nobel Prize for creating
an immortal cell line thatproduced monoclonal antibodies.
So I don't think she was likeinvolved in that, but they won a
Nobel Prize for basically doingwhat she had done, but just
creating an immortal cell lineof that.
(37:36):
Scientists use monoclonalantibodies to target specific
cancer cells to provide targeteddrug treatment, or they can just
be used to mark the cancer cellsso your body knows to destroy
it.
They're used in autoimmunedisorders.
Uh, they're used to test bloodand tissue compatibility for
organ donation.
They're used in diagnostictests.
(37:56):
They're used like in pregnancydiagnostics.
So like pretty much any fieldthat you can think of, we use
monoclonal antibodies.
They were used to like helpprevent coronavirus from
invading our cells..
Like everything.
Arpita (38:10):
It's everywhere.
It's very like, um, what is theword I'm looking for?
Aarati (38:16):
Ubiquitous?
Arpita (38:17):
Yes.
Yes.
Yes.
Aarati (38:23):
They are.
Arpita (38:23):
I was going to say evasive, but I think I meant
pervasive.
And then I was like, oh yes.
Ubiquitous is actually the rightword.
Aarati (38:30):
Pervasive is good too.
So, yeah.
They're credited with creating,like, kind of the first
monoclonal antibodies, which, soit's huge.
Arpita (38:40):
I did not know that.
For, like, how common monoclonalantibodies are and how much they
come up in conversations aboutliterally any kind of therapy,
disease, like, I feel like itcomes up all the time.
I definitely didn't know that itwas discovered kind of by
accident.
Not an accident, but reallyjust, like, as a, you know, this
unintentional consequence.
Aarati (38:59):
Yeah, exactly.
But yeah, in 1973, Ida was aelected to be a fellow of the
Royal Society, which as we knowis a huge honor.
She joined those two women,yeah, that she had met.
Although I think like at thispoint, she's like the 27th woman
or something to be inducted intothe Royal Society.
(39:20):
In 1976, Dr.
Humphrey left the NIMR and Itatook over as head of the
immunology division.
And at this point, Ita had spent21 years studying antibodies and
their synthesis in B cells.
And so she decides, you knowwhat, I've had enough of
studying chemical antigens.
I really want to study realimmune responses to real
(39:43):
infectious pathogens.
So she started working on twoprojects.
The first was looking at adisease called African
trypanosomiasis, which is alsoknown as sleeping sickness.
It's a lot, a lot easier to say.
It's caused by a protozoanparasite that is spread by the
(40:03):
tsetse fly and somehow thisparasite is able to evade and
inhibit the immune system.
So she was really intrigued bythat.
Eventually the person who'sinfected is unable to fight off
the disease and they fall into acoma and die.
So that's why it's calledsleeping sickness.
Arpita (40:22):
Okay.
Aarati (40:22):
Yeah.
Arpita (40:23):
That's aggressive.
Aarati (40:24):
Yeah, so Ita and her students spent years trying to
figure out like what's going onand they were able to untangle
some of it.
They were able to show likecertain things about how
macrophages that had engulfed aprotozoan went through profound
metabolic changes and you couldused that macrophage to infect
(40:45):
an otherwise healthy mouse.
And they found that like knownregulators of the immune system
were secreted during theinfection, but she didn't really
come any closer to finding a wayto reverse the immune system
suppression.
And we do have medications todaythat can kill the parasite, but
they have to be administeredbefore the parasite is able to
shut down your system.
(41:06):
So
Arpita (41:07):
Oh, so if it, if it goes past some point of no return,
you're just.
Aarati (41:11):
Yeah, I think it's like within 30 days or something I
read that you have to take themedication.
Arpita (41:17):
So how do you know you have it?
Aarati (41:19):
Oh, I think there's like a whole host of symptoms because
your immune system is tryingto...
Arpita (41:23):
it's like shutting down.
Aarati (41:24):
Yeah, fever and fatigue and like all this kind of stuff.
Yeah.
Arpita (41:28):
Okay, so then you go and you get like some test and then
they have to administer thisASAP.
Aarati (41:32):
Yeah, I think so.
Arpita (41:34):
That's crazy.
Aarati (41:36):
Yeah, so, I mean, they found out a lot about this
disease, but in her long list ofsuccesses, this was maybe the
only kind of, like, you know, wedidn't really figure out
anything groundbreaking.
Arpita (41:50):
Like, there was no, like, cure, basically.
Aarati (41:53):
Yeah, her other project, though, was on the influenza
virus, and this, again, wasgroundbreaking work in
immunology.
So, she started studying yetanother type of white blood cell
called cytotoxic toxic T cells,which we affectionately know as
killer T cells.
Arpita (42:09):
Killer T cells.
Aarati (42:10):
Yes.
So, Yeah, if you break down theword cytotoxic, it literally
means toxic to cells.
And that's what T cells do.
They find a cell that's aforeign invader or cancerous
cell or a cell that's beeninfected with a virus and it
kills it before it can replicateand become an issue.
But what Ita and her studentsdiscovered was that, T cells
(42:34):
aren't like B cells in that theydon't go after one specific type
of virus or antigen.
The same T cell could recognizeand kill multiple different
types of influenza strains.
And so it's not a total free forall, there are like some rules,
like there's two categories ofinfluenza, A and B, and within
those categories there's a bunchof different strains, but one
(42:56):
cytotoxic T cell could recognizeall the strains in influenza A,
for example.
And one of her students, AlaineTownsend, managed to clone
cytotoxic T cells, which againwas the first time anyone's been
able to do that.
And she and Alaine were able toshow that the T cells weren't
actually recognizing theinfected cell, they were
(43:19):
actually recognizing The viralprotein itself.
And that was weird to thembecause they were like, how can
a T cell detect a virus that'sinside of a body cell?
Like you would think thatthey're detecting something on,
maybe on the cell surface.
Yeah.
Um, so Alain finished up his PhDand moved to Oxford where he
(43:43):
kept on working on this.
And he went on to show that.
Cells that are infected with avirus can grab a small fragment
of the viral protein from insidethemselves and present it on
their cell surface using, again,a major histocompatibility
complex molecule.
It's MHC 1 this time.
(44:03):
So once again, presenting thislike, Hey, look, there's this
thing inside me.
And so the cytotoxic T cell seesa cell presenting a viral
protein fragment on its cellsurface with the MHC 1 molecule,
and that's how it knows to killit.
And again, figuring out how Tcells worked was huge and is
foundational to how we makevaccines against these kinds of
(44:26):
viral infections.
So, another huge contribution toimmunology, but once again, Ita
declined authorship on thispaper because she felt like she
hadn't actually, like, doneanything.
She was just like, no, it's allyou.
You did everything, Alain.
Arpita (44:40):
That's nuts.
Aarati (44:41):
Yeah.
Yeah.
So this is something likeeveryone said about Ida.
She was extremely humble, neverbragged about her
accomplishments.
And in fact, Dame BridgetOgilvie, her friend, said that
even though Ida was extremelyclose to her family, since she
didn't talk about her work much,none of them really understood,
like, what a giant in her fieldshe was.
Arpita (45:04):
Mm.
Aarati (45:04):
And In fact, they kind of seem to be like,"Aw, you're a
scientist.
Like we love that for you.
I mean, good job.
And they're like, you're notlike your cousin, Peter, who
like founded a music and artagency.
Like he's amazing.
Uh, we can barely even trust youto cook dinner." And Ita's just
like, yep.
"I hate cooking.
(45:24):
I'll do the dishes." And shedidn't say like a single word
about her work or what she wasdoing.
Arpita (45:30):
Couldn't be me.
I...
Aarati (45:31):
yeah.
Arpita (45:31):
Couldn't be me.
I think I'm too annoying.
Aarati (45:34):
You worked hard for it, though.
Like, come on, you deserverespect.
