0:00

Welcome to Tick Tick Boom . I'm

0:02

Zac Stritch-Hoddle , your host , and

0:05

in this series we'll be exploring the mysterious

0:07

and often misunderstood world of alpha-gal

0:09

allergy , a unique condition

0:12

sparked by tick bites . Join

0:14

us as we unravel the intricate science

0:16

stories and far-reaching implications

0:19

of this fascinating medical phenomenon . It's

0:22

a journey through the complex relationship between

0:24

humans and nature , a look into

0:26

how our bodies react in the most unexpected

0:28

ways . Whether you're intrigued by

0:30

medical mysteries , passionate about nature

0:33

or simply looking for an engaging story

0:35

, this series has something for everyone

0:37

. Thanks again for joining

0:39

us for our second episode , where we visit

0:41

the Garvin Institute in Sydney , Australia

0:44

, to speak with three leading figures

0:46

in the field of alpha-gal research . The

0:49

Garvan Institute is one of Australia's

0:51

leading medical research centres . It

0:53

has a staff of around 600 people

0:55

dedicated to studying cancer , inflammatory

0:58

diseases like rheumatoid arthritis and

1:00

multiple cirrhosis , immunity

1:03

to and vaccines for infections

1:05

like COVID-19 , and allergic

1:08

diseases , including reactions to ticks

1:10

and mammalian red meat . First

1:14

, I would like to introduce Dr David Langley

1:16

. Dr Langley was originally

1:18

trained in DNA techniques . While

1:20

studying the intricacies of bacterial DNA

1:23

replication during his PhD , whilst

1:30

doing a postdoc in the US , he discovered the magic of proteins and crystallized one by accident . This

1:32

piqued his interest in structural biology and he has been

1:34

attempting to crystallize proteins and solve

1:36

their structures using x-ray crystallography

1:38

ever since . He currently works

1:41

in the Antibody Therapeutics Lab at

1:43

the Garvan Institute of Medical Research , where

1:46

he characterizes the molecular details

1:48

of antibody-antigen interactions

1:50

. Good morning , Dr Langley

1:52

. Thank you for taking the time to speak with me today

1:54

. Could you tell us why

1:57

the Garvin Institute is interested

1:59

in alpha-gal research ?

2:01

Well , I suppose initially because Sheryl

2:03

van Nunen came to us with her discovery of the

2:05

link between tick bites and developing mammalian

2:08

meat allergy , which intrigued us from an

2:10

immunological perspective , and

2:13

one thing we decided to look at was whether we could

2:16

get a molecular understanding of

2:18

the sugar actually bound to an antibody

2:20

. So this is what we set out to do , and

2:23

I'm what's called a structural biologist , which

2:25

means I try and get a molecular picture

2:27

of interactions and

2:29

I use a technique called crystallography . So

2:32

this involves first growing a crystal

2:34

of the antibody in complex with

2:36

the sugar , and then we hit this

2:38

with x-rays and collect diffraction patterns

2:40

and then use a bunch of funky

2:42

mathematics to back calculate

2:45

, if you like , and give us an understanding

2:47

of the molecule within the crystal that produces

2:49

the pattern that we collect . So that's exactly

2:51

what we did , and we managed to get a

2:54

molecular picture , if you like , of how antibodies

2:56

actually bind the sugar .

2:59

So how does this relate to Professor

3:01

van Nunen's research on mammalian

3:03

meat and tick allergies ?

3:10

This is one of the big questions , I suppose , is how does mammalian meat allergy and tick

