The Mind Numbing Medicine

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Hello, Curios.

Another show, penultimate one of this particular run, and it's a very mysterious one today.

Another one in the category of stuff that we don't really understand.

I mean, kind of giving away the entire episode there, Adam.

Sure, it's not a secret.

It is mad, though, that we knock people out with drugs and don't know how we're doing it.

So, this is an episode we should explain.

It's about anesthetics and how they work.

work.

Today's investigation is an absolute knockout, literally.

Yes, by the end of this, you should be blissfully unaware of the pain you've been through.

Because we had a question come in from two different listeners: Alicia Nissen, a train driver in New South Wales, Australia, and Neil Morton from Sterling in Scotland.

And they both emailed curiouscases at bbc.co.uk asking, How do anesthetics work?

I know this one.

Someone in a white coat coat injects you and you wake up handcuffed to an orangutan in the cargo hold of a plane on its way to Jakarta.

Case sold.

Pretty sure that was your stag do that you're describing there.

No, how do they actually work?

So how what's going on in the body?

Have you ever had one, by the way?

I have.

In anger.

No, not

in a hospital environment, yes.

Just once.

I loved it.

I absolutely loved it.

I was just having my wisdom teeth taken out.

The cold sensation as the stuff runs up your arm and then waking up several hours later not with four teeth short and not knowing what the hell had gone on.

I know you've had one

because

you phoned me, video called me about five minutes after waking up to tell me about something to do with work.

Not 100% coherently, I have to confess.

Yeah, I mean, that's probably the thing is, though, I think you're in your truest state when you're coming back from an anaesthetic.

My true state is workaholic.

Incoherent workaholic.

Incoherent Incoherent workaholic, exactly all right.

Well, let's make things a little bit less incoherent because we have two experts joining us today.

We have Dr.

Fiona Donald, who is president of the Royal College of Anaesthetists.

Yeah, that qualification seems appropriate.

And we also have Anil Seth, Professor of Cognitive Neuroscience at the University of Sussex and general consciousness guru.

Anil, let's start with you.

Being under a general anaesthetic, that is not the same as being asleep, right?

So what is the difference?

It really isn't the same.

I've had a number of general anesthetics, and what's always struck me is how different it is.

When you go to sleep and you wake up again, there's always a sense of some time having passed.

You know, you know, it's roughly been a few hours.

But under anesthesia, it's not just the experience of absence, it's the absence of any experience.

You could have been under for five minutes, five hours, or 50 years, even.

The ends just join up.

You're gone, and then you're back.

It's a kind of premonition of the oblivion that might have been there before you were born or maybe after you die.

Goodness, I mean that is quite a profound thought for right at the top of Curious Cases, but let's go with it.

So

we're not going to spend much time talking about the nature of consciousness because that's a whole series in itself.

But it's the absence of

self.

You do,

you kind of cease to exist.

I think that's right.

I think you just go away entirely.

The brain, it's still going, it's still doing stuff.

Your body is still alive.

It's really, I think, it's one of the best inventions ever.

And it just turns the self off, but more than the self, it turns off any experience, an experience of the outside world.

And of course, the experience of the surgeon cutting into your body, which is why it's such a brilliant invention.

And it's also when you need someone like Fiona to be in the room with you.

Fiona, I know that you do a lot of work dishing out the drugs, but have you ever undergone a general anesthetic yourself?

Yes, I have, just once, and I agree.

It is really different to going to sleep.

You just lose that time completely.

And the other thing is that, so at the end, at the end of my operation, when I was in the recovery room, I apparently had a long conversation with the anaesthetist and we discussed many things of which I have absolutely no memory.

I've really enjoyed the last general anesthesia I had because it wasn't for an emergency operation.

It was a planned surgery, a relatively minor one.

And I still remember talking to the anesthesiologist on the way in and asking him all sorts of, probably for him, unexpected questions about exactly what I was getting and what the time scale was going to be and then really trying to pay attention to what happened at the moment that the anesthetic went in.

Adam you mentioned that you feel that cold that real

really weird sensation of chill isn't it from the inside.

But now I'm thinking that you as a professor of consciousness must be singularly the worst patient that an anaesthetist wants to meet on the way in.

Tell me everything about what's happening.

happening.

You know what?

The anaesthetist always has a last word because I can just be gabbling on, but

they turn the tap on and I'm gone.

Now count backwards.

Oh, bye-bye.

Fiona, do they actually do the count backwards thing?

Because they did it with me and I remember thinking, I'm going to do this.

And I got to about seven.