But her friend Bridget wouldjokingly say that actually Ita
was being very clever bylowering her family's
expectations of her so she couldjust duck out of certain chores
and responsibilities, which Iwas like
Arpita (45:50):
That's smart.
Yeah.
She's, she's living in, youknow, 2038 for sure.
She's really just,
Aarati (45:57):
She's playing chess.
We're all playing checkers.
Arpita (46:00):
Yeah, exactly.
Aarati (46:02):
Yeah.
So Ita retired in the late1980s, but she stayed active in
the field discussing science andencouraging new students to
pursue immunology.
In 2007, Ida was elected to be aforeign associate of the U.
S.
National Academy of Sciences,and she was awarded the Robert
Koch Medal for her lifelongcontributions to immunology.
(46:26):
And in 2012, she received anhonorary doctorate from
Cambridge, which she was veryproud of.
Arpita (46:33):
That's amazing.
Wow, she lived a really longtime, wasn't she born in 1923?
Aarati (46:39):
Yes.
Arpita (46:39):
19-
Aarati (46:40):
Yeah.
Arpita (46:40):
Yeah.
Wow.
Aarati (46:41):
Yeah.
The following year, in 1913, shedid pass away at the age of 89.
Arpita (46:47):
Wow.
Aarati (46:48):
Uh, she never got...
yeah.
Like, she lived a long life, andshe was very active during it.
She never got married or had anychildren, but the reason I think
she really deserves the title ofthe mother of immunology is just
the sheer number of people thatshe mentored and supported who
then went on to make suchamazing contributions.
Arpita (47:07):
Their own contributions.
Yeah, exactly.
That is, I know that was likenoticing that as you were
telling the story too, like shewas like, there was a postdoc
and there was a mentor and therewas this PhD student and there
was another PhD student andthere was another institution
and another person.
And so it's actually really,really crazy how many people
there were.
Aarati (47:22):
Yeah.
Arpita (47:23):
And like sometimes people in science will talk
about like your family tree.
Like your scientific family treeand like I feel like having her
in your scientific family treewas probably like A) just clout
but then B) like I'm sure yougot so much guidance and shaping
for how you think aboutquestions and experiments and
roadblocks and I'm sure thatmust have been really
(47:43):
influential.
Aarati (47:44):
Yeah, and, like, the ones that I mentioned in the
story is just, like, barelyscraping the surface of the
iceberg.
Like, I was reading her, like,obituary and, like, her
biography, and in some placesthere was just, like, a list of
names.
It's like, she mentored thisperson, and this person, and
this person, and this person,and this person.
I'm just like, oh, my God.
It's like
Arpita (48:03):
Yeah, and you think about, too, like, I feel like
immunology is kind of in itsheyday, like with how many
therapies and new drugs arebeing produced that are either
using like monoclonal antibodiesor, you know, working against
all of these different diseases,including, you know, um,
autoimmune diseases is what I'mtrying to say, and I feel like
(48:26):
there's, there's so many coolbreakthroughs there.
And so like, just likeunderstanding the foundations of
immunology, just knowing howmany more people have been
working on it and like, alsoknowing that we're truly like
kind of in a heyday ofimmunotherapy is really cool.
Aarati (48:41):
Yeah.
And I was just like, also verysurprised by just how she was
just all over everything.
She was like over plasma B cellsand antibodies and cytotoxic T
cells and macrophages.
It was like, there was no partof the immune system that she
didn't touch, I felt like so Iwas just really surprised.
Arpita (49:01):
And there's a lot.
Aarati (49:02):
Yeah, there's so much like on one hand, I was really
surprised that she doesn't getmore recognition.
But on the other hand, it doesseem like she declined a lot of
recognition, you know,
Arpita (49:12):
Interesting choice.
But yeah, yeah.
Aarati (49:14):
Yeah.
She was just like, no, I don'tneed it.
So yeah, that's her story.
I really enjoyed like readingabout it.
I feel like.
I learned a lot more aboutimmunology than I knew before.
Arpita (49:26):
Honestly, same.
And I feel like I sort of camein with the baseline level of
understanding, and I still did.
Like, I definitely didn't knowthe thing about the monoclonal
antibodies, which is really,really cool.
Aarati (49:36):
Yeah.
Arpita (49:37):
Great story.
I loved it.
Aarati (49:38):
Thank you.
Arpita (49:39):
We love a little girl power.
Aarati (49:41):
Yes.
We need it.
Arpita (49:43):
We do need it.
Aarati (49:43):
We always need it.
Arpita (49:48):
Thanks for listening.
If you have a suggestion for astory we should cover or
thoughts you want to share aboutan episode, reach out to us at
smartteapodcast.
com.
You can follow us on Instagramand Twitter@smartteapodcast and
listen to us on Spotify, ApplePodcasts, and or wherever you
get your podcasts.
And leave us a rating orcomment.
It really helps us grow.
Special thanks to our editor,James Fixx.
(50:09):
New episodes are released everyother Wednesday.
See you next time!
Hi everyone, and welcome back to the Smart Tea Podcast,
where we talk about the lives ofscientists and innovators who
shape the world.
How are you doing, Aarati?
Aarati (00:19):
I'm doing pretty well, Arpita.
How are you?
Arpita (00:23):
I'm okay.
I feel like we're having somecozy vibes with the weather
right now.
Aarati (00:27):
Yeah.
Arpita (00:28):
It's been just like nonstop rain, and so we have
candles going, we have theheater running, and it feels
like kind of cozy vibes.
Yeah.
What about you guys?
Aarati (00:37):
Yeah, same.
I feel like fall really snuck upon me for some reason.
I don't know why, but I'm justlike, why am I so cold?
All right, it's not summeranymore.
I should probably pull out myheavy jacket and my heavy
sweaters.
And for some reason in my mind,I'm really resisting that.
And then I regret it
Arpita (00:56):
Well, you like the warm weather.
Aarati (00:57):
I do like the warm weather.
And I think part of me is indenial that it's over.
And I'm like, that wasn'tenough.
Where's, you know, where's myother 90 degree days.
Arpita (01:08):
Last year, Logan bought a bunch of like, honestly, just
like kind of a little biggerthan a piece of paper heating
pads that are electric.
Aarati (01:16):
Oh my gosh.
Arpita (01:17):
That sometimes people will use for like back pain or
cramps.
Yeah.
And.
We now have three.
One is on my desk chair, so Isit on it, and then we have one
on the couch that the cats siton, but it's honestly so great.
It's kind of like, you know,when you get into your car and
you have heated seats?
Aarati (01:32):
Yes.
Arpita (01:32):
It's like that, but like in your desk chair or like on
the couch, which is...
Aarati (01:36):
Oh my god.
Arpita (01:37):
...perfect, because then you put a blanket over it and
now you've just created thisincubator and you're just
roasting on the couch and itfeels amazing.
So, maybe that'll be yourChristmas present, Aarati.
I'll just Amazon you a heatingpad and you can sit on it for
all of winter.
Aarati (01:53):
Yes, I have a huge, like, hoodie blanket that I use,
like, Like a Snuggie, but like,it's not, it's a knockoff
Snuggie, I guess.
Yeah,
Arpita (02:02):
Like off brand Snuggie.
Aarati (02:03):
Yeah, like from Amazon.
And I just live in that thing.
It's, it's just so amazing.
It keeps me so warm and I'm sohappy in it.
But yeah, this weekend I went tolike a water lantern festival
that was outside and they had towait until it got dark so that
you could see the lit uplanterns on the water and I was
(02:24):
not dressed appropriately.
I was so cold.
I was wearing my sweater, butlike, you know, I was, I was
freezing and I was like, the sunhas set.
The sun has set.
Let's do this and get out ofhere.
I'm so cold.
And I was like, yeah, I reallyneed to just like come to terms
with the fact that it's notfall.