3:12

anaphylaxis actually get triggered by actually being bitten by

3:14

a tick ? So humans

3:16

don't make the alpha-gal sugar , but

3:18

we're constantly exposed to it . We have

3:21

it on the surface of the bacteria that live in our guts

3:23

, and whenever we consume red

3:25

meat we are exposed to it as well . In

3:27

fact , we estimate that about 1% of our

3:29

serum antibodies recognize the alpha-gal

3:31

sugar to some extent , yet

3:34

for some reason that we don't fully understand , this is tolerated

3:36

without any adverse effects . So

3:39

the big question , then , is how do

3:41

we transition from tolerance or

3:43

energy , which is another word for tolerance

3:45

, to the potentially more dangerous

3:48

anaphylactic response , and what role do

3:50

ticks actually play in this transition ? So

3:53

one possibility is that the previous meal

3:55

that the tick consumed before you get

3:57

bitten might be the

3:59

source of the introduced alpha-gal , or

4:02

it may be the alpha-gal present on the

4:04

tick itself , which also makes

4:06

this sugar and gets injected into

4:08

us . So why does alpha-gal

4:10

in the context of a tick bite produce

4:12

this transition , whereas normal exposure

4:14

to alpha-gal seems to be relatively

4:16

benign ? So that's what we're interested

4:18

in .

4:20

So why is it that our body has an allergic

4:22

response to this sugar in particular

4:24

?

4:31

Humans and great apes , as I mentioned previously , don't actually make alpha-gal , but we used to because

4:34

all mammals generally , apart from the great apes and humans , make this sugar

4:36

. So within our genomes

4:38

we actually have the enzymes there

4:40

to actually make the sugar . However , they carry

4:42

some mutations so that we can't do

4:44

it anymore , even though we've got ostensibly

4:47

most of the machinery in place

4:49

. And the reason for this might

4:51

be traced or we believe is traced back

4:53

about 30 million years ago , when the

4:55

great apes diverged away from the rest of the mammals

4:57

and we accumulated

5:00

this mutation . So we no longer made

5:02

the sugar and , as a consequence , we could develop an immune response

5:04

against this mutation . So we no longer made the sugar and , as a consequence , we could develop an immune response against

5:06

this sugar . And it could

5:08

be that there was a selective pressure 30

5:11

million years ago that helped cement

5:14

this mutation as a good mutation to have

5:16

, and it could be that this

5:18

selective pressure was provided by

5:20

an infectious agent such as

5:22

malaria itself

5:25

, which then conferred us

5:27

with our ancestors , with an advantage to

5:29

being able to produce an immune response against

5:31

this sugar .

5:33

I understand that this research has now evolved

5:35

to have much broader implications for the

5:37

field . Could you tell me a bit more about

5:39

that ?

5:40

Having gained a molecular understanding

5:42

of the way antibodies bind this sugar , we're now

5:44

striving to develop antibodies

5:47

that bind this sugar much more powerfully

5:49

, and once

5:51

we develop these antibodies , it's possible that this

5:53

might be useful not just in

5:55

a diagnostic sense but also as

5:58

a preventative against infection . So

6:01

antibodies that bind alpha-gal very tightly

6:03

might conceivably also be useful in

6:05

the context of combination therapy with other

6:07

antibodies , for instance used to fight

6:09

cancer . So some of these

6:11

antibodies used to fight various diseases

6:14

are derived in mice

6:16

, for instance , and mice , being mammals , also

6:18

make this sugar , and there have been instances

6:21

where people getting an

6:23

antibody treatment then have a nasty

6:25

reaction against the treatment itself because

6:27

of the introduction of alpha-gal

6:30

into the bloodstream . So it could be that you

6:33

then might co-treat with

6:35

an antibody that masks this

6:37

sugar as a combination therapy

6:39

for certain other treatments , for instance .

6:42

So , Dr Langley , have there been any particularly

6:45

surprising or eye-opening moments

6:48

in your research on alpha-gal ?

6:50

I suppose the eye-opening moment for me

6:52

was solving the structure of the antibody

6:54

in the context of the sugar , because

6:57

it revealed that a whole class

6:59

of our antibodies , without actually

7:01

going through any of the fine tuning

7:04

that antibodies normally go through , are capable

7:06

of binding this sugar to some extent

7:08

right from the get-go , and this perhaps

7:10

explains why such a large

7:12

percentage of our circulating

7:15

immunoglobulin proteins

7:17

are able to recognize this sugar to

7:19

some extent .

7:21

Dr Langley , if you could resolve one outstanding

7:24

question about alpha-gal , what would it

7:26

be ?

