Dr. David Linden: Life, Death & the Neuroscience of Your Unique Experience

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science and science-based tools

00:00:04.880 | for everyday life.

00:00:05.900 | I'm Andrew Huberman,

00:00:10.200 | and I'm a professor of neurobiology and ophthalmology

00:00:13.240 | at Stanford School of Medicine.

00:00:15.080 | Today, my guest is Dr. David Linden.

00:00:17.480 | Dr. David Linden is a professor of neuroscience

00:00:19.700 | at Johns Hopkins School of Medicine.

00:00:21.740 | His laboratory has studied neuroplasticity,

00:00:24.220 | that is, how connections in the brain change

00:00:26.800 | in response to experience.

00:00:28.560 | Much of that work focused on a structure

00:00:30.320 | called the cerebellum,

00:00:31.960 | which is also sometimes referred to as the mini brain,

00:00:34.540 | because it looks like a mini brain

00:00:36.360 | in the bottom and back of the human brain,

00:00:38.400 | and it's responsible for an enormous number

00:00:40.120 | of basic functions that we use in everyday life,

00:00:42.520 | including our motor behavior,

00:00:44.660 | that is, our ability to walk and talk,

00:00:46.600 | but also dance, play instruments,

00:00:48.520 | and it's responsible for an enormous number

00:00:50.200 | of basic functions that we use in everyday life,

00:00:53.300 | including our sense of balance,

00:00:55.200 | our ability to learn new motor behaviors,

00:00:57.760 | as well as our sense of timing.

00:00:59.720 | Today, we will discuss the cerebellum and what it does,

00:01:02.320 | but Dr. David Linden will also teach us

00:01:04.640 | about the important sense of touch,

00:01:07.040 | as well as what makes us different as individuals.

00:01:10.000 | The reason today's discussion encompasses

00:01:11.840 | so many important topics is that Dr. David Linden's

00:01:14.640 | laboratory has focused on many of those topics,

00:01:17.120 | and he is also the author of five excellent popular books

00:01:21.080 | about neuroscience that focus on, for instance,

00:01:23.980 | our sense of pleasure and where it originates from

00:01:26.420 | and what controls it in the brain,

00:01:28.260 | as well as our sense of touch.

00:01:30.360 | And today, we start off our discussion

00:01:32.160 | by talking about the recent discovery of a set of neurons

00:01:35.820 | that have been known about for a long period of time,

00:01:38.240 | but that only recently have been characterized

00:01:40.680 | that are involved in sensual touch in particular,

00:01:43.520 | and it's a fascinating conversation, I assure you.

00:01:46.260 | In addition to that, Dr. David Linden informs us

00:01:48.660 | about what makes us individuals,

00:01:51.080 | how each and every one of us

00:01:52.120 | perceives the same things differently,

00:01:54.280 | and it's an absolutely fascinating conversation,

00:01:57.380 | which tells you, for instance,

00:01:58.440 | why some of you think a smell is putrid,

00:02:01.060 | indeed smells like vomit,

00:02:03.260 | whereas others perhaps are not bothered by that smell,

00:02:06.580 | and why others still are attracted to that smell,

00:02:09.820 | or something that you look at or something that you hear.

00:02:13.120 | We also talk about nature versus nurture

00:02:15.500 | and how we come to be who we are,

00:02:17.200 | not just through our genes and epigenetics,

00:02:20.140 | but also through our early childhood experience

00:02:22.580 | and adult experience.

00:02:24.400 | And then in the latter third of our conversation,

00:02:26.200 | we shift to talking about

00:02:27.480 | the so-called mind-body connection

00:02:29.460 | and the science underlying how our thoughts

00:02:31.980 | inform our bodily health, or lack thereof,

00:02:35.020 | as well as how the organs of our body

00:02:36.980 | control the chemicals, hormones,

00:02:38.900 | and thoughts within our brain.

00:02:41.100 | Then we shift to discussing Dr. David Linden himself

00:02:44.140 | and the fact that in 2020,

00:02:46.020 | he was diagnosed with a form of heart cancer

00:02:48.760 | that led his physicians to tell him

00:02:50.880 | that he had six to 12 months to live.

00:02:53.700 | Now, obviously, because he was in our studio

00:02:56.260 | to record this conversation,

00:02:58.220 | he has outlived that prognosis,

00:03:00.780 | but he lives day-to-day with the knowledge

00:03:03.840 | that his death may very well come soon,

00:03:06.060 | although it isn't clear exactly

00:03:07.980 | when that day will come, of course.

00:03:10.600 | He tells us how the initial prognosis of his cancer,

00:03:13.620 | as well as outliving that prognosis,

00:03:16.040 | has informed his day-to-day life,

00:03:18.180 | as well as his thinking and his relationships.

00:03:20.740 | And that leads to a very direct

00:03:22.260 | and frankly emotional conversation

00:03:24.680 | that includes advice on how all of us

00:03:27.300 | can get the most out of our daily living

00:03:29.620 | and out of our overall life.

00:03:31.800 | It's an extremely powerful conversation

00:03:33.860 | that I believe everyone,

00:03:35.160 | regardless of age or health status, can benefit from.

00:03:38.500 | And it's one that makes clear

00:03:39.500 | that not only is Dr. David Linden a spectacular scientist,

00:03:43.040 | but also a spectacular educator,

00:03:45.180 | a spectacular popular writer,

00:03:47.420 | a spectacular family man,

00:03:49.080 | including husband and father and friend

00:03:51.420 | to many people and his colleagues,

00:03:53.620 | but he is also a courageous

00:03:55.760 | and spectacularly generous human being.

00:03:59.140 | Before we begin, I'd like to emphasize

00:04:00.960 | that this podcast is separate

00:04:02.360 | from my teaching and research roles at Stanford.

00:04:04.640 | It is, however, part of my desire and effort

00:04:06.760 | to bring zero cost to consumer information

00:04:08.760 | about science and science-related tools

00:04:10.640 | to the general public.

00:04:11.960 | In keeping with that theme,

00:04:13.000 | I'd like to thank the sponsors of today's podcast.

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00:07:43.780 | the best possible content here at the Huberman Lab Podcast.

00:07:47.760 | And as always, thank you for your interest in science.

00:07:51.020 | And now for my discussion with Dr. David Linden.

00:07:53.980 | Professor Linden, welcome.

00:07:55.500 | - Thanks so much for having me.

00:07:57.420 | - I've been looking forward to our conversation,

00:07:58.940 | and we have a lot to talk about.

00:08:00.740 | - We do.

00:08:02.020 | - Lots of different aspects of science,

00:08:04.380 | lots of different aspects of personal journey

00:08:08.020 | and what you're confronting now

00:08:10.640 | as it relates to your health and your future.

00:08:12.840 | I want to start off with a question

00:08:15.460 | that I learned from the one and only

00:08:18.780 | the great Carl Deisseroth,

00:08:20.260 | who was the first guest on this podcast,

00:08:23.180 | my colleague at Stanford.

00:08:24.240 | And for those of you that don't recognize Carl's name,

00:08:27.040 | he is a absolute phenom.

00:08:29.320 | He's a active clinical psychiatrist.

00:08:33.780 | So he's an MD, and he also is a bioengineer

00:08:36.600 | who's developed a lot of the modern tools

00:08:38.160 | for probing the brain.

00:08:40.040 | And anytime I've met with Carl,

00:08:43.220 | the first thing he says is,

00:08:45.120 | "What are you most excited about lately?"

00:08:47.480 | - That's a good question.

00:08:48.320 | - It is.