It's winter.
Arpita (02:43):
Does Kyro keep you warm?
Aarati (02:44):
No, he's not a snuggle.
He's not a snuggly dog.
Arpita (02:47):
Oh yeah, he's not a snuggly dog.
Aarati (02:48):
He'll put up with it.
Like, I'll hug him and he'll belike, okay, fine.
But he's very happy in his ownbed and I'm like, okay.
I see how it is.
Arpita (02:56):
The utility is not there for sure.
Aarati (02:58):
Yeah.
And he's also like, he doesn'tlike having blankets on him
either.
Like, I've felt so cold beforeand I'm like, Oh my gosh, Kyro
must be feeling so cold.
Let me put a blanket on him.
And he's like, why have you donethis to me?
And he like crawls out of it assoon as I am not looking.
He's like, okay, enough of that.
Arpita (03:18):
I feel like that's like, probably the shepherd, you know,
he's just like, no, he's like,yeah, this is not, I don't need
this.
Aarati (03:24):
I mean, he does have a fur coat at all times, so I
guess..
Arpita (03:27):
It's true, but yeah.
Well, let's have a little cozystory.
Shall we?
Aarati (03:33):
Yes.
Arpita (03:34):
Who are we talking about today?
Aarati (03:35):
You know, I'm still not really over the election.
And so I felt like I just neededa little bit of girl power.
Arpita (03:42):
Nice.
Aarati (03:42):
Yeah, so today we are going to be talking about
Brigitte Askonas.
And she basically is the motherof immunology.
And she really earns that title.
She's just crazy smart and justbasically everything we know,
like the foundations ofimmunology, it's thanks to her.
Arpita (04:05):
That's amazing.
Okay, I'm super excited to hear.
Aarati (04:08):
Yeah, this is a little scary for me because I feel like
I have a mental block when itcomes to immunology for some
reason.
Arpita (04:14):
Don't we all a little bit though?
Like I see the T cells and I seethe B cells, the cytokines.
I'm just like...
Aarati (04:21):
Like what is happening?
Why are there so many cellsinvolved in keeping us safe and
healthy?
Yeah, but she was all over it.
She was all over it.
So I'm going to do my best andreally try to explain the immune
system So Brigitte, who went byIta, was born in Vienna, Austria
(04:42):
on April 1st, 1923.
Her parents, Carl, Frederick,and Rose, immigrated to Vienna
from Czechoslovakia.
And they were part of aprominent Jewish community
there.
There isn't a ton of informationabout Ita's childhood.
We know that she had an olderbrother, Fred, and her father
and uncle owned a chain ofknitting mills across Europe.
(05:05):
And her mother had studied fineart, and she passed down her
love of art and music to Ita.
So it sounds like the family waspretty well off in general if
they owned this, you know, chainof knitting mills.
The mothers into fine art, theybuilt up a collection of art as
well, and both parents were verysupportive of their children.
So it just kind of sounds like avery happy childhood.
Arpita (05:27):
Uh huh.
Aarati (05:29):
However, when Ita was 15, Austria was annexed by
Germany just before World WarII, and so Ida and her family
had to flee, and they had toleave behind their house and
most of their art collection.
They hopped around Europe for abit, and then they fled to New
York, but they didn't have avisa to stay in the U.
(05:49):
S., so they ended up settling inCanada in 1940.
And so by this time, Ita is 17.
So she's starting to think aboutcollege and, um, what she wants
to do in life, but she wasn'treally drawn to any one field of
study because her mom was likeinto art and music.
(06:09):
And she loved that.
She loved languages.
She loved literature.
She liked nature.
She liked biology, but shewasn't really like sure what she
wanted to major in.
So she spent 2 years atWellesley College in
Massachusetts beforetransferring to McGill
University.
Arpita (06:27):
Oh nice.
Aarati (06:27):
And even at McGill she kind of spent some time
undecided about what she wantedto study.
Until she started taking classesfrom a biochemistry professor,
who was also the Dean ofScience, Dr.
David Thompson.
And Ita thought he was, quote,"The most brilliant lecturer
I've ever heard speak with amarvelous sense of humor."
Arpita (06:47):
Oh, love that.
Aarati (06:48):
Yeah.
And so solely because of hisinfluence, she decided to pursue
her degree in biochemistry.
Arpita (06:55):
Honestly, I can't relate.
I had a terrible biochemistryteacher in college.
Aarati (06:59):
Yeah.
Arpita (07:00):
Cannot relate.
That class was so hard for me.
And then I did take organicchemistry also for like a short
bit there.
And I was like, get me out ofhere.
That was actually, no, I almostfailed two classes in college.
One was organic chemistry 2.
Then the other was physics.
It was like optics and waves.
Aarati (07:20):
Oh, yeah.
Arpita (07:21):
Like there's like kinematics.
There's like, whatever.
There's like different likesection.
It was like the optics andweight.
Those were the two classes Ialmost failed in college.
Aarati (07:28):
Yeah.
Organic chemistry.
Man, that's, that's like theclass that, you know, everyone
drops out and it's like, I canno longer be a science major.
Organic chemistry is crazy.
Arpita (07:39):
I feel like they did it on purpose.
Like, they must have done it onpurpose.
Like, I think about it now andlike, sometimes it'll like, pop
up, you know, every now andthen, like principles of organic
chemistry.
But I'm like, this makes a lotof sense.
Like, I feel like if someone hadexplained it to me properly, I
would have been fine with it.
But there's also this, like,intimidation factor around it.
Aarati (07:56):
Yes.
Arpita (07:56):
And I feel like the tests were, like, unnecessarily
hard on purpose.
Aarati (07:59):
Yeah.
They definitely made it harderthan it needed to be.
Yeah.
Arpita (08:02):
They made it way harder than it needed to be.
I feel like it was actually notthat bad.
Aarati (08:06):
Yeah, no, it wasn't.
Like I remember, I was taking anorganic chemistry class once and
I was studying for an exam withmy friend and so I was reading
the textbook like tryingdesperately to understand what
was going on.
Arpita (08:19):
That's when you know, it's bad, but yeah.
Aarati (08:20):
Yeah.
And she's like memorizingwhatever was taught to us and
and they had given us some likecrazy mnemonic device that had
15 exceptions to the rule, youknow, and she was like trying to
memorize all those exceptions.
And I was just like, you know,I'm, I'm not good at that.
I'm not good at memorizingthings.
And so I was like trying tounderstand like what's going on.
(08:41):
I read the textbook and it tookme a while, but I finally
understood what the textbook wassaying.
And I'm like, Oh my God, if youjust go through like these five
steps and you answer these fivequestions about the reaction
that you're studying, you getthe answer right every single
time.
There are no exceptions.
Like this is how it worksbecause that's how nature works.
Because...
Arpita (09:00):
Rather than like going the long way around.
Yeah.
Aarati (09:03):
And creating some weird mnemonic devices that has 15
exceptions, why don't you justteach us how it actually works?
Yeah.
And I was just like, Oh, thismakes so much more sense.
But then I told my friend aboutit, who I was studying with.
And she was like, I'm just goingto memorize it.
And I'm just like, why though?
This is so much easier.
And it makes so much more sense.
(09:24):
Yeah, but I don't know whatthey're doing with, with O chem,
but I actually majored inbiochemistry because my dad was
a biochemistry major also and Iwas just like, I'll just do that
and then I'm like, what have Igotten myself into?
Oh no! But Ita decided to pursueher degree in biochemistry.
And after five years at McGill,she graduated with a masters.
(09:47):
So at the time she graduated.
There was another professor, Dr.
Karl Stern, who had just beenappointed to the Allen Memorial
Institute of Psychiatry and wasconducting job interviews
looking for someone inbiochemistry to join his lab.
So Ita went to this interviewand that was being held in Dean
Thompson's office.