I witnessed my son having some surgery one time and they asked him to count backwards from 10 and he didn't get to 10.

I don't know.

I don't.

I have to say, I just tend to sort of chat inanely to people as they're drifting off, just to sort of have a kind of reassuring noise in the background.

I've not used the number thing, but I think people do still do it.

And we always win, as Anil says.

Yeah, you always win.

I think the last time I had it, I was definitely, I think I got about three numbers in before Oblivion took over.

People try and count really quickly.

Beat the system.

But have you been, I mean, that conversation when you come round, there is something kind of interesting about that.

Do people say mad stuff?

Do people generally come up with complaints and

bonkers ideas as they're coming round?

I think they might be a little bit more disinhibited than normal, but in general, they make sense.

And so, that's what sort of lulls you into a false sense of security that you think you're having a really good conversation with them.

And what do we know about the pharmacology of what's actually going on?

That loss of self that Anna was describing there.

Do we understand what's going on in terms of the drugs?

So, yeah, I don't think we've got a full understanding of how every drug works, but we do know quite a bit.

So there's been a lot of theories over the years, but I think the sort of most recent theories are it's around ion-gated channels and that that's their GABA channels.

So GABA is gamma aminobutyric acid.

And

it's probably not just one thing, but in general, what's happening is that by interacting with those receptors, they're kind of reducing the amount of excitation and the amount of transmission of signals, essentially, so that you then lose consciousness.

Okay, I'm just bit, I mean, I heard some stuff about ions, I heard some stuff about receptors, but what I did hear there was that people aren't sure about how this thing works.

Have I understood that correctly, that people have been dishing out general anesthetics without knowing what they're doing?

So I wouldn't put it quite like that.

I would say that

we know how they're going to work and we know the effect they're going to have and the side effects and how to manage things.

But I think the complete, exact mechanism of exactly how general anesthetics work hasn't been completely worked out yet okay let me let me see if i've understood this then so in your brain you've got neurons firing around all over the place and you want to get something that stands in the way and stops the receptors picking up on those neurons firing i think that's that's the sort of thing so what it what it does is blocks

blocks a receptor where that transmission might occur and thereby causes causes the effect.

Yeah.

And that happens, as I say, at the GABA receptors.

And we also know that it happens at NMDA receptors.

Fiona, I do want to ask you about just the practicalities of it, because all four of us, and I expect many of the listeners, have had general anesthetics at some point.

What happens?

How do you apply the drugs?

What happens after we go under?

So we first of all have to...

pop a little tube into one of the veins so that we can give the drugs into the vein because most of the drugs that we give go in through the through the veins and people would just gradually drift off to sleep and then you can either keep people asleep by getting them to breathe gases that will keep them asleep or you can continue with the drugs through the vein and then at the end you just stop the drugs and then they wake up it's magic it's basically magic it does sound a bit like magic i mean what you're what you're describing here is is essentially it sounds like you pump some magic into the veins and then and then magical things happen but okay the drugs that you're giving this cocktail of drugs that you're giving do you also have to

are there different physiological things that you need to control?

I'm thinking about swallowing and breathing while you're under.

That's a really interesting question.

And people will generally continue to breathe under anesthetic for themselves unless you paralyze their muscles.

So then they can't breathe, and then you have to take over their breathing.

So if you're going to take over their breathing, we have ventilators that we use.

But a lot of anesthetics are done with people just continuing to breathe for themselves.

What about swallowing?

What about sort of

you know clearing your throat of saliva?

So, people don't generally swallow under anesthetic because you're at a kind of deep level of loss of consciousness, such that you wouldn't necessarily swallow.

If people are swallowing, it might be a sign that they're a bit lighter under the anesthetic than you would like.

Do people ever wake up?

Has that ever happened?

Have you ever been there where someone

so

this again is an important issue in anesthesia?

And we talk about accidental awareness under general anesthesia.

And that's where someone is unintentionally awake.

Now, that doesn't happen very often at all.

And we have monitoring that we can use.

So we have clinical monitoring where we're looking at the patient because we're always with the patient when they're asleep.

But we also have brain monitors that we can use to look at the brain activity.

And that gives us a very good idea of whether the anesthetic is deep enough, not too deep, because of course you don't want to give people too much anesthetic either.

Must be a very serious thing to need to avoid.

I mean I imagine quite life-threatening if somebody were to wake up while they're having major abdominal surgery.

It's not so much that it's life-threatening, it's that

it's horrible and it can lead to post-traumatic stress, all sorts of very unpleasant

sequelae.

So obviously we do everything we can to avoid that.

And as I say, it is very rare.