00:08:49.380 | So I'm gonna steal that approach and say,

00:08:52.600 | "What are you most excited about lately?"

00:08:55.260 | - Well, very, very lately,

00:08:57.760 | the most interesting thing that I read in neuroscience

00:09:01.780 | is the answer to a scientific problem

00:09:06.780 | that I think is really dear to a lot of people's hearts.

00:09:09.580 | And that is, what are the nerve endings in the genitals

00:09:14.580 | that are responsible for sexual sensation?

00:09:18.120 | And if you think about it, right,

00:09:20.920 | people can feel sexy from being touched

00:09:23.740 | on lots of different parts of the body.

00:09:27.440 | But there's something special about the genitals.

00:09:30.480 | Doesn't matter male or female or intersex

00:09:33.640 | or gay or straight or bi or whatever you are,

00:09:36.480 | the genitals are a hotspot.

00:09:39.100 | And why?

00:09:40.240 | And you'd think as biologists, we'd know this by now.

00:09:43.720 | This would be something we could just answer.

00:09:46.780 | But it's been a mystery for a long time.

00:09:49.520 | And if you go back to 1860,

00:09:53.200 | there was a German neuroanatomist named Krauss.

00:09:56.020 | And he cut thin sections of tissue

00:09:59.040 | from the penis and the clitoris.

00:10:00.440 | And he looked at them under the microscope.

00:10:02.560 | And he saw a particular kind of nerve ending there

00:10:06.040 | that has since been called the Krauss corpuscle.

00:10:09.840 | And there were lots of them in these two places.

00:10:12.460 | And so he thought, well,

00:10:13.620 | maybe this is the cellular basis of sexual sensation.

00:10:17.240 | Maybe these are the particular nerve endings

00:10:20.540 | that are responsible for this.

00:10:24.840 | But there were some things that were in favor of that

00:10:28.960 | and some not.

00:10:30.520 | So these nerve endings are also in some other places

00:10:33.500 | that people can find more or less sexy,

00:10:38.040 | like they're in the nipples and they're in the lips

00:10:40.580 | and they're in the anus,

00:10:41.640 | all places that get popular in that domain.

00:10:45.580 | But they're also in places like the cornea

00:10:48.780 | or the lining of the joints.

00:10:51.400 | So the distribution doesn't quite make sense.

00:10:54.540 | And so it was never known.

00:10:56.760 | And so if you wanted to really test as a scientist

00:11:00.240 | whether these nerve endings are responsible,

00:11:02.320 | you want to record their electrical signals

00:11:05.840 | while the genitals are being touched.

00:11:08.280 | You'd want to inactivate these cells

00:11:09.960 | and see if you could interfere with sexual sensation.

00:11:14.400 | And this in a preprint from David Ginty's group at Harvard

00:11:18.580 | is just what they have been able to do in mice.

00:11:22.280 | They found a way to label and record from

00:11:25.920 | and activate and inactivate artificially

00:11:28.840 | the Krauss corpuscles.

00:11:31.080 | And so you see a nerve ending in the skin,

00:11:34.320 | it could be conveying all kinds of information.

00:11:36.880 | It could be tuned for hot or for cold or for itch

00:11:40.200 | or for pain or for inflammation

00:11:43.840 | or for mechanical sensation,

00:11:46.920 | stretching, vibration, indentation.

00:11:50.520 | And sure enough,

00:11:51.800 | when they recorded from these Krauss corpuscles,

00:11:54.160 | they really are mechanical sensors,

00:11:57.120 | as you would expect if they were involved

00:12:00.160 | in sexual sensation, so that was good.

00:12:02.720 | And then the other thing,

00:12:05.320 | then what they did is they tried

00:12:06.740 | to artificially turn them on.

00:12:09.400 | And so the way they did that is they used genetic tricks

00:12:12.200 | to express one of Karl Deisseroth's molecules

00:12:17.200 | that activates neurons when blue light is shown on them.

00:12:20.880 | And they found that if they express

00:12:23.160 | this artificial protein in the Krauss cells

00:12:28.320 | in a male mouse and then shine blue light,

00:12:31.760 | the mouse gets an erection.

00:12:33.280 | All right, so far so good.

00:12:35.120 | What happens if you turn them off?

00:12:36.680 | Well, if you turn them off in a male mouse,

00:12:40.800 | it's just as interested in females when they're in heat,

00:12:45.160 | but it won't mount and thrust and ejaculate as much.

00:12:50.160 | And if you turn them off in a female mouse,

00:12:53.040 | during the time of her cycle

00:12:54.360 | where she would normally be sexually receptive,

00:12:57.260 | you find that she is much less interested.

00:12:59.920 | She's much less likely to let him mount.

00:13:01.960 | She's much less likely to let him finish.

00:13:04.920 | So this is the remarkable result

00:13:09.880 | that finally after all these years, since 1860,

00:13:14.880 | now we know what the nerve endings are

00:13:18.540 | that convey sexual sensation.

00:13:20.980 | And like all good science, then there are a lot of questions

00:13:25.900 | that are really interesting to our everyday lives.

00:13:28.240 | Like people like different things in bed

00:13:31.360 | and have different propensity for orgasm

00:13:34.160 | or like to be touched in different ways.

00:13:36.880 | Well, is part of that reason because of individual variation

00:13:41.700 | in their Krauss corpuscle structure?

00:13:45.260 | We know that sexual sensation diminishes with aging.

00:13:51.040 | Is that in part because Krauss corpuscle density

00:13:54.800 | is lost from the skin of the genitals?

00:13:57.880 | And that's a reasonable idea because we know, for example,

00:14:00.520 | that fine touch sensors in the fingertips,

00:14:04.280 | so-called Merkel and Meisner endings,

00:14:06.840 | also named after German anatomists like so many things are,

00:14:11.400 | are also lost with age.

00:14:12.760 | So that's a reasonable idea.

00:14:14.060 | So this finding from Ginty's lab

00:14:16.360 | has opened up a whole world of science.

00:14:19.740 | And I've been, my own lab doesn't work on touch,

00:14:23.280 | but I've been a fanboy of touch for many, many years,

00:14:27.760 | mostly because where I work at Johns Hopkins Medical School,

00:14:31.780 | there have been many terrific touch researchers.

00:14:33.920 | It's been a world center for it.

00:14:35.440 | And I hear about it over lunch and I got all fired up.

00:14:38.140 | So years ago I wrote a book about it

00:14:40.120 | and I still follow the field.

00:14:41.680 | And this is the most interesting thing

00:14:43.040 | in that field recently.

00:14:44.360 | - And as I recall, Ginty was your neighbor at Hopkins

00:14:47.200 | before he moved to Harvard.

00:14:48.720 | - That's right, that's right.

00:14:49.840 | He was one of the ones, Ginty, Stephen Shao,

00:14:54.840 | Michael Katerina, Xin Zhongdong.

00:14:58.200 | There've been a number of world leaders

00:15:00.600 | in the cellular basis of touch sensation at Hopkins.

00:15:04.760 | - Do you recall if in the pre-print that you were describing

00:15:08.780 | there was an experiment where they activated

00:15:10.880 | these Krauss corpuscles in females?

00:15:14.800 | - It's funny, you should mention that.

00:15:16.120 | I sent that exact email to David Ginty

00:15:18.920 | and they said they are in the process

00:15:22.000 | of doing that right now and they don't quite know yet.

00:15:25.240 | And so I asked him, I said, so for example,

00:15:27.520 | is erection of the clitoris even a thing in mice?

00:15:30.720 | And he says, well, we're really not sure.