7:27

So the big question really is what

7:30

triggers the switch from

7:32

an IgG response

7:34

to an IgE response . And

7:37

this is not just a problem

7:39

in relation to alpha-gal , but

7:41

with all sorts of imagines peanut

7:44

allergy , dust mites , etc . So

7:46

it's the elephant in the room , in the sense that we don't

7:48

actually understand what triggers

7:50

this switch from an IgG switch

7:53

, which our bodies have fairly good

7:55

control over , to an IgE switch

7:58

which is potentially quite nasty

8:00

. So unravelling that

8:02

in the context of alpha-gal might actually give

8:04

us the answer to why this switch happens

8:07

with all sorts of other allergies

8:09

and now for

8:11

a discussion about the health implications

8:13

of alpha-gal allergy .

8:15

I would like to introduce Professor Antony

8:17

Basten . Professor Basten

8:20

is a medical doctor and distinguished

8:22

figure in the field of immunology . His

8:25

career includes prestigious appointments such as Officer in the field of immunology . His career includes prestigious appointments

8:27

such as officer in the General Division

8:29

of the Order of Australia , fellowships

8:31

in the Australian Academy of Science

8:34

and the Australian Academy of

8:36

Technological Sciences , and

8:38

the role of an inaugural executive

8:40

director of the Centenary Institute of

8:42

Cancer Medicine and Cell Biology

8:44

. Professor Basten has over

8:47

270 publications to

8:49

his name and is currently a professor of

8:51

medicine at the University of New South Wales

8:53

, as well as an honorary senior principal

8:55

research fellow in immunology at the Garvin

8:58

Institute of Medical Research . So

9:01

, Professor Basten , at the centre of all

9:03

this research is the allergic reaction

9:05

to ticks and alpha-gal in red meat

9:07

and other mammalian animal products . Could

9:10

you describe the underlying process

9:12

of an allergic reaction to alpha-gal ?

9:15

Well , allergenical , sensitising

9:17

antibodies cause

9:19

allergic reactions , and

9:22

they do so by attaching to the surface

9:24

of what are known as mast

9:26

cells in body tissues

9:29

like the skin , the airways

9:31

and the intestine . These

9:34

cells contain packages of inflammatory

9:36

molecules like histamine . On

9:39

exposure to alpha-gal in

9:42

tick saliva or mammalian red

9:44

meat , the alpha-gal binds

9:47

to the allergenic antibody

9:49

which is sitting on the surface

9:51

of those cells . As a result

9:54

, the mouse cells burst open

9:56

and release histamine , causing

9:58

acute inflammation and

10:00

an allergic reaction involving

10:03

those tissues like

10:06

skin , lungs and intestine

10:08

. If extensive enough , anaphylaxis

10:11

occurs .

10:13

You mentioned sensitizing antibodies

10:15

before . What does it mean to be sensitized

10:17

to alpha-gal , and do we know how many people

10:20

are affected by it ?

10:21

Well , alpha-gal sensitization means

10:24

that a person has been exposed

10:26

systemically to this sugar

10:28

, the most common cause being

10:30

a tick bite . As

10:33

a result , the person has the potential to

10:35

make allergenic or IgE

10:37

antibodies to it on subsequent

10:40

exposure . This can be

10:42

in the form of red meat , other

10:44

foods of animal origin

10:46

such as gelatin , and even some

10:48

vaccines . The best

10:50

estimates we have for sensitization

10:53

of people living in the Sydney

10:55

Basin is around 12%

10:57

, although it could be higher among

11:00

those living near the coast , where

11:02

ticks are more common living

11:06

near the coast , where ticks are more common .

11:09

Why is it then that only 30% of alpha-gal sensitized people experience an allergic reaction

11:11

to alpha-gal containing products ?

11:14

Well , this figure applies to the

11:16

Sydney Basin , where the incidence

11:18

of mammalian meat allergy is

11:20

around 1% . The

11:23

reason why only 30% of

11:25

sensitized people experience

11:27

an allergic reaction at any point

11:30

in time is due to the

11:32

influence of a number of co-factors , as

11:35

mentioned previously by Professor

11:37

Van Noonen . These include amount

11:40

of alpha-gal ingested , co-ingestion

11:42

of alcohol or spicy foods

11:45

, exercise and prior

11:47

administration of anti-inflammatory

11:49

drugs . In addition

11:51

, there is a rare condition known

11:53

as mastocytosis , characterized

11:56

by a large increase in mast

11:58

cells that can amplify

12:00

the chances of a severe

12:03

allergic reaction . This

12:05

condition can be detected by

12:07

what is called a trypsin assay

12:09

.