So I want the public to be reassured.

I can't imagine much more terrifying than waking waking up in a hospital, not being able to.

I was wondering whether you were going to mention that, because that's the other terrifying thing about

these sort of incidents of awareness during anesthesia, which is that the person may often be paralyzed as well.

So not able to demonstrate that they're, in fact, awake.

Which is, I think some of the older, and Fiona, you can correct me if I'm wrong, but I think some of the older methods here involved basically putting a tourniquet on so that the paralytic, the curare didn't affect one limb, so that if the person did wake up, they would be able to wave with their left hand to say that I'm awake.

Yeah, the isolated forearm technique.

Yeah, the isolated forearm technique, yeah.

So, what this is, so hang on, let me make sure I understand this then.

So, historically, I mean, back when people didn't know how anesthesics worked,

you could be conscious but paralyzed, physically, physically placid,

but totally awake in your mind, and unable to signal to surgeons and those around you that that this was going on and so how long ago we talked i mean you you said this as it was like a standard thing fiona no i mean i've i've never seen the isolated forum technique it's a it's an ancient you know it's a historical technique

the most serious forms of awareness under general anesthesia which are extremely rare rare are the ones where people are completely awake but paralyzed Now that does still happen and that is

generally a medical error, But it's very, very rare.

And the fact that we've got all the machinery that we've got now, that makes it much, much less likely to happen now.

And of course, I mean, I don't want to trivialize this too much, but of course, your job is not done as soon as the person

is knocked out.

You don't sit there, you know, playing solitaire on your phone for the rest of the surgery.

You're monitoring for changes in physiology, right?

That's right.

So before we start, we wire people up to lots of monitors to look at all their physiological variables, heart rate their oxygen levels their blood pressure and obviously what the surgeon is doing will have an effect on that as well as what we're giving so sometimes we need to give drugs to help keep things like the blood pressure normal or sometimes we just need to give a little bit more painkiller or something like that you mentioned there fiona about

not giving too much anesthetic

I mean I imagine these these drugs are pretty potent but but what would happen if you were to give somebody too much?

Does it affect when when they wake up?

So, the main anaesthetic that we use is a drug called propofol.

I mean, all anesthetics generally will drop the blood pressure anyway, but it could drop the blood pressure more than you'd like.

It might slow down someone's breathing more than you'd like.

But equally, we know that, particularly in the elderly and the frail, or people who are generally unwell,

those effects can be exacerbated.

And so, you really want to make sure that you're in that sweet spot where you're giving enough anesthetic to make sure that they're obviously asleep during the operation, but not causing too many side effects.

You're walking a tightrope then, it sounds like.

We're skilled professionals and we do this a lot and so actually it's not as much of a tightrope as it sounds.

But we do, you know, we do need to pay very close attention to what's going on.

I still can't quite get over the idea that you could have an entire career in administering drugs to people and still not really be totally sure about the ways in which it's working.

Yeah,

I can see where you're coming from.

I mean I think the thing is that they have a consistent way of working.

So when you give the drug it has a consistent way of working and so you recognize that that is happening.

So I'm not sure that you actually need to know the molecular basis of what's happening in order to be able to use those drugs.

I mean there are lots of things we do in life where we don't know the full mechanism of why something's working.

You could still play ball sports before Newton came along and explained gravity to us.

Absolutely.

So obviously one of the roles of the anaesthetist is to monitor the physiology and that includes monitoring brain activity as Fiona mentioned.

Now we're going to delve deep into the brain now because we want to know what's going on in the brain during a general anaesthetic and what that can tell us about awareness and alertness and how consciousness normally works.

And to kick us off, we spoke to an old friend of yours, Adam, Irene Tracy.

You remember her, Adam?

Yeah, well, she's no friend of mine.

Oh, come on now.

Irene is a professor of anesthetic neuroscience at Oxford University.

And listeners might remember her because she runs a little torture lab.

And she stabbed and electrocuted and burnt Adam with chilies.

Unfortunately, nothing,

we couldn't get sign-off or anything.

No, I think there was a heat gun involved as well.

Okay, sure, okay.

Anyway, it was all part of our episode on pain.

And I seem to recall you quite liked it.

Well, maybe, I mean, a little bit.

Okay, anyway, we spoke to Irene about an exciting experiment that she did to explore how patterns of brain activity change as doses of anesthetic increase.

And that involved putting people in little EEG caps, like swimming hats with electrodes inside, as well as looking at their brain activity in a scanner.

We actually did what we call a multimodal imaging experiment.