(10:08):
And during the interview, shestarts laughing uncontrollably
at a cartoon that Dean Thomashad on his wall.
The cartoon was by this guynamed James Thurber, and it
showed a psychiatrist that wassitting at his desk, but instead
of a normal human head, thepsychiatrist had a rabbit's head
and there's a woman sittingacross from him and the
(10:30):
psychiatrist rabbit guy issaying,"You said a moment ago
that everybody you look at seemsto be a rabbit.
Now what did you mean by that,Mrs.
Sprague?" And apparently Itafound this so hilarious.
That she couldn't stop laughing.
I didn't get it either.
I was just like, I looked at thecartoon, like, I looked it up
and I'm just like, what?
(10:52):
I'm like, maybe this is like1940s humor or something.
Arpita (10:56):
Like, he's supposed to, like, he is a rabbit and he's
saying, you think everyone lookslike a rabbit?
So he's, like, she's nothallucinating.
It's real.
Aarati (11:05):
Or maybe she is hallucinating, and we're seeing
her perspective, and it's likeliterally everyone's a rabbit?
I don't know.
I didn't understand it either,but she found it hilarious.
She was just like
Arpita (11:17):
And then also started laughing during an interview.
Aarati (11:19):
During an interview, she was like laughing so hard, she
couldn't stop laughing at thiscartoon.
Arpita (11:24):
Interesting tactic, but okay.
Aarati (11:26):
Yeah, but it worked.
Dr.
Stern was like, I like yoursense of humor, I will hire you.
And so, I mean, that's how Itatells the story of how she got
her first job.
But, you know, I'm sure Dr.
Stern was very impressed withher knowledge and passion for
science and her, like, you know,biochemistry acumen.
Arpita (11:46):
Speaking of sense of humor, I one time during a grad
school interview had someonestraight up ask me, tell me a
joke.
And I was like, what?
Aarati (11:55):
What?
Arpita (11:56):
Yeah,
Aarati (11:57):
That's so random.
Arpita (11:59):
Isn't that terrifying?
And then like also, I was like21 or 22, you know, like I was,
Aarati (12:05):
oh my God.
Arpita (12:05):
Like already petrified to be in this room, you know?
Like, I was like, I shouldn't bein this room to begin with.
Aarati (12:10):
Yeah.
Arpita (12:10):
Like I'm already feeling horrendous things.
And I was just like, how do youwant me to answer that question?
Aarati (12:18):
Yeah.
Did you tell them a joke?
Arpita (12:20):
I don't even remember what I said.
I honestly, I think I blackedout.
I don't even know what I said.
But I have, now I have two backpocket jokes.
Aarati (12:29):
Are they science jokes?
No, not really.
Arpita (12:35):
One is inappropriate and one is very G rated.
Aarati (12:38):
Okay.
Arpita (12:39):
So, you know, it's audience specific.
Aarati (12:41):
Yes, it depends on who you're talking to.
That's a good tactic though.
Arpita (12:45):
Thank you.
Aarati (12:46):
So, yeah, so she got this job and she starts working
on the biochemistry of dementiawith Dr.
Stern.
Dr.
Stern thought there must be somechemical imbalances in the brain
that were leading to dementia,but since it's the 1940s, they
didn't really have good enoughtools to properly test these
theories.
And pretty soon, Ita alsorealized that her master's
(13:09):
degree just wasn't gonna cut itin addition to not having the
tools to study dementia, shejust didn't have enough training
in science.
And so if she wanted to work asa scientist, she needed more
education.
So she talked to Dean Thompsonabout it.
And he helped her get into theSchool of Biochemistry at
Cambridge to do her PhD.
(13:30):
Uh, she had a wonderful time atCambridge.
Here she met two scientists,Drs.
Margaret Stephenson and DorothyNeedham, who were some of the
very first women to be electedinto the Royal Society, which
was very encouraging to Ita as ayoung woman scientist.
Arpita (13:45):
That's super cool.
I was gonna say two women.
That's really like, I guess, notexpected.
Aarati (13:52):
Yeah.
She said they made her realizethat quote,"Good science gets
recognition regardless of thesex of the scientist." End
quote, which I thought was verynice.
Arpita (14:00):
I feel like we've maybe had some episodes to the
contrary, but...
Aarati (14:04):
Yes, I was thinking of Svetlana Mosjov.
Yeah, I was.
Yes, I was thinking of her.
Arpita (14:10):
I do appreciate the sentiment.
I do.
But yes.
Aarati (14:12):
Yeah.
I'm glad that that was hertakeaway and that she was
inspired.
Arpita (14:17):
Agree.
Aarati (14:18):
Uh, her PhD supervisor was Dr.
Malcolm Dixon and Ita reallyappreciated him because he
basically gave her a project andlet her go at it and let her
figure it out herself.
And that really gave her theconfidence to believe that she
could pursue independentresearch.
So after completing her PhD, shegot a staff position at the
(14:38):
National Institute for MedicalResearch or NIMR in Mill Hill,
London, studying proteinsynthesis.
And the question Ita was reallyinterested in was whether
proteins were translated fromRNA in one long continuous
strand or whether multiple smallsegments were translated and
then they all came togetherafterwards.
Arpita (15:00):
Mm-hmm.
Aarati (15:00):
Because remember, like we don't really know, this is
like basic biology.
We don't know the answer to thisvery basic question.
Um, and so to look at this, theywere working with lactating
goats and studying their milkproteins.
Arpita (15:16):
Interesting.
Okay.
Aarati (15:17):
Yeah.
So Ita would give the goatsshort pulses of radio labeled
amino acids, which are thebuilding blocks for proteins.
And then she would collect themilk, purify the milk protein
that she was studying, which wascalled lactoglobulin.
And the theory was that if shehad seen certain segments of the
protein were made withradiolabeled amino acids and
(15:40):
other segments were not, thenthat would have indicated that
the proteins were translated insmall pieces and then came
together into a long chainlater.
But that's not what she saw.
Instead, she observed that thewhole lactoglobulin protein was
made with radiolabeled aminoacids, so that meant that the
proteins were being translatedrapidly in one long, continuous
(16:01):
piece.
Arpita (16:01):
One long chunk.
Aarati (16:02):
Yeah.
Arpita (16:02):
Yeah.
Aarati (16:03):
And this was later confirmed, in, various other
ways by other scientists.
And ultimately we got the doublehelix model of DNA, which, you
know, that all fit together.
So that was a successfulproject, but Ita had a few
issues.
One was that she really didn'tlike working with the goats.
Especially there was one namedUrsula who she found nearly
(16:26):
impossible to catch and milk.
Arpita (16:28):
Okay.
What are all of these modelorganisms?
Like, I'm just like, what ishappening?
Like, there's just like.
Whatever animal they could gettheir hands on, like, I just
feel like this range of modelorganisms that we've discussed,
I don't even know, this doesn'teven count as a model organism,
but like.
Aarati (16:42):
Yeah, I don't know why goats.
I don't know what they weredoing, but...
Arpita (16:45):
Like, why was it goat milk, like lactating goats,
like,
Aarati (16:49):
I don't know.
I have no idea.
Arpita (16:51):
Why are we milking goats?
There's no other way to findprotein?
Aarati (16:56):
Yeah.
So that was her problem exactly.
She was just like, why are, whyam I, these, these goats are so
annoying.
They don't wanna be milked.
I have to chase them around thepen and I have to like try and
catch them.
And they're so like...
ugh, irritating.
And I actually watched thisYouTube video where one of Ita's
friends was talking about herand she said that Ita was a big
(17:17):
fan of flora but not of fauna.
She really didn't like dogs,cats, babies.
Arpita (17:23):
I was about to be like, relatable, but then I was like,
wait, wait, wait, wait, wait,wait.
Aarati (17:26):
No, no, no.
She just didn't like anyanimals.