00:15:32.360 | So we're activating the Krauss corpuscles in female mice

00:15:35.840 | and we're just kinda staring at it

00:15:37.920 | and looking and see if anything happens.

00:15:40.040 | Does the body change shape?

00:15:45.040 | Is there a color change?

00:15:46.700 | They don't even quite know what it is.

00:15:48.680 | They're looking for it 'cause it's that much

00:15:50.540 | on the leading edge of things, but it's a good question.

00:15:52.520 | - Yeah, or perhaps the female mice would be more willing

00:15:55.320 | to mate outside of the usual timeframe of receptivity

00:15:59.060 | if these Krauss corpuscles are stimulated.

00:16:02.680 | - That's possible.

00:16:03.520 | My suggestion, my guess would be not

00:16:06.520 | because I think that the hormonal regulation of receptivity

00:16:11.200 | is like a sledgehammer and very hard to overcome,

00:16:14.440 | but they might be more willing to continue mating

00:16:18.380 | or mate for longer during their fertile time.

00:16:23.080 | - And I just wanna remind people

00:16:24.480 | because we had a guest recently, Dr. Rina Malik,

00:16:28.320 | who's a urologist, reproductive and sexual health expert.

00:16:32.400 | She's an MD.

00:16:33.400 | And she made clear that the clitoris and the penis

00:16:38.400 | come from the same embryonic origin.

00:16:41.460 | They are analogous tissues in different individuals.

00:16:47.300 | I do have one more question about this sexual touch thing.

00:16:50.540 | These are peripheral nerves, right?

00:16:54.240 | So these are not of the brain and spinal cord.

00:16:57.240 | They're in what we call the periphery.

00:16:59.360 | And my understanding is that peripheral neurons regenerate

00:17:03.840 | and can remodel themselves extensively in ways

00:17:06.920 | that neurons within the brain and spinal cord

00:17:11.160 | tend to remodel less, especially as one gets older

00:17:14.640 | out of the so-called critical period.

00:17:17.440 | Is it possible that these cross corpuscles

00:17:20.200 | and their patterns of innervation within the genitals

00:17:22.780 | change according to the stimulation that people experience?

00:17:27.700 | In other words, is sexual sensation experience dependent?

00:17:32.700 | - That is a great question.

00:17:34.300 | And so we don't know because monitoring this in people

00:17:39.300 | is not technically possible, right?

00:17:45.120 | It requires cadaver tissue.

00:17:47.860 | So you can only do it once.

00:17:49.820 | In animals, it will be possible.

00:17:53.440 | And it could be for a couple of different reasons.

00:17:56.300 | In other words, it could be, I think what you're imagining

00:17:58.900 | is that there's actual structural plasticity.

00:18:01.060 | If you looked at these cross corpuscles

00:18:04.340 | or that you would actually see them changing

00:18:07.260 | their shape or their size or their density

00:18:10.420 | as a result of experience.

00:18:12.460 | But what can also happen is a phenomenon

00:18:16.720 | like desensitization.

00:18:19.100 | That is to say when there's stimulation for a long time,

00:18:23.240 | then the receptors transiently can become

00:18:28.240 | less sensitive to touch.

00:18:29.960 | And it's well known, particularly in males,

00:18:34.760 | that chronic masturbation can produce desensitization

00:18:40.200 | of sexual sensation in the penis.

00:18:42.760 | And that could be as a result of a physical change,

00:18:47.380 | a morphological change in the cross corpuscles.

00:18:50.680 | But it's more likely to be a change in their function

00:18:54.080 | that you wouldn't be able to simply see

00:18:56.200 | by looking at an outline of their structure

00:18:59.300 | in the microscope.

00:19:01.120 | - Such an interesting topic.

00:19:02.480 | Thanks for opening things up with that.

00:19:04.920 | And I'll have to check out this preprint.

00:19:06.200 | I'm also a huge fan of David Guinty's work and colleagues.

00:19:09.400 | There are many people involved in that domain of work,

00:19:12.640 | of course.

00:19:13.480 | I'd like to talk about your recent book

00:19:18.180 | and the sort of underlying basis of what led you to write it

00:19:23.180 | and what intrigued you about this idea

00:19:27.480 | of human individuality.

00:19:29.500 | The book "Unique" is one that we'll provide a link to

00:19:32.080 | in the show note captions.

00:19:33.140 | And it's a very interesting idea that we are all different,

00:19:38.780 | especially coming from a neuroscientist who,

00:19:41.680 | we were trained at least similarly to learn that,

00:19:44.200 | sure, the bumps and ripples of the brain

00:19:46.260 | and the fine wiring of the brain is different

00:19:48.920 | and we are all unique and different.

00:19:50.640 | We have different shapes, AKA morphologies,

00:19:53.140 | but focusing on human individuality is not something

00:19:55.720 | that modern neuroscience or classic neuroscience

00:19:59.080 | has really done much of.

00:20:00.700 | It's really focused on how people do X

00:20:03.980 | or people do Y this way.

00:20:07.120 | - Tell us about "Unique" and tell us

00:20:09.040 | about human individuality.

00:20:11.360 | - Yeah, well, I mean, you're absolutely right.

00:20:14.260 | So when I look at the experiments in my own lab,

00:20:16.880 | how do we do them?

00:20:17.940 | Well, we work on mice.

00:20:19.580 | Do we work on mice with genetic variation?

00:20:21.700 | No, we work on highly inbred mice that are designed

00:20:25.700 | to be as genetically similar to each other as possible.

00:20:29.120 | And then we raise them basically in prism,

00:20:32.040 | in little cells, which may not be a good idea.

00:20:36.340 | And we try to give them as similar experience as possible.

00:20:39.520 | - They are given toys and food and water,

00:20:41.340 | but I agree, it resembles a prison of sorts.

00:20:44.840 | They aren't free to roam.

00:20:46.620 | - They have nothing like the experience of a wild mouse.

00:20:48.860 | Let me put it that way.

00:20:50.260 | And yes, there are, as you said correctly,

00:20:54.300 | there are plenty of experiments

00:20:56.140 | where there's enrichment for mice and they love it.

00:20:59.320 | So for example, in our lab, when we put running wheels

00:21:03.540 | in the cages or mice and let them run overnight,

00:21:05.900 | they're active at night, your average mouse

00:21:09.020 | will run two kilometers in a night for a little tiny mouse.

00:21:12.340 | And some of the mice are so intense,

00:21:16.100 | they will run 20 kilometers.

00:21:18.220 | Imagine a mouse doing 20K, but it will happen.

00:21:22.140 | They really, really like it.

00:21:23.420 | They don't like being in prison.

00:21:25.800 | They want to exercise and they're really bored.

00:21:29.260 | So yes, to get back to your general point,

00:21:33.520 | so much of science is designed to try to find

00:21:38.400 | general principles of function of the brain,

00:21:43.400 | of physiology, of genetics,

00:21:47.020 | and to ignore individual variation.

00:21:49.360 | But individual variation is so important

00:21:52.720 | to our human experience and actually is so important

00:21:55.720 | to the process of evolution and natural selection

00:21:59.620 | and how species make their way in the world

00:22:04.420 | that it's something that requires a lot of attention.

00:22:09.420 | And to me, what's really fascinating

00:22:12.400 | is that when you look at the variation

00:22:17.400 | in the way sense organs function,

00:22:22.500 | it's almost a miracle that we can agree

00:22:26.680 | on a common reality at all, even within the human species.

00:22:31.680 | And this is true of some senses more than others.

00:22:37.180 | Obviously in your world, in the retina,

00:22:40.040 | we have various kinds of loss of color vision

00:22:44.060 | that are well known and some other more complicated

00:22:47.260 | phenomena having to do with impairments

00:22:49.880 | in the perception of motion or form.