So we had people with those swimming caps on, the EEG kit, and we put them inside our large brain imaging scanner.

Whilst the subjects were being bombarded with painful stimuli and auditory stimuli.

So we were seeing how the brain was reacting to that.

But what we did then was started to infuse in the anesthetic agent, propofol, but instead of just squirting it in, we very, very slowly gave the anesthetic.

So instead of taking them into deep unawareness in 15 seconds, we took about 30 minutes to take them down, allowing each person's brain to react to that increasing dose of anesthetic and to switch off in the way that that brain wanted to.

Now I've spent 30 years looking at people's brains and I know that people's brains are very different and the brain is what you're switching off during general anesthesia.

And so what we were looking for in the analysis was are there common things that are happening to everybody in terms of how the brain is switching off and are there things that are unique to each person's brain?

So we stumbled across this incredible serendipitous finding that when people were having an increasing dose of anesthetic, the dose was carrying going up, up, up, up And as it went up, everybody mounted these slow waves.

And then suddenly, one person would reach a limit and they wouldn't make any more.

And even though the dose of anesthetic kept on going up, that was it for them.

And then the next subject did exactly the same, but maybe they reached a different level that was maybe a little bit more or a little bit less.

But when they reached their own individualized maximum level of slow waves, we realized the brain had gone into what I call perceptual unawareness.

It was sort of lights out.

So even though the signals were coming coming in, they were not being routed to the right bits of the brain.

So we're very excited about this as a potential new device that we could create that could really help an esotist deliver in a more titrated and bespoke way just the right amount of anesthetic.

Okay, Anil, there's a lot going on there and a lot to unpack from my friend Irene there.

So basics first, when she talks about mounting slow waves,

what is Irene talking about?

She's talking about these very slow oscillations in overall brain activity.

The brain is always oscillating.

Its activity flows, it comes and it goes, it goes up and it goes down.

And it does this at various different frequencies.

There's the alpha rhythm which is very prominent usually over the visual cortex at the back of the brain.

This is an oscillation at about 10 Hertz, 10 cycles per second.

But what Irene is talking about are delta oscillations.

These are much slower at about one to four cycles per second.

And what she observed in her brilliant experiment just to infuse the anesthetic very slowly is that these delta waves, these very slow waves, those become much more prominent.

And this hints at an underlying mechanism for anesthesia and loss of consciousness in general,

which has been called cortical bistability.

And what does that mean?

That just means that the brain can be in two different states.

It can be in its normal active state, and then it can be in a very quiescent, very low-level, not much going on state.

And basically these slow waves, these delta oscillations, they show that the brain is periodically, a few times every second, just entering this state of very little activity.

And what that means is for each individual neuron, each individual brain cell,

it sort of forgets what it's doing.

It's normally getting inputs from a bunch of other neurons.

And then in these down states, these low states, everything goes quiet.

And the neuron just stops.

And then when it restarts, it's like, well, what was happening?

And it starts just behaving a little bit randomly and what this means is that the overall patterns of information flow and communication throughout the brain are broken and that's what we really see at a whole brain level we see an interruption of how different parts of the brain speak to each other that's really interesting because you see you're saying that we see that at a neuronal level at a brain level but also as we started the program you know talking about having a chat with Hannah when she just woken up from her last general anesthetic.

It also works at a sort of personality level.

You've had a pause in your personality and you wake up slightly confused.

Yeah, that's right.

And yeah, your neurons forget and you forget as well.

There's a nice parallel there.

And she seems to be talking about there being a sort of threshold, that there's lots of variants.

It seemed to be very individualized at which point the drug turns your brain off.

Yeah, I think that's interesting.

It's not that surprising, really.

I mean, we all have different brains, so it's very likely that we're going to respond to anesthetics in different ways.

I mean, that's part of the art of anesthesia that Fiona was talking about.

You can't just know exactly how much anesthetic it's going to take to keep someone at that fine balance between just enough and not too much.

So looking for a signature in the brain that can tell us when someone is anesthetized, when they've lost consciousness, just at that threshold, that's an extremely useful thing to be able to do.

That's an interesting point there, Fiona, that Anil makes.

Do you notice this variation in different individuals, the level of anesthetic that they each require?

Yeah, yeah, no, people are different.

With certain people, it takes quite a long time for them to go off to sleep and they're quite restless as they're going off to sleep, whereas other people will go to sleep quite quickly, seemingly with the same amount of drugs.

So, yeah, quite a lot of variation.

One of the things that we know about pain thresholds from the episode back a few series ago where it involved me being tortured by Irene is that we know that for localised pain, for topical pain, that people vary and we know that my colleague sitting across from me with her ginger hair.