Arpita (17:29):
What I don't like is animals in the lab.
Aarati (17:31):
Yes.
Yeah.
Arpita (17:32):
Yeah.
Aarati (17:32):
Like she just didn't like animals in general, so this
was probably even worse for her.
Arpita (17:36):
Yeah.
Okay.
Yeah.
Aarati (17:37):
But the second problem was that purifying lactoglobulin
or really any milk protein wasdifficult because milk contains
something called casein.
And we talked about this brieflyin the Wilbur Scoville episode
about how when you eat somethingspicy, drinking dairy products
is a great remedy because itcontains casein, which is a
really sticky molecule and itwill surround the capsaicin and
(18:01):
wash it away.
But because it's so sticky, Itahad a really hard time getting
rid of it in order to study thelactoglobulin.
Arpita (18:07):
To purify it.
Yeah, that makes sense.
Aarati (18:10):
So Ita, like you said, was like, there has to be a
better way to study proteinsynthesis than chasing around
goats and crystallizing tinyamounts of protein.
Arpita (18:19):
Hard agree.
Aarati (18:20):
So around this time, she attended a lecture at the NIMR
given by an immunologist, Dr.
John Humphrey.
And his lecture was aboutantibodies, which Ita knew
nothing about at all.
So, I know you know this,Arpita, but maybe just for our
listeners who kind of needsomething to form an image in
(18:40):
their head like I do, um,Antibodies are proteins that are
shaped kind of like the letterY, and that top part of the Y
can detect and bind to otherproteins called antigens.
And antibodies are naturallyprogrammed to detect foreign
invaders like viruses orbacteria that do not belong in
our bodies.
(19:00):
And once they detect somethinglike that, they can trigger an
immune response, which basicallytells our body to destroy that
invader.
So Dr.
John Humphrey was giving hislecture and he gave a
demonstration of how thisworked.
He had two clear solutions.
One was a solution of purifiedantibodies, which are the Y
shaped proteins.
(19:21):
And one was the antigen, whichis what the antibodies detect
and bind to.
And when he mixed the twosolutions together, all of the
antibodies glommed onto theantigens and formed a
precipitate that settled to thebottom of the mixture.
Arpita (19:36):
That's cool.
Aarati (19:37):
And so when Ita saw this, she's like, that's
brilliant.
That's such an elegant answer tomy protein purification problem
because that precipitate that'sforming in Dr.
Humphrey's flask is mostlyantibody.
So, if she studied proteinsynthesis using antibodies
instead of lactoglobulin, firstof all, she could use any small
(19:58):
animal.
She didn't have to use goats.
She could use rabbits or micethat she didn't have to chase
all over the place.
And instead of collecting milk,she could instead trigger an
immune response so that theanimal created antibodies and
then she would just have tocollect some blood or some serum
and then use that same methodthat Dr.
Humphrey just used toprecipitate out the antibodies
(20:20):
and then you've got pretty muchpurified antibody protein that
she could study.
Arpita (20:25):
Oh, interesting.
I see.
So her protein of choice is nowjust antibodies.
Aarati (20:30):
Yeah, exactly.
Arpita (20:31):
Got it.
And like a particular antibodyor she's just casting a wide net
here?
Aarati (20:36):
Um, at this point, not yet.
Arpita (20:38):
Okay.
Aarati (20:38):
I mean, actually throughout her life she kind of
hops around differentantibodies, but right now she's
just like, what antibody canI...
Arpita (20:45):
yeah.
Aarati (20:45):
Use to study protein synthesis and antibody
synthesis.
Yeah.
So she ran this idea by Dr.
Humphrey and he was all for it.
He's like, I'll help you howeverI can.
So, Ita asked him, well, since Iwant to study antibody
synthesis, it would be reallyhelpful to know which tissue or
organ they're made in.
Arpita (21:04):
Right.
Aarati (21:04):
And, Dr.
Humphrey's like, well, that's agreat question.
Um, the antibodies aredefinitely made in a type of
white blood cell called plasmacells.
And they didn't have the namefor it at the time, but today we
call them plasma B cells.
Um, But as for which tissuethey're made in, he didn't know.
And so Ita's like, great, let'sstart there.
Arpita (21:27):
Yeah.
Aarati (21:27):
So Ita and another scientist Bob White start using
guinea pigs to systematicallyfigure out which tissue the
antibodies are coming from.
They would inject the guinea pigwith ovalbumin, which is a
protein found in egg whites.
And actually, if you have an eggallergy, you're probably
allergic to ovalbumin.
Arpita (21:47):
Yeah I,, I'm not allergic to this, but I, I do, I
did know that because that'swhen you get the flu shot.
They always ask you if you havean egg allergy.
Yeah,
Aarati (21:54):
We learn about that in like bio and biochemistry
because it's a really easyprotein or it's, it's really
easy to purify.
And so it's a very commonantigen that's used to create an
immune response in lab animalsall the time so that scientists
can study the immune system.
It's like very common.
Arpita (22:10):
Yeah.
And in vaccine development,which is why they ask you that.
Aarati (22:14):
Yeah, that's why they ask you.
Exactly.
So she uses ovalbumin to triggeran immune response and then
collected a tissue sample fromwhatever tissue they thought
might be producing theantibodies.
She chopped up the tissue, addedradiolabeled amino acids and
then collected the antibodies,which if they were being made in
that tissue would now beradiolabeled and she could
(22:37):
detect that.
So if they thought like, hey,maybe the antibodies are being
made in the liver, they choppedit up, added radio labeled amino
acids, and then look to see ifany radio labeled antibodies
were made.
And in the case of the liver,not many radio labeled
antibodies were detected,indicating that they're not
being made there.
The tissues where she did findthe highest amount of radio
(22:58):
labeled antibodies were in thelymph nodes, bone marrow, and in
the lungs.
Arpita (23:04):
Oh, the lungs.
Interesting.
Aarati (23:05):
Yeah.
But they also discoveredsomething called the bystander
effect, which is that it wasn'tjust antibodies that was
specific to ovalbumin beingformed, but generic antibodies
as well.
And that was pretty surprisingto them at the time.
But now we know that when theimmune system is highly
activated, non specificantibodies are created to help
(23:25):
drive the overall immuneresponse.
So that's kind of what washappening there.
Arpita (23:29):
Right.
Aarati (23:30):
And I think that maybe explains why they were seeing
antibody synthesis in the lungs.
Cuz that's...
Arpita (23:36):
That is interesting.
I did not know that.
Lymph and bone marrow make a lotof sense.
That's what we typically thinkof as like, kind of like hubs
for the immune system, butinteresting about the lungs.
Aarati (23:50):
Yeah, so under Dr.
Humphrey, Ita is really makingsome huge contributions to the
field of immunology already.
In 1957, a new immunologydivision was created at NIMR,
and Dr.
Humphrey was asked to lead it.
And so Ita joined him, and they,along with a core group of
scientists, became really thefounding team for this division.
(24:13):
But Ita's still not happy aboutthe fact that she has to do
these experiments in animalsbecause she couldn't isolate the
specific cells that created theantibodies to ovalbumin and then
create a cell line from them.
So she couldn't study this invitro, or in a petri dish.
And that's because the lymphnodes contain a whole bunch of
(24:34):
different cells, So the cellsthat Ita is interested in are
the B cells.
And there are two types of Bcells.
There's the plasma B cells,which I mentioned are the ones
that make and secrete theantibodies, and there are memory
B cells that can live for yearsjust hanging out, and their job
is to remember a specificpathogen and trigger an immune
(24:56):
response if it ever enters yourbody.
So, there will be a memory Bcell for ovalbumin, which was
what Ita was triggering to startmultiplying and create a bunch
of plasma B cells, which wouldthen create the ovalbumin
specific antibodies.