12:10

I understand there's also research suggesting

12:12

an increased risk of coronary heart

12:14

disease in those who are alpha-gal sensitized

12:16

. Could you explain what this research

12:19

could mean In ?

12:20

The case of coronary heart disease , there

12:23

are two studies , one from the

12:25

USA and one from here in

12:27

Sydney , Australia , showing

12:29

that alpha-gal sensitization

12:32

is independently associated

12:34

with an increased risk of developing

12:36

plaques that cause

12:39

narrowing of the coronary arteries and predispose

12:41

to heart attacks . In other words , alpha-gal

12:45

sensitization is an additional

12:47

risk factor for coronary

12:49

heart disease , over and above

12:52

high blood pressure , cigarettes

12:54

, alcohol consumption and obesity

12:56

. The important thing , though

12:58

, to remember is that people can

13:00

be sensitized by a tick

13:02

bite without necessarily

13:04

developing a clinical allergic

13:07

reaction .

13:08

If alpha-gal sensitivity doesn't always

13:11

result in an allergic reaction , should

13:13

people still take precautions to avoid

13:15

developing it ?

13:17

Yes , they certainly should , and there are several

13:19

reasons for that . First , some

13:21

people can develop allergic reactions to

13:23

other substances in tick

13:25

saliva , including the proteins there

13:27

. Secondly , as just

13:29

mentioned , it may reduce the risk

13:32

of coronary heart disease . And thirdly

13:34

, tick bites can become infected

13:37

, although here in Australia there

13:39

is no evidence whatsoever for

13:41

the presence of the germs

13:43

causing Lyme disease in

13:45

our particular tick populations

13:47

. What's more , measures

13:50

to avoid sensitization are simple

13:52

, for example , wearing protective

13:54

clothing when you go on a bushwalk

13:56

and removing

13:58

ticks correctly . For

14:01

those already sensitized , being

14:03

aware of all the cofactors predisposing

14:06

to these reactions is vitally

14:08

important .

14:10

Up until now , our discussion is primarily

14:12

focused on the allergic responses to alpha-gal

14:15

. However , there seems to be a

14:17

flip side to this . Could you tell us about

14:19

the potential benefits of the alpha-gal

14:21

immune response , particularly in relation

14:23

to its implications for disease control

14:26

and prevention ?

14:28

Regular internal exposure

14:30

to alpha-gal on microbes

14:32

normally present in intestine

14:35

can lead to another type

14:37

of antibody called IgG

14:39

, which is non-sensitizing

14:42

but is important for

14:44

protection against certain

14:46

common infections . For

14:49

example , non-sensitizing

14:51

IgG antibodies have been shown

14:53

to decrease transmission of malaria

14:56

by mosquitoes . Presumably

14:58

this is due to the fact that the malarial

15:00

parasites carry alpha-gal

15:02

on their surface , which can

15:05

be targeted by the antibodies . The

15:07

same may apply to transmission

15:10

of another common infection in

15:12

the developing world , namely tuberculosis

15:15

.

15:15

another common infection in the developing world , namely

15:17

tuberculosis . Considering the recent impact that COVID-19

15:19

has had on the world , I have to ask is

15:21

there any connection between alpha-gal research

15:23

and COVID-19 ?

15:38

That's an interesting question . An association has been reported between

15:41

the severity of COVID infection and the level of antibodies to alpha-gal

15:43

Surprising and very interesting . In other words , more severe disease

15:45

is associated with lower levels of anti-alpha-gal antibodies

15:47

. Well , what does this mean

15:49

? Is it of any value ? This

15:51

raises the prospect of boosting alpha-gal

15:54

antibody levels through the use of probiotics

15:58

, which , in turn , could benefit patients

16:00

with severe COVID

16:02

disease .