Gingers need more anesthetics.

Gingers have a higher pain threshold.

That is supposed to be true, yes.

Now, that's local anesthetic, that's local pain.

Does this sort of variation transfer into general, into the brain waves that we're talking about?

I think it's more around pain than actual anesthesia.

Oh,

interesting.

Not as dose.

You know what?

Even so,

I need a pump me full of drugs, enough to knock out a small horse.

That's a...

Yes.

Well, anyway, but that individual variation i want to go back to thinking about what's happening in the brain anal that that that must give us clues to what the actual physiology what the neurochemistry

it what what neurochemistry is happening in the brain when consciousness is switched off if there is so much variance between people there's a lot of variance i think there's important levels to think about how anesthetics work one is this very basic level of what are anesthetic

chemicals doing to the neurons or to the synapses, the connections between neurons.

And here a really important clue comes from the fact that anesthetics don't just work on humans.

They work on pretty much anything that's alive.

They work on mice, they work on insects, they work on fruit flies, they work on bacteria, and they even work on plants.

Now you have these plants called mimosa pudica, the so-called don't touch me plant, touch me not plant.

If you touch it, its leaves retract.

If you infuse a plant like that with anesthetics, it loses the ability to respond.

So, anesthetics at some level work on something that's shared across pretty much everything that's alive.

And that might be, as we were talking about earlier, it might be something very, very fundamental to do with the membranes at the surfaces of cells and how their shapes are formed and so on.

Anil,

do you think we should start anesthetizing carrots before we cut into them?

I mean, I think you should, yeah.

I think,

yes.

Well, anyway, I want to go back to thinking about what's happening in the brain.

Is it possible to even score levels of consciousness?

How do we actually, do we, is there a metric?

How do we know how conscious one is?

There are a number of metrics that, as Fiona was mentioning, there have been brain monitoring has been happening in operating theatres for a very long time to try and keep track of the level of anesthesia.

And there's actually been some very exciting research that has developed new kinds of consciousness or anesthesia meters that go a little bit beyond just measuring how strong particular waves are, like these delta oscillations in the brain.

So there are, it's a kind of a new generation of consciousness meters that have been tested under anesthesia, but also under other ways of losing consciousness like sleep or in people with severe brain injury as well.

And these are all based on measuring the complexity of the brain dynamics under these different conditions.

And by complexity, I mean something very intuitive here.

Like when the brain is doing something very, very predictable, you know, just repeated patterns over and over again, that's very low complexity.

And when the brain is behaving completely randomly, like every neuron doing its own thing, every neuron for itself, that's also not very complex either.

Complexity in this sense is this balance between simplicity, predictability, and randomness.

And a new approach that's been pioneered for the last 20 years or so has been measuring levels of brain complexity.

And one really really good way of doing this, a very impressive way I think is very cool actually, is by using a combination of EEG, which we've already talked about, which measures the tiny electrical field generated by brain cells, and a method called TMS, transcranial magnetic stimulation.

And this is basically put a big magnet by the brain, turn it on very briefly and it injects a pulse of energy into the brain.

And you don't notice this, it just activates the brain through the skull and you can see the response to the this activation in the EEG it's a bit like banging on the brain with an electrical hammer and listening to the echo

and what you find is that by measuring the complexity of the echo you know is it is it just like throwing a stone into a pond and there's a there's a single response but it all dies out very quickly that's goes along with unconscious states.

But if the echo is complex, like you throw a few stones into the pond and all these waves are bouncing around and you just see this complicated patterns that come and go over space and time,

that's indicative of a conscious state.

And what's really exciting is that researchers have been able to put a number to this complexity.

And this number seems to be able to track conscious level both in anesthesia but also in sleep and after brain injury and many other conditions too.

And this gives us a clue about everyday consciousness as well.

We need these complex interactions where different parts of the brain speak to each other in different ways in order to be conscious.

So there's, I mean, in summary, still quite a lot we don't understand.

I think there's still a lot to discover.

I didn't mention this at the beginning of the program, but I'm actually having a general anesthetic tomorrow.

So I'm not sure whether I'm going to be more fearful after this conversation or less.

I think I'm going to ask, though, Fiona, for the little drug that they give you that makes you feel like you've had three gen and tonics

before I go in.

Thank you so much to our guests Anil Seth and Fiona Donald.

So Professor Fry, when it comes to the question of how anesthetics actually work, can we say case solved?

Absolutely not Dr.

Rutherford.

Real doctors use them every day and no one quite knows what magic chemistry is happening in our brains.