But there are also other memoryB cells for like flu virus or
(25:17):
bacterial pathogens that wouldall just kind of be hanging out
together in the lymph node.
And so if you only wanted tocollect the B cells that are
responsible for creating, like,one type of antibody, it's
really hard to separate.
them out from the lymph nodefrom all the other cells.
Arpita (25:32):
Like if you're doing this in the animal, in vivo,
that's really hard to do.
Yeah, that makes sense.
Aarati (25:36):
And then if you wanted to take those cells and put them
like in a petri dish and thenkind of create a line that you
could study and just take theseexperiments out of animals and
not have to deal with animals atall, it's really hard to do
that.
Fortunately, around this time atthe NIH, A group led by Dr.
Mike Potter had discovered acancerous cell line in which the
(25:58):
plasma cells were secretingantibodies out of control.
So cancerous, right?
Arpita (26:03):
Wow.
Okay, great.
Love that serendipity.
Aarati (26:06):
Yes, exactly.
And so these plasma cells wouldproduce antibodies, both in
vivo, in mice, and in vitro.
Arpita (26:15):
Oh, great.
Aarati (26:16):
Yeah.
Ita's like, perfect.
Exactly what I needed.
Yeah.
That's what I need to studyantibody synthesis and how these
proteins are being synthesized.
That's great.
And this became a reallyvaluable tool for her for
studying antibody formation.
And I'm not.
going to go super into detailabout all of her experiments
here, but once Dr.
Potter sent them the cell line,Eda was really able to pin down
(26:40):
like some of the nitty grittydetails as to what parts of the
antibodies were formed first andhow the different parts of the
antibodies come together to formthat Y structure.
So she really like nailed downantibody synthesis.
Arpita (26:54):
That's super cool.
Aarati (27:00):
Hi everyone.
Aarati here.
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If so, and you wish someonewould tell your science story, I
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Okay back to the story.
(27:44):
So now Ita's been working onprotein synthesis and
particularly antibody synthesisfor nearly a decade.
She decides to take a bit of astep back and revisit her
biochemistry roots.
So from 1961 to 62, she did asabbatical at Harvard Medical
School, and here she wasreminded about our good friend,
(28:04):
Elie Metchnikoff, who youcovered in Episode 6.
At this point, it's been about ahundred years since he
discovered macrophages, andpeople knew that macrophages
were another type of white bloodcells that were different from
plasma B cells but still relatedto the immune system because
(28:25):
they went around engulfing anddegrading foreign invaders in
the body.
Arpita (28:29):
I also feel like macrophages are conceptually
just so easy to understand.
Like you very much think aboutthem as like Pac- man, you know?
Like it just makes a lot ofsense that you have something
that's just like eating trash.
Aarati (28:40):
Yes.
Arpita (28:41):
And it really is not that much more complicated than
that.
Like that is really the scienceis that it's just kind of
engulfing things and thendegrading them.
Aarati (28:49):
Yes.
Arpita (28:50):
I feel like once you start getting into antibodies
and the rest of immunology, likeeverything hits the fan.
But...
Aarati (28:57):
Yeah, yeah, no, macrophages are simple.
Arpita (29:00):
Macrophages we can do.
We can do macrophages.
Aarati (29:02):
Yeah.
So that's what people knew.
They're like, macrophages goaround and if it runs into like
a foreign bacterial cell orvirus, it'll eat it and degrade
it.
And so Ita was like, huh, goodpoint.
I wonder what a macrophage woulddo if it encountered a foreign
antigen.
So just like a protein that, youknow, didn't belong in the body,
would it just gobble it up orwas there's some way that it
(29:24):
could trigger an immune responseor at least spread the
information that it hadencountered something foreign
to...
Arpita (29:31):
Yeah.
Aarati (29:32):
...the other immune cells, so that the other immune
cells were like aware that thisthing was in your body.
So she and another scientist,Joan Rhodes fed a radio labeled
large antigen protein tomacrophages.
And they were able to observethat it rapidly broke down the
antigen into smaller proteinfragments.
(29:53):
And then a few years later, apostdoc fellow, Emil Unanue
joined Dr.
Humphrey's group and startedworking on the macrophage
experiments with Ita.
And together they discoveredthat they could use macrophages
to jumpstart the immune system.
So if they gave the macrophagesan antigen, and the macrophages
(30:16):
engulfed it and degraded it andthen they took those macrophages
and put them in mice andtriggered an immune response in
the mice, the immune responsehappened a lot faster than mice
that didn't get the macrophages.
So, they were like, huh, that'sinteresting.
They published this finding, butthey didn't know how to explain
(30:36):
it.
They were just like, yeah,somehow these macrophages are
helping facilitate the immuneresponse, but we don't know how.
And so a lot of scientists werereally skeptical about this.
But a few years later, Emil wentback to Harvard.
And he really nailed down thatwhat these macrophages were
doing was they were keepingsmall parts of the antigen so
(30:58):
that they could show it to atype of immune cell called
helper T cells, which, as thename suggests, help trigger the
immune response.
Arpita (31:08):
Yeah, it's actually like kind of cute.
I feel like when macrophagesbreak stuff down and they're
just like, look what I have,like, look what I found.
Aarati (31:14):
Yeah.
Arpita (31:14):
And look what I have.
What do we do now?
Like, what do we do?
I have these little pieces.
I started to break it down, butlike, what do we do now?
Aarati (31:23):
Yeah, I saved this for you.
I thought you might find itinteresting.
Arpita (31:27):
I thought you would like it.
What do we do now?
Aarati (31:31):
I do have to say, immunology diagrams are really
cute.
Arpita (31:34):
They are real cute.
Aarati (31:35):
All the little soldiers, and all the like, little helper
T cells.
Arpita (31:39):
The little cartoons are extremely adorable, I will say.
Immunology itself, real toughfor me.
I won't lie.
But the little cartoons are cute
Aarati (31:49):
Cartoons are great.
Um, but there's another postdocthat eat a mentored Hugh
McDevitt, who figured out thatthere's a specific molecule
called the majorhistocompatibility class two
molecules on the self surface ofthe macrophage, so MHC II
molecules.
Those are on the cell surface ofthe macrophage, and that's what
(32:12):
it uses to present the antigento the helper T cells.
So it's like the little armholding out the antigen to the
helper T cells to show it tothem.
Arpita (32:23):
Or the little plate with all the little cookies on it.
Aarati (32:26):
Exactly.
Yeah, so this is like a hugebreakthrough for immunology.
Like, this is reallyfoundational work, right?
Like, we learned about MHC class2.
Arpita (32:36):
This is like all very just like Immunology 101, for
sure.
Aarati (32:41):
Exactly.
So it's very foundational workbeing done.
But Ita declined authorship onboth Emil and Hugh's papers
because she didn't think she hadcontributed enough to be an
author.
She was just like, I justmentored you and like pushed you
in the right direction.
I didn't actually do anything.
Arpita (32:57):
I have never met a PI like that in real life, but
continue.
Aarati (33:00):
But both of them have said on numerous occasions that
they would not, they would nothave figured this out without
her, like, they would not bewhere they are today without
her.
So I think because of that, alot of times, like, people don't
know about Ita Askonas You know,she just like, was like, uh, no,
don't put me on that paper.
You really did all the work.
Arpita (33:20):
I've put people on papers for less.
Aarati (33:22):
Yeah, right?
Yeah.
Arpita (33:26):
But, like, the random person who, like, sometimes
shows up in the lab every oncein a while, the fellow who,
like, isn't really part of thelab anymore, they're on the
paper.
Yeah.
Like,
Aarati (33:34):
The person who took your plate out of the incubator when
you were in a meeting, it'slike...
Yeah, but Ita just like helpedso many graduate students and
postdocs and every single one ofthem was like, she could be
really tough on you and verychallenging, but in the end the
people that she helped mentorbecame better scientists because
(33:55):
of it.