00:22:53.140 | But the place where this really happens

00:22:56.240 | is in the olfactory system.

00:22:59.840 | So we have approximately 400 functional receptors

00:23:04.840 | for different odorant molecule smells in our nose.

00:23:09.960 | And if you sequence the genomes of many people,

00:23:14.720 | you find that the DNA that encodes

00:23:19.720 | for these odorant receptors is unusually variable

00:23:26.200 | from individual to individual.

00:23:28.560 | As a matter of fact, if you take two different people,

00:23:33.560 | on average, they will have functional differences

00:23:36.700 | in 30% of their odor receptors.

00:23:40.920 | And if you do as Leslie Vosall and her colleagues did

00:23:45.840 | at Rockefeller University and give odor tests

00:23:49.880 | where they give people different things to smell

00:23:52.920 | and then they dilute them and find the threshold

00:23:55.080 | at which they can detect them,

00:23:56.680 | you find enormous changes from people to people,

00:24:00.800 | both in general terms.

00:24:02.540 | Some people are just better smellers than others.

00:24:05.480 | But in terms of individual odors as well,

00:24:07.940 | there are some odors that some people can't detect

00:24:10.120 | and other people smell one way.

00:24:12.400 | For example, there is a secreted hormone

00:24:16.840 | called androstenone.

00:24:19.360 | Androstenone, there are some people who can't smell it all.

00:24:23.840 | For some people, it smells like rather pleasant,

00:24:28.080 | like cut grass.

00:24:29.580 | And for some people, it smells foul, like urine or sweat.

00:24:33.700 | And it just depends on genetic variation

00:24:37.920 | in one particular odorant receptor.

00:24:41.240 | - Sorry to interrupt.

00:24:42.520 | Another phenomenal researcher who studies olfaction,

00:24:45.960 | among other things, Catherine Dulock,

00:24:48.620 | I once heard say that some people have a gene

00:24:52.800 | that for them makes the smell of microwave popcorn.

00:24:57.800 | They experience that smell as vomit.

00:25:01.680 | And other people who lack this gene

00:25:04.760 | like the smell of microwave popcorn,

00:25:06.920 | or at least for them, it's not aversive.

00:25:08.460 | So it can really be a binary response.

00:25:11.600 | - Well, it can.

00:25:12.420 | And actually, that's a very particular funny case.

00:25:16.340 | So the relevant chemical there is butyric acid

00:25:20.360 | and also isovaleric acid.

00:25:22.440 | And so there are researchers,

00:25:27.040 | I think Rachel Hertz is one of them,

00:25:30.240 | who have given a mixture of these two chemicals to people.

00:25:33.120 | And if they say, "This is Parmesan cheese,"

00:25:36.020 | they go, "Oh, yeah, that's Parmesan cheese."

00:25:38.400 | And if they give it to other people and say,

00:25:39.740 | "This is vomit," they'll go, "Oh, yeah, that's vomit."

00:25:43.440 | And if they tell people, they give them one vial

00:25:46.320 | and say, "This is Parmesan cheese,"

00:25:47.440 | and they go, "Yeah."

00:25:48.280 | And they give them another one, they say, "It's vomit."

00:25:49.100 | They go, "Yeah."

00:25:49.940 | And then they say, "Well, actually, we fooled you.

00:25:51.120 | "It was the same vial."

00:25:52.100 | They say, "No, you didn't.

00:25:52.940 | "You must have made a mistake."

00:25:54.340 | They're convinced that they couldn't have been

00:25:57.360 | the same thing.

00:25:58.360 | So this points out not only is there genetic variation

00:26:02.440 | that is responsible for how individuals perceive odor,

00:26:07.440 | but we are incredibly suggestible in terms of odors.

00:26:13.180 | And we are very dependent upon them

00:26:18.840 | in terms of cultural context.

00:26:21.620 | And this can be learned.

00:26:23.960 | And this is central to our humanity

00:26:27.440 | in the sense that we humans

00:26:31.400 | are what I like to call the anti-pandas.

00:26:33.760 | Pandas live in one spot in southern China,

00:26:38.860 | and they eat one thing, bamboo, and that's it.

00:26:43.160 | Humans are the opposite.

00:26:44.400 | Humans can live in any ecological niche in the world

00:26:48.880 | from the tropics to the poles,

00:26:50.720 | and humans eat a wide, wide, wide variety of foods.

00:26:55.500 | And as a result, it means that we have to have

00:26:58.600 | a very plastic olfactory system.

00:27:00.480 | There have to be very few things

00:27:02.380 | that we find innately aversive.

00:27:06.160 | There are only a handful of odors, rotting meat odors.

00:27:10.240 | Molecules with the evocative names like cadaverine

00:27:14.020 | and putrescine are things that even babies,

00:27:18.080 | when they're newborn, find aversive.

00:27:20.560 | But other things happen that they need to be learned.

00:27:23.520 | For example, pretty much every adult

00:27:27.780 | finds poop odors unpleasant,

00:27:31.600 | but babies happily play with their own poop.

00:27:34.160 | They have to learn that that's disgusting.

00:27:36.240 | It's not 'cause babies have a different nose.

00:27:38.240 | It's because they have to learn culturally.

00:27:39.720 | - It's not innate.

00:27:40.720 | - It is not innate.

00:27:42.640 | There are only a few innate odor aversions

00:27:47.880 | and a few innate taste aversions that we're born with,

00:27:52.240 | and the other things are elaborated culturally.

00:27:55.000 | And we can think about this in terms

00:27:56.680 | of how we talk about odors.

00:27:59.460 | So for example, we might say vanilla smells sweet.

00:28:04.240 | Well, that's weird.

00:28:07.040 | Those are two different senses.

00:28:08.080 | How can something smell sweet?

00:28:10.200 | That's like saying it sounds red, right?

00:28:13.120 | - It's a statement about synesthesia.

00:28:15.340 | - Right, but how did it come to pass?

00:28:18.240 | And do people say that vanilla smells sweet

00:28:21.440 | everywhere in the world?

00:28:22.720 | Well, the answer is no.

00:28:24.500 | So in places in the world where vanilla is used with sugar

00:28:29.000 | in sweet foods like desserts,

00:28:31.340 | then people say that vanilla smells sweet,

00:28:33.400 | or mint, similarly, smells sweet

00:28:38.020 | if it is typically used together with sugar.

00:28:40.760 | But if you go to a place like Vietnam

00:28:45.580 | where mint is mostly used in savory dishes,

00:28:48.260 | people won't say that mint smells sweet.

00:28:52.620 | - So there's a paired association there

00:28:54.280 | that at least at our level of conscious understanding

00:28:58.180 | feeds back onto what we call olfactory or smell perception,

00:29:02.420 | but really it must be a paired association

00:29:05.760 | at some point in development.

00:29:07.300 | - Yeah, it is.

00:29:08.140 | It absolutely is a paired association,

00:29:09.940 | and it's something that goes on continually

00:29:12.980 | through your life, right?

00:29:14.080 | I mean, lots of people, for example,

00:29:16.780 | have stories of foods that they wouldn't eat as a child,

00:29:21.080 | but they came to like as an adult.

00:29:24.580 | A good example of that is coffee.

00:29:26.840 | A lot of people have to overcome bitter aversion

00:29:31.080 | to become coffee aficionados.

00:29:35.300 | So this feeds into the more general theme

00:29:40.100 | that there is no pure perception.

00:29:46.100 | Perception is inference.