16:04

And finally , Professor Bastin , if

16:06

you could resolve one outstanding question

16:08

about alpha-gal , what would it be ?

16:12

As far as we're concerned , in

16:14

the laboratory where I work , we

16:16

really want to know why

16:18

it is that 10%

16:21

of people are allergic and

16:23

make sensitizing IgE antibodies

16:25

to alpha-gal and lots of other allergens

16:28

, and 90% of

16:30

the population make different

16:33

protective but not harmful

16:35

antibodies .

16:37

For our last guest , I'd like to introduce

16:39

Professor Daniel Christ , who

16:41

unfortunately only had limited time

16:43

to speak with me . Daniel joined the Garvin

16:45

Institute in 2007 as head

16:48

of antibody therapeutics to translate

16:50

structural and genomic advances into

16:52

drug candidates and treatments for cancer

16:54

and inflammatory conditions . He's

16:56

also the director of the Centre of Targeted

16:59

Therapy at the Garvan Institute . Professor

17:02

Christ , if you could resolve one outstanding

17:04

question about AlphaGo , what would that be

17:06

?

17:18

Is what we call this IgG to IgE switch , where the immune system switches from producing antibodies

17:20

that neutralize and protect to those that mediate allergy

17:23

and autoimmunity , and I

17:25

think it's fair enough to say that we don't

17:27

fully understand that question at the moment

17:29

, but it's certainly a matter

17:32

of intense research and tests

17:34

. It's probably related to the fact on

17:36

how the alpha-galactose

17:39

antigen is presented in the context

17:42

of the tick bites or in the skin , and

17:45

then also in the context of tick

17:47

proteins and then also other

17:49

tick components such as alpha-galactose

17:52

linked lipids and the like .

17:54

Professor Christ , have there been any

17:57

particularly surprising or eye-opening moments

17:59

in your research on alpha-gal ?

18:01

So I think one of the things that

18:03

surprised us is the discovery

18:05

of what we call sort of public antibodies

18:07

. So if you look at the human

18:09

immune system , we have different

18:12

germlines or sort of different flavors

18:14

of antibodies , and in fact humans have over 70

18:17

of those right , and what you

18:19

get in many cases is , you

18:21

know , what we call a polyclonal response , so that all

18:24

of the 70 or most of the 70s are

18:26

used , and that's also the case in the

18:28

alpha-galactose response . However

18:30

, we did find certain preferences and

18:32

in particular we found one germline which

18:35

is called 3-7 , which didn't

18:37

dominate the response but was sort of overrepresented

18:40

in the response . And then we also did a lot of

18:42

structural and biophysical characterization

18:45

of the response and we found that this

18:47

germline so antibody germline 3-7

18:49

, had sort of basically genetically encoded

18:51

properties that seems to make it particularly

18:54

suited for binding alpha-galactose , and

18:56

I mean that to one extent provides an

18:58

interesting biology insight

19:00

. So we do seem to have some genetic

19:02

predisposition of making antibodies that

19:04

can recognize , structurally recognize alpha-galactose

19:07

. And then also it's early days . I

19:09

think this might also open up some pathways towards

19:11

the development of therapeutic antibodies , because

19:14

it's basically nature telling us

19:16

what is an optimal solution to this

19:18

recognition problem . So how do we

19:20

bind alpha-galactose with

19:23

maximum affinity and

19:25

maximum specificity ?

19:27

On behalf of TiARA . org . au , we'd like to thank

19:29

everyone at the Garvan Institute

19:31

for speaking with me today . Everyone

19:35

at the Garvan Institute for speaking with me today and , as always , a reminder if you're

19:37

ever bitten by a tick , please freeze , don't squeeze

19:40

. For more on preventing alpha-gal

19:42

allergy , visit tiARA . org . au

19:45

, where you'll find research papers and

19:47

show notes . Make sure you stay

19:49

tuned for our next episode with Dr

19:51

Stephen Doggett , a renowned Entomologist

19:53

from Sydney , Australia , discussing

19:56

all things tick related . Thanks

19:58

for tuning in to Tick , Tick , Boom

20:01

!