So it's like a theme throughouther life that she was just like,
this helping hand, this forcethat mentored people.
Arpita (34:02):
It's best case scenario.
Aarati (34:04):
Yep.
So while she's helping with theproject on macrophages.
She also continued to work on Bcells, and she had another
scientist, Alan Williamson, didexperiments that showed that a
single B cell will only form asingle specific type of
antibody.
So remember, there are two typesof B cells.
(34:25):
There's the memory B cells andeach memory B cell remembers one
specific pathogen, whether it'sa flu virus or a bacterial
pathogen or ovalbumin.
And so when the immune responseis triggered to the specific
thing that that memory B cellremembers, it starts to divide
and it makes more memory Bcells.
(34:46):
But it also makes plasma Bcells, which will produce
antibodies to that specificpathogen, and so because of
that, if you look at a singleplasma B cell, it only makes one
type of antibody.
So they figured that out.
Arpita (35:01):
It is kind of crazy.
And you think of how manyantigens you encounter.
It's constant.
It's like literally anything isan antigen.
Like it could be a virus.
It could be pollen.
It could be dander.
It could be anything that causesany sort of immune reaction.
Aarati (35:19):
Yeah, it could be a little bug that you inhale by
accident.
Arpita (35:22):
Exactly.
Exactly.
It could be anything.
It could be something on adoorknob.
It could be.
And so you think about truly howmany antigens we encounter and
then how many corresponding Bcells you have.
It actually is quite crazy.
And so when you think about yourwhole immune system, it like
incorporates all of these thingsin the memory of all of these
past antigens.
Aarati (35:43):
And I think that's why they had such a hard time like
isolating any specific B cellthat they wanted to study from
the lymph nodes, because thereare just so many things, you
know, that your body isprogrammed to remember.
But actually they kind ofsucceeded.
So Ita and Williamson and athird scientist, Brian Wright,
(36:04):
are also credited withdeveloping a way to clone memory
B cells in mice.
And so, this was huge because noone had been able to do that
before either in vitro or invivo, like she had been working
with the cancerous plasma cellline for that purpose.
Um, but they finally figured outa method to do it and they were
(36:25):
able to clone or create copiesof a single memory B cell.
And because they did that, theyessentially produced the first
monoclonal antibodies.
So mono means one and clonerefers to like identical cells
from a single parent And so,since the cells making the
(36:47):
antibodies are identical, theantibodies that they make are
also identical.
So.
Um, they were doing this reallyas a larger project to figure
out how long a memory B cellwould survive and divide before
dying out.
They didn't really set out tomake monoclonal antibodies, but
they're credited really withmaking the first ones kind of as
(37:08):
a byproduct.
Arpita (37:10):
Yeah.
Aarati (37:10):
But just to like provide some context for how important
monoclonal antibodies are (37:14):
a few years later, two scientists,
Cesar Milstein and George Kohlerwon the Nobel Prize for creating
an immortal cell line thatproduced monoclonal antibodies.
So I don't think she was likeinvolved in that, but they won a
Nobel Prize for basically doingwhat she had done, but just
creating an immortal cell lineof that.
(37:36):
Scientists use monoclonalantibodies to target specific
cancer cells to provide targeteddrug treatment, or they can just
be used to mark the cancer cellsso your body knows to destroy
it.
They're used in autoimmunedisorders.
Uh, they're used to test bloodand tissue compatibility for
organ donation.
They're used in diagnostictests.
(37:56):
They're used like in pregnancydiagnostics.
So like pretty much any fieldthat you can think of, we use
monoclonal antibodies.
They were used to like helpprevent coronavirus from
invading our cells..
Like everything.
Arpita (38:10):
It's everywhere.
It's very like, um, what is theword I'm looking for?
Aarati (38:16):
Ubiquitous?
Arpita (38:17):
Yes.
Yes.
Yes.
Aarati (38:23):
They are.
Arpita (38:23):
I was going to say evasive, but I think I meant
pervasive.
And then I was like, oh yes.
Ubiquitous is actually the rightword.
Aarati (38:30):
Pervasive is good too.
So, yeah.
They're credited with creating,like, kind of the first
monoclonal antibodies, which, soit's huge.
Arpita (38:40):
I did not know that.
For, like, how common monoclonalantibodies are and how much they
come up in conversations aboutliterally any kind of therapy,
disease, like, I feel like itcomes up all the time.
I definitely didn't know that itwas discovered kind of by
accident.
Not an accident, but reallyjust, like, as a, you know, this
unintentional consequence.
Aarati (38:59):
Yeah, exactly.
But yeah, in 1973, Ida was aelected to be a fellow of the
Royal Society, which as we knowis a huge honor.
She joined those two women,yeah, that she had met.
Although I think like at thispoint, she's like the 27th woman
or something to be inducted intothe Royal Society.
(39:20):
In 1976, Dr.
Humphrey left the NIMR and Itatook over as head of the
immunology division.
And at this point, Ita had spent21 years studying antibodies and
their synthesis in B cells.
And so she decides, you knowwhat, I've had enough of
studying chemical antigens.
I really want to study realimmune responses to real
(39:43):
infectious pathogens.
So she started working on twoprojects.
The first was looking at adisease called African
trypanosomiasis, which is alsoknown as sleeping sickness.
It's a lot, a lot easier to say.
It's caused by a protozoanparasite that is spread by the
(40:03):
tsetse fly and somehow thisparasite is able to evade and
inhibit the immune system.
So she was really intrigued bythat.
Eventually the person who'sinfected is unable to fight off
the disease and they fall into acoma and die.
So that's why it's calledsleeping sickness.
Arpita (40:22):
Okay.
Aarati (40:22):
Yeah.
Arpita (40:23):
That's aggressive.
Aarati (40:24):
Yeah, so Ita and her students spent years trying to
figure out like what's going onand they were able to untangle
some of it.
They were able to show likecertain things about how
macrophages that had engulfed aprotozoan went through profound
metabolic changes and you couldused that macrophage to infect
(40:45):
an otherwise healthy mouse.
And they found that like knownregulators of the immune system
were secreted during theinfection, but she didn't really
come any closer to finding a wayto reverse the immune system
suppression.
And we do have medications todaythat can kill the parasite, but
they have to be administeredbefore the parasite is able to
shut down your system.
(41:06):
So
Arpita (41:07):
Oh, so if it, if it goes past some point of no return,
you're just.
Aarati (41:11):
Yeah, I think it's like within 30 days or something I
read that you have to take themedication.
Arpita (41:17):
So how do you know you have it?
Aarati (41:19):
Oh, I think there's like a whole host of symptoms because
your immune system is tryingto...
Arpita (41:23):
it's like shutting down.
Aarati (41:24):
Yeah, fever and fatigue and like all this kind of stuff.
Yeah.
Arpita (41:28):
Okay, so then you go and you get like some test and then
they have to administer thisASAP.
Aarati (41:32):
Yeah, I think so.
Arpita (41:34):
That's crazy.
Aarati (41:36):
Yeah, so, I mean, they found out a lot about this
disease, but in her long list ofsuccesses, this was maybe the
only kind of, like, you know, wedidn't really figure out
anything groundbreaking.
Arpita (41:50):
Like, there was no, like, cure, basically.
Aarati (41:53):
Yeah, her other project, though, was on the influenza
virus, and this, again, wasgroundbreaking work in
immunology.
So, she started studying yetanother type of white blood cell
called cytotoxic toxic T cells,which we affectionately know as
killer T cells.
Arpita (42:09):
Killer T cells.
Aarati (42:10):
Yes.
So, Yeah, if you break down theword cytotoxic, it literally
means toxic to cells.
And that's what T cells do.
They find a cell that's aforeign invader or cancerous
cell or a cell that's beeninfected with a virus and it
kills it before it can replicateand become an issue.