We fully lose a sense of self though, our consciousness is erased temporarily.

Anesthetics involve blocking certain neurochemical pathways and putting the brain into a holding pattern of slow brain waves.

But precisely how anesthesia actually works remains one of science's great mysteries.

I woke up during an operation once.

Did you?

A general anesthetic.

No, it was like twilight.

I think that's what they call it.

It's essentially where they give you local anesthetic and then they heavily sedate you.

It's lower risk.

So this is when I had

an operation on my my lymphedema,

which I've spoken about a number of times in the past.

Anyway, what happened was I woke up and then I wanted to see what was going on.

So I sat up and had a look.

And I don't really remember seeing that much, but I do remember the reaction of everyone in the room.

They were like, oh no, and then they pushed me back down.

Crikey.

I mean, we should reassure the listeners that that is.

a different process

to general anesthetics.

And it was very, it was, I mean, it's subcutaneous, right?

So it's very superficial.

I probably could have got away without even being sedated.

That's a sedation process.

That was just the being a wimp.

Still, not.

I also file that in the category of suboptimal.

There's so many interesting things about this.

And I know that it is one of science's great mysteries that this thing that doctors use day in, day out, and we don't have a fundamental understanding of what is happening in this weirdness.

There's another thing that we didn't quite get to in the show, which I think is fascinating.

Irene Tracy was talking about the natural variants, how people are different and people's brains are different.

And a while back, I was involved in a project talking about the genetic differences and reactions to anesthetics.

And there's a really interesting category.

There's one particular anesthetic

which is used, pseudocolonesterase, it's called, and it's

addressing a system which is so you can intubate people.

So during anesthetics, you need to get a tube down their throat, and our throats generally don't like that happening.

So you give a local anesthetic, which suppresses the muscles.

And it normally lasts about five minutes.

But in the late 70s, early 80s in India,

a doctor started to notice that some of their patients were going in for voluntary

operations and they were not waking up.

from their anesthetics for up to five or six hours.

And then they wake up and they're absolutely fine, right?

So it wasn't clinically problematic.

So they went through this process of trying to understand which bit of the anesthetic cocktail was causing this and this particular group of people was reacting to.

And it was in fact this succinylconate bit of the anesthetic cocktail mix, which is for suppressing the gag reflex.

And then they noticed that it was only happening in one particular group of people.

And that, so in India, there's still a lot of caste-based endogamy, it's called.

So, you know,

different groups of people that don't necessarily interbreed with each other.

That's a very bad way of explaining it.

Yeah, but it makes, I mean, it makes it, I mean, like, there's all sorts of extremely problematic cultural history associated with this, but ultimately,

ultimately, you have groups that tend to marry and have children within their own groups.

Exactly, that's exactly right.

That's a much better way of explaining it.

You're welcome.

You know what?

I can teach you to hear me on eugenics.

Wait a minute.

Just explain genetics and race to me.

I think you did.

Anyway, so what was noticed was that it was one particular caste that was.

Just to be clear to anyone that doesn't know how heavily associated Adam is in his work with work on genetics, he has a Radio 4 series at the moment called Bad Blood on eugenics.

I wasn't just popping the word eugenics in as a lol.

It's important to just

80% of my work.

Anyway, the point is that this one group of people, the Visia caste, which is like a merchant caste in India,

all of the people that weren't waking up for four, five, six hours from this particular pseudocholinesterase anesthetic were all from this one group.

And so

it was worked out that there was a particular genetic mutation in the chemical pathway, the metabolic pathway, which is processing this particular anesthetic.

And it only exists in this one particular group.

So when you notice things like that,

you can go back through history and work out when that mutation occurred.

And we think it occurred about 2,000 years ago, existed for 2,000 years with absolutely zero effects because no one was being anesthetized with cholinesterase.

How crazy.

And then all of a sudden you see, oh, there you go.

So there's a real thing.

So when we when we were talking about that I was thinking about that because both Anil and I have Indian heritage.

But

I wonder what mutations have already happened that

have not yet revealed themselves because we're not yet drinking the draft

that will show themselves to be.

Well, alcohol is a good example of that because there's natural variation in alcohol dehydrogenase, which is the enzyme that processes alcohol.

And it's distributed in wildly different ways around the world.

And it only has an effect

if you drink.

And that's a big part of the history of scientific racism, in fact.

Oh, it's happened.

I've got to it.

It only took 55 series.

Yeah.

But that's for another time.

Should we do some Curio correspondence?

Curio correspondence, which comes before Curio of the Week.