00:29:48.800 | It's not like there is a purely objective world

00:29:53.620 | that can somehow make its way through the senses,

00:29:56.760 | and we can perceive that as the truth.

00:29:58.900 | All of our perception through all of our senses,

00:30:02.740 | both the outward-pointing senses of the world,

00:30:05.380 | like smell and taste and sight and hearing,

00:30:08.980 | and the inward-pointing senses,

00:30:11.540 | like balance and is my stomach full, and things like that,

00:30:16.540 | all of them are based on experience and expectation

00:30:22.220 | and the situation of the moment.

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00:31:21.820 | Are there any examples of uniqueness of visual perception

00:31:26.580 | that come to mind?

00:31:27.620 | I recently did a social media post

00:31:30.540 | that involved, it was essentially three rings,

00:31:34.620 | a blue ring, a red ring, and a blue ring in the center.

00:31:39.620 | Or perhaps it was the other way around.

00:31:41.500 | Excuse me, it was red, blue, red.

00:31:44.580 | And I asked which ring is in front

00:31:48.140 | or are they all in the same plane?

00:31:50.380 | Now, of course, it's a two-dimensional image.

00:31:53.440 | And interestingly, it splits out into about thirds.

00:31:57.380 | Some people see the blue ring in front quite a bit.

00:32:00.780 | Others see a red ring out in front.

00:32:03.160 | Others see them all in the same plane.

00:32:04.760 | And this, we think, has to do with differences

00:32:09.380 | in two things between individuals.

00:32:11.520 | One is the distribution of the cone photoreceptors,

00:32:15.680 | which we know is essentially random between individuals,

00:32:18.980 | maybe even between the two eyes.

00:32:20.660 | And then, and that gives rise to this phenomenon

00:32:23.820 | of chromatic aberration, which is the displacement

00:32:27.700 | of the visual image according to the wavelength

00:32:29.940 | of the light.

00:32:30.780 | And we won't get into the physics of it now.

00:32:32.300 | I'll soon do a post that hopefully distills it

00:32:34.680 | in a manner that's simple enough that people understand.

00:32:36.740 | But clearly, some people see certain colors

00:32:39.220 | in front of others, and the person right next to them

00:32:42.800 | could see the opposite color in front.

00:32:45.340 | And others say, "What are you talking about?

00:32:47.600 | All the colors are in exactly the same plane of vision."

00:32:52.380 | So that's the one that I know.

00:32:53.780 | I'm guessing you know some others

00:32:55.500 | and perhaps some more robust ones.

00:32:57.620 | - Well, I think perhaps this is maybe not

00:33:02.500 | what you had in mind, but one way in which experience

00:33:06.620 | modifies the visual world has to do with how much light

00:33:10.460 | you're exposed to in the first five years or so of your life.

00:33:15.460 | And so kids that don't get outside

00:33:21.020 | are much more likely to be myopic.

00:33:25.380 | And it actually is--

00:33:26.780 | - Near-sighted.

00:33:27.620 | - Near-sighted, yes, when they grow up

00:33:32.420 | than kids who got outside.

00:33:34.060 | And we now know that at least part of the story

00:33:36.840 | is that light seems to stimulate the expression

00:33:41.840 | of a class of molecules called trophic factors

00:33:45.600 | that you're well acquainted with

00:33:47.140 | that actually change the shape of the eyeball.

00:33:49.680 | So it's not really the structure of the retina

00:33:51.360 | or the lens of the cornea.

00:33:53.260 | The actual degree of elongation of the eyeball changes,

00:33:58.260 | changing the way the retina sits relative to the lens,

00:34:02.200 | and that seems to be light-dependent early in life,

00:34:06.600 | and which gives rise to a higher incidence of myopia.

00:34:11.600 | And to me, this is really, well, first of all,

00:34:17.540 | it's news you can use.

00:34:20.360 | You should get your kids outside for all kinds of reasons.

00:34:23.280 | - And you should get outside too,

00:34:24.520 | especially in the morning, set that circadian rhythm.

00:34:26.720 | - I know that's a famous Huberman-esque point.

00:34:31.160 | - They're going to be putting me in the grave, David,

00:34:32.880 | and I'm going to be telling people to,

00:34:34.840 | or maybe it'll be on my tombstone.

00:34:36.820 | He'll say, "Get sunlight in your eyes,"

00:34:39.240 | especially on cloudy days, 'cause there is still sunlight,

00:34:43.480 | even if you can't see the physical object of the sun,

00:34:46.300 | on cloudy days.

00:34:48.260 | - Well, I think this whole idea of having traits

00:34:53.260 | that are dependent upon early life experience

00:34:57.960 | is fascinating, because there are a number of situations

00:35:01.940 | where you would guess that something is genetic,

00:35:06.500 | but it isn't.

00:35:07.420 | It's actually dependent on early life experience,

00:35:09.940 | and there's an amazing story about this having to do

00:35:13.200 | with the early days of World War II.

00:35:15.800 | So in the early days of World War II,

00:35:18.040 | the Japanese army just swept through Asia.

00:35:21.720 | They defeated the British and Malaysia and Singapore.

00:35:25.560 | They overran Thailand and Burma,

00:35:27.480 | and they were knocking on the gates of India,

00:35:30.240 | and everything was going great,

00:35:31.480 | except the Japanese army had a problem.

00:35:34.880 | There were an enormous number of their soldiers

00:35:38.160 | who became incapacitated with heat stroke.

00:35:41.000 | They got, their core temperature got too hot.

00:35:44.160 | And when the army doctors examined them,

00:35:48.960 | they found this was much more likely to happen

00:35:51.240 | in soldiers who came from the northern part of Japan,

00:35:56.040 | Hokkaido, where it snows in the winter,

00:36:00.680 | as opposed to the southern part of Japan,

00:36:02.560 | like Kyushu, which is a semi-tropical environment.

00:36:06.440 | And the classical explanation the biologists like us

00:36:10.320 | would guess would say, oh, all right,

00:36:11.720 | well, this has happened genetically over many years.

00:36:15.600 | You have a family that's been in Kyushu

00:36:17.920 | for many generations, and you've selected

00:36:20.440 | four gene variants that allow you

00:36:21.880 | to tolerate the heat better.

00:36:23.200 | And we know actually what this is.

00:36:25.580 | So if you're more heat tolerant,

00:36:27.820 | it's because you have more of a particular class

00:36:30.700 | of sweat gland called the eccrine sweat glands,

00:36:34.020 | the sort of saltwater sweat glands,

00:36:35.740 | not the lippety, stinky, armpit sweat glands

00:36:39.300 | called the apocrine ones.

00:36:40.880 | The eccrine ones, you have a higher fraction of them

00:36:43.600 | that are innervated, meaning that the signals

00:36:46.580 | from your brain that say your core is too hot

00:36:48.680 | can then make you sweat.

00:36:50.600 | So the total density of sweat glands

00:36:53.000 | between northern and southern soldiers in Japan

00:36:56.560 | wasn't different, but the southern soldiers

00:36:59.680 | tend to have a higher degree of innervation.

00:37:01.840 | All right, so you say, okay, well,

00:37:02.740 | this happened genetically over many generations.

00:37:05.320 | But if you look at those rare cases

00:37:07.660 | where you have soldiers from a long-established

00:37:09.720 | northern family and their parents move south

00:37:12.720 | and they grew up in the southern location,

00:37:16.500 | they had high sweat gland innervation.

00:37:18.840 | They were well heat tolerant.