But what Ita and her studentsdiscovered was that, T cells
(42:34):
aren't like B cells in that theydon't go after one specific type
of virus or antigen.
The same T cell could recognizeand kill multiple different
types of influenza strains.
And so it's not a total free forall, there are like some rules,
like there's two categories ofinfluenza, A and B, and within
those categories there's a bunchof different strains, but one
(42:56):
cytotoxic T cell could recognizeall the strains in influenza A,
for example.
And one of her students, AlaineTownsend, managed to clone
cytotoxic T cells, which againwas the first time anyone's been
able to do that.
And she and Alaine were able toshow that the T cells weren't
actually recognizing theinfected cell, they were
(43:19):
actually recognizing The viralprotein itself.
And that was weird to thembecause they were like, how can
a T cell detect a virus that'sinside of a body cell?
Like you would think thatthey're detecting something on,
maybe on the cell surface.
Yeah.
Um, so Alain finished up his PhDand moved to Oxford where he
(43:43):
kept on working on this.
And he went on to show that.
Cells that are infected with avirus can grab a small fragment
of the viral protein from insidethemselves and present it on
their cell surface using, again,a major histocompatibility
complex molecule.
It's MHC 1 this time.
(44:03):
So once again, presenting thislike, Hey, look, there's this
thing inside me.
And so the cytotoxic T cell seesa cell presenting a viral
protein fragment on its cellsurface with the MHC 1 molecule,
and that's how it knows to killit.
And again, figuring out how Tcells worked was huge and is
foundational to how we makevaccines against these kinds of
(44:26):
viral infections.
So, another huge contribution toimmunology, but once again, Ita
declined authorship on thispaper because she felt like she
hadn't actually, like, doneanything.
She was just like, no, it's allyou.
You did everything, Alain.
Arpita (44:40):
That's nuts.
Aarati (44:41):
Yeah.
Yeah.
So this is something likeeveryone said about Ida.
She was extremely humble, neverbragged about her
accomplishments.
And in fact, Dame BridgetOgilvie, her friend, said that
even though Ida was extremelyclose to her family, since she
didn't talk about her work much,none of them really understood,
like, what a giant in her fieldshe was.
Arpita (45:04):
Mm.
Aarati (45:04):
And In fact, they kind of seem to be like,"Aw, you're a
scientist.
Like we love that for you.
I mean, good job.
And they're like, you're notlike your cousin, Peter, who
like founded a music and artagency.
Like he's amazing.
Uh, we can barely even trust youto cook dinner." And Ita's just
like, yep.
"I hate cooking.
(45:24):
I'll do the dishes." And shedidn't say like a single word
about her work or what she wasdoing.
Arpita (45:30):
Couldn't be me.
I...
Aarati (45:31):
yeah.
Arpita (45:31):
Couldn't be me.
I think I'm too annoying.
Aarati (45:34):
You worked hard for it, though.
Like, come on, you deserverespect.
But her friend Bridget wouldjokingly say that actually Ita
was being very clever bylowering her family's
expectations of her so she couldjust duck out of certain chores
and responsibilities, which Iwas like
Arpita (45:50):
That's smart.
Yeah.
She's, she's living in, youknow, 2038 for sure.
She's really just,
Aarati (45:57):
She's playing chess.
We're all playing checkers.
Arpita (46:00):
Yeah, exactly.
Aarati (46:02):
Yeah.
So Ita retired in the late1980s, but she stayed active in
the field discussing science andencouraging new students to
pursue immunology.
In 2007, Ida was elected to be aforeign associate of the U.
S.
National Academy of Sciences,and she was awarded the Robert
Koch Medal for her lifelongcontributions to immunology.
(46:26):
And in 2012, she received anhonorary doctorate from
Cambridge, which she was veryproud of.
Arpita (46:33):
That's amazing.
Wow, she lived a really longtime, wasn't she born in 1923?
Aarati (46:39):
Yes.
Arpita (46:39):
19-
Aarati (46:40):
Yeah.
Arpita (46:40):
Yeah.
Wow.
Aarati (46:41):
Yeah.
The following year, in 1913, shedid pass away at the age of 89.
Arpita (46:47):
Wow.
Aarati (46:48):
Uh, she never got...
yeah.
Like, she lived a long life, andshe was very active during it.
She never got married or had anychildren, but the reason I think
she really deserves the title ofthe mother of immunology is just
the sheer number of people thatshe mentored and supported who
then went on to make suchamazing contributions.
Arpita (47:07):
Their own contributions.
Yeah, exactly.
That is, I know that was likenoticing that as you were
telling the story too, like shewas like, there was a postdoc
and there was a mentor and therewas this PhD student and there
was another PhD student andthere was another institution
and another person.
And so it's actually really,really crazy how many people
there were.
Aarati (47:22):
Yeah.
Arpita (47:23):
And like sometimes people in science will talk
about like your family tree.
Like your scientific family treeand like I feel like having her
in your scientific family treewas probably like A) just clout
but then B) like I'm sure yougot so much guidance and shaping
for how you think aboutquestions and experiments and
roadblocks and I'm sure thatmust have been really
(47:43):
influential.
Aarati (47:44):
Yeah, and, like, the ones that I mentioned in the
story is just, like, barelyscraping the surface of the
iceberg.
Like, I was reading her, like,obituary and, like, her
biography, and in some placesthere was just, like, a list of
names.
It's like, she mentored thisperson, and this person, and
this person, and this person,and this person.
I'm just like, oh, my God.
It's like
Arpita (48:03):
Yeah, and you think about, too, like, I feel like
immunology is kind of in itsheyday, like with how many
therapies and new drugs arebeing produced that are either
using like monoclonal antibodiesor, you know, working against
all of these different diseases,including, you know, um,
autoimmune diseases is what I'mtrying to say, and I feel like
(48:26):
there's, there's so many coolbreakthroughs there.
And so like, just likeunderstanding the foundations of
immunology, just knowing howmany more people have been
working on it and like, alsoknowing that we're truly like
kind of in a heyday ofimmunotherapy is really cool.
Aarati (48:41):
Yeah.
And I was just like, also verysurprised by just how she was
just all over everything.
She was like over plasma B cellsand antibodies and cytotoxic T
cells and macrophages.
It was like, there was no partof the immune system that she
didn't touch, I felt like so Iwas just really surprised.
Arpita (49:01):
And there's a lot.
Aarati (49:02):
Yeah, there's so much like on one hand, I was really
surprised that she doesn't getmore recognition.
But on the other hand, it doesseem like she declined a lot of
recognition, you know,
Arpita (49:12):
Interesting choice.
But yeah, yeah.
Aarati (49:14):
Yeah.
She was just like, no, I don'tneed it.
So yeah, that's her story.
I really enjoyed like readingabout it.
I feel like.
I learned a lot more aboutimmunology than I knew before.
Arpita (49:26):
Honestly, same.
And I feel like I sort of camein with the baseline level of
understanding, and I still did.
Like, I definitely didn't knowthe thing about the monoclonal
antibodies, which is really,really cool.
Aarati (49:36):
Yeah.
Arpita (49:37):
Great story.
I loved it.
Aarati (49:38):
Thank you.
Arpita (49:39):
We love a little girl power.
Aarati (49:41):
Yes.
We need it.
Arpita (49:43):
We do need it.
Aarati (49:43):
We always need it.
Arpita (49:48):
Thanks for listening.
If you have a suggestion for astory we should cover or
thoughts you want to share aboutan episode, reach out to us at
smartteapodcast.
com.
You can follow us on Instagramand Twitter@smartteapodcast and
listen to us on Spotify, ApplePodcasts, and or wherever you
get your podcasts.
And leave us a rating orcomment.
It really helps us grow.
Special thanks to our editor,James Fixx.
(50:09):
New episodes are released everyother Wednesday.
See you next time!
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