We don't have a jingle

correspondence.

What are you saying?

It's just been suggested that one of us sings.

Emma, our studio manager, who suggested that, I don't know, Adam and I, we've now got to the stage with Curious Latins where we've done an episode on every conceivable thing, including an episode on singing.

And if you'd listened to that, you would know that it is not wise to ask particularly me, but also Adam, because he'll bang on about being a chorister.

Have I mentioned that I used to be a chorister?

Let's do correspondence.

Go on, there's no, there'sn't a theme tune.

So I left a pause then for the theme tune, but there isn't one.

There isn't one.

So a couple of episodes ago, we did A Fantasia, the concept of the blind mind's eye, the inability to visualize in your head.

And both of us did the test

online.

Then I came up as a hyper-visualizer, and I think you were a pretty good visualizer.

and a fantastic.

Average.

I think I was bang average.

A fantastic,

I still can't remember how to pronounce that.

A fantastic, yeah, that's right.

A fantastic.

But lots and lots of people were stunned

to realize as this program went out that they themselves were A-Fantastic and had thought that as people all around them were saying, picture in your mind's eye, they thought it was metaphorical and didn't realize that other people could actually picture things in their mind's eye.

And there were so many, so many emails that came in about this.

Yeah, and Twitter was all wash with it as well.

It's quite, it's very interesting that, because it's not a well-known phenomenon.

And yet 3%, you know.

Yeah, and didn't know about it.

But anyway, so there is an Aphantasia network.

So if this is something that you've come across, then get in touch with those guys if you just share your experiences and support.

Yeah, loads of correspondence.

This one from Martin Clist was rather lovely.

My wife, Kate, and I have just had the most incredible evening.

I had no idea that Aphantasia even existed and had always assumed the phrase mind's eye was a metaphor.

We've had a lovely evening laughing about how our mad differences that we never even knew despite being married for 10 years.

God, I wonder if that,

you know, you could actually explain some of the joys and maybe not joys in relationships

when discovering that you've got a condition that no one knew about.

How extraordinary.

I mean, it's like one in 30 people.

One in 30.

3%?

Yeah, man.

That is 3%.

Don't call me a a professional mathematician for nothing.

Okay, should we do cure of the week?

We got a letter in from Greg Walson.

He has proposed an exchange of badges.

Badges.

Badges.

Oh, Oh, right, not the mammals.

Right.

I don't.

As I know that you are fans of Matt Damon.

How does he know that?

I think he's.

Have we ever seen that again?

You may recognise us as the employer of his character in Goodwill Hunting.

You may recognise us as the employer of his character in Goodwill.

Okay, so either...

Right, so he was a builder at one point.

Yes.

But he also was at university.

He was a janitor.

Janitor.

In the the university, yes.

And he kept solving mathsy things on glass, which is how mathematicians are.

No, no, no, no, no, no, no, no, no, no.

There was no glass.

It was a mirror in the toilet.

Do you know what?

I've got to be careful about correcting you about films because I did it in an episode recently and I was wrong.

Were you?

Yes.

Okay, there is a mirror.

I accept there's a mirror, but I don't think that counts as glass.

That's the mirror.

Look, I think he does it with a chalkboard.

Yeah, you're right.

And I think it's, and you're right about the mirror.

Let's call that one a square draw.

What What did you get wrong?

It was when I said Chariots of Fire was about the four-minute mile, it wasn't, it was about Harold Abrahams running in the Olympics years before Roger Bannister.

I can see you looking confused about whether you should be smugged that I got it wrong and absolute lack of interest in what I'm saying.

No, it was more that I thought it was about Roman races.

So I think

like the niche, the like nuanced differences between your two things.

But men on Twitter did enjoy pointing it out, so men on Twitter.

Okay, you ready?

Yeah, what is it?

Okay.

Okay, it's two badges.

Here you go.

Here you go.

And they say E over C squared.

Oh, I know what it is.

I know what it is.

Let me see if I can work it out.

No, we should read it out.

It's an equation.

It says E over C squared times square root of minus one times P V over N R.

Oh, crikey, can I do this?

Right, E is energy.

Well, what's an equation with E and C squared in it?

It equals M C squared.

So C is the square, the speed of light.

Yes?

So what's the other letter in the...

M.

Yeah, so M equals E over C squared.

M equals E over C squared.

Yeah, the middle bit, square root of minus one, is

an imaginary number, which is next week's show.

Correct.

The square root of minus one is minus one.

No, one?

I don't know.

It's I, come on.

Oh, I, yeah, an imaginary number.

Thank you, Descartes.