00:37:20.600 | Conversely, if you had a well-established

00:37:23.160 | southern Kyushu family and they moved to Hokkaido

00:37:26.500 | and then had their child, that child developed

00:37:29.840 | the northern sweat gland innervation pattern.

00:37:34.120 | - So meaning less nerve innervation of those sweat glands,

00:37:36.580 | as you mentioned before, just as many sweat glands,

00:37:38.560 | just less nerve innervation.

00:37:39.920 | Therefore, those sweat glands could not be activated.

00:37:42.440 | They couldn't dump heat as well.

00:37:43.500 | Their heat tolerance was lower, correct?

00:37:45.080 | - Exactly right, and what's wonderful

00:37:48.880 | is that this gives an advantage

00:37:53.880 | that you can't get through evolution

00:37:57.720 | and that it can happen right away in one generation, right?

00:38:01.840 | Evolutionary change is slow, right?

00:38:04.560 | And you can adapt as a species and as a family

00:38:08.040 | over many, many, many generations,

00:38:10.840 | but when you have a phenomenon that is set

00:38:14.500 | by early life experience, well, then you can benefit

00:38:19.080 | from that early life experience within your own life.

00:38:21.480 | It's not that your great, great, great, great,

00:38:22.880 | great grandchildren will ultimately benefit.

00:38:25.880 | You benefit.

00:38:27.920 | Another wonderful example of this

00:38:30.040 | comes from field mice, voles, and we were talking earlier

00:38:35.200 | about how we both worked with the scientist Irv Zucker

00:38:38.520 | at Berkeley, who was a specialist in voles,

00:38:44.800 | and what people found is that

00:38:48.000 | if you take wild-caught field mice

00:38:52.280 | and you have pregnant mothers and you have them in the lab,

00:38:57.280 | but you manipulate the lights

00:39:00.200 | so that you have artificial spring.

00:39:03.080 | In other words, day length is getting longer

00:39:05.560 | day after day during the pregnancy.

00:39:08.520 | Then what happens is when their pups are born,

00:39:12.300 | they will have a low density of fur

00:39:14.760 | anticipating summer temperatures.

00:39:17.100 | If you, however, put them in artificial fall

00:39:24.040 | where day length is getting shorter,

00:39:26.240 | they will be born now with high density

00:39:29.680 | of fur anticipating winter temperatures,

00:39:32.560 | and of course, you can do this

00:39:34.040 | no matter what the season actually is in the world

00:39:38.120 | by manipulating these lights in the lab,

00:39:40.600 | and so like the sweating Japanese soldiers,

00:39:43.580 | this is a great example of early life plasticity

00:39:47.700 | and just the sort of trait that if you ask someone,

00:39:50.040 | they would probably guess is heritable,

00:39:52.580 | but actually is not.

00:39:54.700 | - Thanks for mentioning Irv Zucker,

00:39:57.120 | who, as you also mentioned, was an advisor to us both,

00:40:00.640 | who's done incredible work in circadian biology,

00:40:02.800 | seasonal rhythms, hormones and behavior.

00:40:05.140 | I have such reverence for Irv,

00:40:07.080 | and the experiment you mentioned made me smile wide

00:40:09.880 | because it's but one of, gosh,

00:40:12.800 | maybe hundreds of incredible studies,

00:40:15.160 | so if people are interested in seasonal rhythms

00:40:17.500 | and circadian rhythms and biology

00:40:20.240 | of the most interesting kind,

00:40:21.480 | definitely check out Irving Zucker's work at Berkeley.

00:40:24.780 | I'll provide a link to his PubMed there.

00:40:28.560 | Since we've been taking a tour of individual variation

00:40:30.800 | in olfactory perception, visual perception,

00:40:34.360 | and now heat tolerance, I have to ask,

00:40:39.160 | are you aware of any examples off the top of your head

00:40:42.440 | in the auditory domain that particularly intrigue you?

00:40:46.400 | - Yeah, well, I would say one really interesting example

00:40:50.360 | has to do with perfect pitch, so perfect pitch as a trait,

00:40:54.360 | that is to say, you have the ability to hear a note played

00:40:59.360 | and say, oh, that's a C sharp, right?

00:41:02.920 | This is a pretty rare trait,

00:41:04.480 | so even if you look among highly trained musicians,

00:41:09.040 | if you went to Peabody Conservatory at my university,

00:41:12.600 | Johns Hopkins, and tested people there,

00:41:14.880 | you would find a higher incidence of perfect pitch

00:41:17.280 | than you would in the general population,

00:41:18.880 | but still, maybe one in 10 trained musicians

00:41:23.760 | have perfect pitch, and parenthetically,

00:41:25.520 | having perfect pitch doesn't necessarily

00:41:27.640 | make you a better musician,

00:41:29.600 | but it's an interesting phenomena,

00:41:30.960 | and so the question is, well, is perfect pitch heritable?

00:41:35.840 | And the answer is, when you look at twin studies,

00:41:40.820 | which is what we use to estimate heritability,

00:41:43.280 | the answer is, it's kinda low.

00:41:46.120 | There's a heritable component,

00:41:47.560 | but it accounts for, my recollection is on the order

00:41:51.440 | of 30, 40% of the variability in perfect pitch.

00:41:56.000 | However, if people receive ear training

00:42:00.360 | starting at a young age,

00:42:02.600 | the chance that they will develop perfect pitch

00:42:06.140 | can improve drastically.

00:42:09.160 | - In your book, Unique, do you cover aspects

00:42:12.880 | of human individuality that extend beyond

00:42:15.680 | the perception domain into the cognitive domain?

00:42:20.180 | - Well, yeah, absolutely, and you know,

00:42:24.060 | I think it's good to set the stage here

00:42:27.460 | if we're gonna be talking about heritability

00:42:29.580 | and human individuality,

00:42:31.540 | and so if I can go off on a little bit of a riff

00:42:34.720 | for the benefit of your listeners and viewers here.

00:42:39.520 | So if you look at human traits,

00:42:43.080 | whether they're behavioral traits like shyness

00:42:46.320 | or very straightforward morphological traits

00:42:49.640 | like height, what you tend to find

00:42:53.740 | is that there are very few traits

00:42:57.320 | that are entirely heritable,

00:42:59.340 | where all their variability can be predicted

00:43:01.940 | based on the gene variants you get

00:43:03.280 | from your mother and father,

00:43:04.900 | and there are a few traits that are absolutely unheritable,

00:43:09.760 | but that most fall in between.

00:43:11.720 | So let me give an example.

00:43:13.720 | Everyone in the world has either wet or dry earwax,

00:43:19.080 | and it turns out that this is determined

00:43:21.680 | by variation in the single gene.

00:43:23.920 | The name of the gene is boring.

00:43:25.360 | It's ABCC11.

00:43:27.760 | It's an ion transporter,

00:43:30.360 | and there's a variation in this gene

00:43:34.000 | gives rise to either wet or dry earwax.

00:43:38.080 | It doesn't matter how your parents raised you.

00:43:39.800 | It doesn't matter what foods you ate growing up.

00:43:41.680 | It doesn't matter what diseases your mother had

00:43:45.140 | when you were in the womb.

00:43:46.280 | It's 100% heritable.

00:43:49.940 | Well, does this mean that ABCC11,

00:43:53.540 | we should call it the earwax type gene?

00:43:56.440 | Well, no, because it's not there just for that.

00:43:59.000 | Like this gene is expressed in cells

00:44:02.460 | in all parts of the body doing all kinds of things.

00:44:05.860 | Earwax is just something that we notice.

00:44:08.560 | Genes don't code for traits.

00:44:10.040 | They code for proteins,

00:44:11.880 | and so we have to be careful

00:44:13.800 | about how we refer to them in that way.

00:44:17.320 | For example, the wet earwax variant of the ABCC11 gene

00:44:22.320 | also confers a slightly higher risk for breast cancer.

00:44:27.160 | So clearly it's not just for earwax.

00:44:30.880 | It's for a bunch of things,

00:44:31.920 | most of which we don't yet know about.

00:44:35.020 | But in the case of earwax, this trait is 100% heritable.

00:44:39.200 | At the other end of the scale,

00:44:40.840 | speech accent is 0% heritable.

00:44:44.560 | It is entirely dependent upon the speech

00:44:47.500 | that you experience in your childhood.

00:44:51.100 | And interestingly, it's the speech of your peers

00:44:54.280 | more than the speech of your family,

00:44:56.920 | which is why the children of immigrants

00:44:59.080 | sound like the place where they wound up,

00:45:00.760 | not like their parents.

00:45:02.840 | And there is no evidence for any degree of heritability.

00:45:06.260 | Now just to be clear, I'm talking about speech accent,

00:45:09.280 | like whether you have a high or a low voice

00:45:11.320 | or it's nasal or more or less resonant.

00:45:13.560 | These are physical things having to do with the vocal tract

00:45:16.240 | and they are in part heritable.

00:45:19.240 | Okay, so we've got one thing that's 100% heritable

00:45:21.960 | and one thing that's 0% heritable,

00:45:23.920 | but where do most things fall?

00:45:25.060 | Most things fall in the middle.

00:45:26.800 | One of the most heritable traits

00:45:30.720 | that we know about in humans is height.

00:45:33.240 | And in the United States,

00:45:35.840 | height is about 85% heritable.

00:45:40.840 | 85% of the variation in the trait of height

00:45:42.960 | can be explained by what you inherit

00:45:46.300 | from your mother and your father.

00:45:49.440 | Well, what's the rest?

00:45:50.440 | Well, it's nutrition, it's the diseases you fought off,

00:45:54.200 | it's also random variation,

00:45:57.200 | which we'll talk about a lot later.

00:45:58.960 | Now, you might say, okay, well,

00:46:03.080 | that's an estimate for people in the US.

00:46:04.900 | Is this true all over the world?

00:46:06.220 | Well, no.

00:46:07.600 | If you go to a place where people routinely

00:46:12.160 | don't get enough nutrition

00:46:14.620 | and are routinely fighting off infectious diseases,

00:46:18.400 | like this has been studied in rural Bolivia,

00:46:21.120 | for example, or rural India,

00:46:23.440 | now height is no longer 85% heritable,

00:46:27.120 | it's only 50% heritable.

00:46:30.280 | Why?

00:46:31.280 | Because people in these situations

00:46:36.280 | where they don't get enough nourishment,

00:46:38.980 | where they're fighting off these diseases,

00:46:40.300 | can't live up to their genetic potential for height.

00:46:44.520 | If you want to make things better

00:46:48.040 | for the people of the world,

00:46:49.700 | then everyone needs to have basic things

00:46:54.700 | like the ability to learn and enough nutrition

00:46:57.140 | and decent medical care and schools

00:46:59.840 | in order to fulfill their genetic potential

00:47:04.120 | for positive traits.

00:47:07.880 | And height I've used as an example

00:47:11.200 | because it is very uncontroversial,

00:47:15.720 | but we could apply the very same analysis

00:47:20.020 | to intelligence, general intelligence.

00:47:23.640 | Now, there are people who argue about,

00:47:25.960 | do things like IQ tests really measure anything real?

00:47:29.120 | And there's been a lot of fighting

00:47:31.440 | in the scientific literature about this,

00:47:32.920 | but I think intelligence tests aren't perfect

00:47:36.660 | and they are sometimes culture-bound,

00:47:39.080 | but they are actually quite predictive of later success.

00:47:44.080 | And much more so than, say, SAT tests or GRE tests

00:47:49.440 | or MCATs or other standardized tests.

00:47:53.200 | - But presumably those correlate in some way.

00:47:55.640 | - They do, I do.

00:47:56.760 | But the IQ tests are better, actually.

00:47:59.560 | - You're talking about the classic IQ test?

00:48:02.960 | - I am talking about the modern variance

00:48:06.080 | of the classic IQ tests that are administered

00:48:09.480 | by trained psychologists and aren't just a paper form.

00:48:13.840 | And so they're not perfect and no test will be perfect,

00:48:18.160 | but they're pretty good.

00:48:19.400 | And so then if you ask the question,

00:48:20.880 | well, what is the heritability for IQ test score

00:48:26.720 | well, the answer tends to be different

00:48:30.840 | depending upon the population.

00:48:33.040 | If you look again in countries like the US

00:48:38.040 | or in Western Europe that are fairly affluent

00:48:40.840 | where people tend to have good access to nutrition

00:48:45.840 | and medical care and schooling and kids get to play

00:48:49.040 | and they're not traumatized by war,

00:48:52.660 | then IQ test score is heritable in the ballpark of 60, 70%.

00:48:57.660 | But if you look at people who don't have those benefits,

00:49:06.240 | who are poor, and this can be in the United States as well,

00:49:10.720 | if you look at communities that face discrimination

00:49:15.720 | and have consistently poor healthcare and schools,

00:49:20.740 | then IQ is less heritable.

00:49:23.400 | Why?

00:49:24.240 | For the very same reason that it is in height,

00:49:26.440 | because people can't live up to their genetic potential

00:49:31.440 | when they don't have the basic things that everybody needs.

00:49:35.320 | - So presumably if two identical twins,

00:49:40.760 | and I realize they aren't identical,

00:49:42.520 | but you're familiar with twins, you have twin children.

00:49:45.460 | If two identical twins are raised separately,

00:49:51.420 | the correlation in their IQ, is it that only 60,

00:49:56.420 | I think you said about 66% of their IQ can be predicted

00:50:02.080 | on the basis of their genetic makeup alone?

00:50:04.820 | I mean, it makes perfect sense to me as to why

00:50:06.980 | if one of those twins went to schools that were demanding

00:50:11.940 | of a lot of different topic matter,

00:50:14.460 | and the other one went to schools

00:50:16.420 | where the instruction level was really deficient,

00:50:20.980 | that one would perform far less well on an IQ test,

00:50:24.640 | unless of course the IQ test

00:50:26.740 | isn't tapping into school-based knowledge,

00:50:29.340 | it's tapping into some other thermometer

00:50:32.900 | of so-called intelligence or IQ.

00:50:36.500 | - Well, you know, the thing is that good schools

00:50:39.900 | correlate with many other things, right?

00:50:42.940 | So the students that go to good schools

00:50:44.620 | aren't just benefiting from good schools,

00:50:46.540 | they tend to also have good medical care

00:50:48.740 | and safer, less traumatizing neighborhoods,

00:50:50.900 | and they're more likely to have books,

00:50:52.900 | parents with books in the home,

00:50:54.380 | and a whole number of things that are all beneficial.

00:50:58.860 | So when you try to do epidemiology on this,

00:51:01.700 | you have to be aware that things

00:51:03.420 | are very deeply interconnected,

00:51:05.700 | but you bring up a good point.

00:51:07.600 | So it turns out that the way we get these estimates

00:51:11.020 | of heritability, there's two ways.

00:51:12.900 | One way is to compare so-called identical

00:51:17.900 | or monozygotic twins with so-called fraternal

00:51:22.400 | or dizygotic twins.

00:51:24.740 | So the identical twins will share nearly 100%

00:51:29.740 | of their gene variance, and on average,

00:51:33.420 | fraternal twins share 50% of their gene variance.