So I, E, M, I.

Now, what's P V over N N R?

P V.

Pressure?

What's the equation?

E equals M C squared.

No, P V.

P V over N R.

What is it?

Is that an electrical one?

No.

P V.

Pressure?

Volume.

Voltage.

Yes.

Volume.

Volume.

Oh, is this Hooke's law?

Boyle's law?

No.

Oh, I don't know.

It's the ideal gas equation.

Embarrassing.

What R?

Radius.

Of a circle, of a sphere.

I don't have to think about this stuff.

What else do you get with gases?

What are the...

Smell?

Look, it says M-I and they're an employer.

M-I,

an employer.

Five.

Mission impossible.

M is equals

P V equals N R T.

Come on.

P V equals N R T.

Time.

MIT.

M-I-T.

M-IT.

M-IT.

Matt Damon worked.

Will Hunting worked at M-I-T.

Well done, Sherlock.

Crying.

The thing that I've noticed the most about this is that Greg spent $17.85 in airmailing this to us.

Yeah.

Thank you, Greg.

I mean, I struggled to get through it with a lot of hand-holding by my colleague there.

I enjoyed that.

I enjoyed that.

That's cool.

Also, neither of us work at MIT.

You can't have a badge.

Yes, you can.

I'm saying that you can.

She vetoed it.

She used the veto.

We do have something else that's connected to Matt Damon because Duncan Macmillan shared this surprising news with us.

Every year, Stephen

Soderbergh.

Soderbergh.

Who's that?

Stephen Soderbergh is like one of the great living directors.

Is he?

Yeah, yeah.

He's made amazing films like

all of the oceans films, Oceans 11, that's great, 12 and 13, not so much.

But also some complete classics like I believe he made Magic Mike, which is a brilliant film.

And the one about the pandemic that happened before the pandemic, where Gwyneth Potter dies, contagion.

He's a superb director.

What's going on here?

Aaron Brockovich.

He made Erin Brockovich.

Oh, that's cool.

Oh, he's cool.

Oh, and one of the films he made with Matt Damon was the

biography of Liberace, which is excellent.

Oh, okay, cool.

All right.

So, anyway, this guy,

this man, Mr.

Stephen, he summarises everything that he's read and watched every year, and he consumes a lot.

But I noticed that on the 29th of January last year, he read the complete guide to absolutely everything, which is mine and Adam's book.

No way.

I thought you should know if you don't already.

We didn't know.

Adam very clearly did not know.

That is no way.

I clicked on the link.

Holy

smokes.

He's like one of my favourite directors of all time.

Is he?

And he's read one of your books.

One of our books.

Our book.

Well, you really.

Where is it?

I can't see the little...

I can't see the...

I made it.

Yeah, but

what?

That's cool.

That is rid.

That is really cool.

You know what, though?

What I've noticed is that he's got basically something every single day, apart from the day when he read our book

where he doesn't have anything for

five entire days afterwards.

He was just washing, allowing it to wash over.

I'm looking over the list here, it's really interesting.

But also a couple of days later he watched Beavers and Butthead Do the Universe.

Love this guy.

Stephen Soderbergh, if you're listening to this show, having read our book, I love your films and I want to be your friend.

And I'm sorry I didn't know who you were, but I mean, I'll happily be your friend too.

Watch Jaws on the 4th of September.

Okay, Adam's just reading

everything that he's read now.

He's watched.

Okay, this is,

let's leave it there.

We'll leave it there.

Next week, we're talking about imaginary numbers.

Bye, everyone.

The Glass Onion he watched.

All about Eve.

RRR, that was really good.

The thick of it.

Oh my God, I love this so much.

That is the best thing that's ever happened to me.

I'm Paris Lees.

Welcome to the Flipside from BBC Radio 4.

In each episode, I'll tell two stories from opposite sides of the coin and use science to ask questions about elements of the human experience that we sometimes take for granted.

Turns out that this person that I sub-led my apartment to, he was, you know, a scammer.

I feel like now I am the person that I was when I was on the internet at 13.

It's lies and it's covered with lipstick and glitter.

Subscribe to the flip side with me, Harris Lees, on BBC Sounds.

Sucks!

The new musical has made Tony award-winning history on Broadway.

We demand to be home.

Winner, best score.

We demand to be seen.

Winner, best book.

It's a theatrical masterpiece that's thrilling, inspiring, dazzlingly entertaining, and unquestionably the most emotionally stirring musical this season.

Suffs!

Playing the Orpheum Theater October 22nd through November 9th.

Tickets at BroadwaySF.com.