00:51:38.420 | And generally speaking, when people do these studies,

00:51:41.800 | in order to avoid confounds of sex,

00:51:44.880 | they'll compare same sex fraternal twins,

00:51:47.840 | so boys to boys and girls to girls.

00:51:50.320 | And when you put these incidents into a formula

00:51:56.760 | called Fisher's equation, then you can come up

00:51:59.580 | with an estimate of the heritability of the trait.

00:52:03.040 | But there is an assumption present in that,

00:52:08.040 | and it's called the equal environment assumption.

00:52:10.740 | You're saying, well, two kids raised in the same family

00:52:14.900 | have the same environment.

00:52:17.180 | Well, that's not always true, right?

00:52:20.980 | That can be violated by a number of different situations.

00:52:25.980 | So it turns out that a more powerful

00:52:29.460 | but much more difficult way to estimate heritability

00:52:33.740 | is by looking at twins reared apart,

00:52:38.300 | either identical twins or fraternal twins reared apart.

00:52:42.100 | And there was a landmark study called the Minnesota Study

00:52:46.300 | of Twins Reared Apart, which is abbreviated MYSTRA.

00:52:51.200 | That is really the gold standard for assessing

00:52:55.220 | the heritability of many different human traits,

00:52:58.300 | both behavioral traits, but also disease incidents.

00:53:02.420 | But of course, it's a small M, because the population

00:53:06.180 | of identical twins reared apart that you can get

00:53:08.820 | into the lab isn't that large.

00:53:11.980 | They had something, I don't remember the exact numbers,

00:53:14.060 | but they had something like 80-some identicals

00:53:18.800 | and 50-some fraternals in their sample.

00:53:23.800 | But by doing this, they were able to come up

00:53:27.140 | with a lot of interesting estimates.

00:53:28.940 | And so, for example, most personality traits,

00:53:34.260 | what the psychologists use the acronym OCEAN to mean,

00:53:38.460 | openness, conscientiousness, empathy,

00:53:41.900 | agreeableness, and neuroticism, I think I got that right.

00:53:44.860 | - Spelled right, yep.

00:53:47.500 | - That these traits, on average,

00:53:49.680 | tend to be about 50% heritable.

00:53:54.020 | And so, okay, you say, right, well,

00:53:56.220 | 50% of those personality traits is heritable,

00:53:58.820 | the rest has gotta be like how you were raised.

00:54:01.220 | It's gotta be in your family.

00:54:03.860 | And so, everyone was shocked when they actually

00:54:06.860 | did the analysis and found that family

00:54:11.860 | has almost nothing to do with it.

00:54:13.540 | What, are you kidding?

00:54:19.340 | It's got to.

00:54:22.220 | And I think the important thing to realize

00:54:24.160 | is these traits I just listed,

00:54:26.460 | we call these personality traits,

00:54:28.100 | but they are not the sum total

00:54:29.820 | of the way you are in the world.

00:54:32.340 | Parents can inculcate many things in their children.

00:54:36.620 | They can demonstrate trades,

00:54:38.740 | so people are much more likely to go into an occupation

00:54:41.820 | if their parents did.

00:54:43.260 | They can inculcate moral ideas and religious ideas,

00:54:48.260 | but in terms of these ocean personality traits,

00:54:54.740 | they have astonishingly little to do with it.

00:54:57.260 | So then, this brings up the question,

00:54:59.780 | well, if 50% of the variation in these personality traits

00:55:04.540 | is not from your genetics and it's not from your family,

00:55:08.820 | where does it come from?

00:55:10.820 | And the answer seems to be is that it comes

00:55:14.780 | from the random nature of the development

00:55:19.780 | of the body and the nervous system.

00:55:23.060 | And this is a point that I think

00:55:25.140 | many people don't understand.

00:55:28.100 | This is something that biologists know,

00:55:30.220 | but we've done a very poor job of communicating

00:55:35.180 | to the general public.

00:55:38.140 | The genome, all your DNA, all three billion bases of DNA,

00:55:43.140 | all 19,000 or so genes in a human,

00:55:48.500 | don't make a blueprint for making your body and brain.

00:55:53.500 | It's not a schematic diagram

00:55:56.100 | that connects everything to everything,

00:55:57.380 | particularly in the nervous system

00:55:59.020 | where we have these hundreds of trillions of connections.

00:56:01.940 | Rather, it's a rather vague recipe.

00:56:05.780 | So the genome doesn't say, oh, okay,

00:56:08.300 | you glutamate using neuron in the brain region

00:56:10.900 | called the thalamus, grow for 200 microns towards the top

00:56:14.860 | and then cross the midline and then grow towards the ear

00:56:19.060 | for another distance.

00:56:21.220 | No, it says something like, hey,

00:56:23.180 | you bunch of glutamate neurons in the thalamus

00:56:25.340 | over here in this area, about half of you

00:56:27.900 | cross the midline.

00:56:29.620 | And so what does this mean in terms of individual variation?

00:56:32.260 | Well, it means, well, for some individuals,

00:56:35.500 | 40% of their axons will cross the midline of the brain.

00:56:38.700 | And for another individual, 60% will,

00:56:42.700 | even in identical twins.

00:56:45.780 | And as you correctly said a moment ago,

00:56:47.580 | identical twins aren't really identical,

00:56:49.980 | either in their bodies or their temperament.

00:56:53.420 | So if you take newborn identical twins

00:56:55.940 | and you give them a CT scan

00:56:58.060 | just to measure the shape of their organs,

00:57:00.660 | they're not the same.

00:57:02.300 | You might have one twin whose spleen

00:57:04.300 | is 30% larger than the other twins

00:57:06.940 | or whose liver is 30% smaller than the other twins,

00:57:11.060 | even though they have the exact same DNA

00:57:13.340 | and they're lying right next to each other in the womb

00:57:15.940 | and presumably have the same

00:57:18.220 | or very similar fetal environment.

00:57:21.100 | And the reason is the random, or as we say,

00:57:24.660 | stochastic nature of neural development.

00:57:29.580 | A great way to study this is with nine banded armadillos.

00:57:34.460 | I know we're getting weird here, but.

00:57:36.300 | - I love the armadillo because I've been told,

00:57:38.780 | tell me, I don't want to interrupt you too long,

00:57:42.340 | but as far as I know, the only animal in North America

00:57:46.780 | that carries leprosy?

00:57:49.460 | - That is true.

00:57:51.700 | - And there's a lot of twinning going on

00:57:54.940 | in armadillos, right?

00:57:56.180 | - Well, what there is is actually quadding.

00:57:58.900 | So armadillos, or the nine banded armadillo in particular,

00:58:03.100 | and there are different armadillos.

00:58:04.180 | I'm not really an armadillo specialist,

00:58:06.060 | so I don't know if this holds for all of them,

00:58:07.460 | but the nine banded armadillo

00:58:10.220 | is born as identical quadruplets.

00:58:13.740 | - Awesome. - Awesome.

00:58:16.420 | So you can take these identical quadruplet,

00:58:19.360 | newly born armadillo.

00:58:21.780 | I don't know if you think you'd call them pups.

00:58:23.020 | I don't know what a baby armadillo is called.

00:58:24.640 | I'm sure there's some particular word for it.

00:58:27.140 | - Someone will tell us in the comments on YouTube,

00:58:30.060 | what is the name of a baby armadillo?

00:58:31.780 | I know like a ferret, baby ferrets are kits.

00:58:34.220 | The moms are Jills, the dads are Bobs.

00:58:38.020 | I used to be obsessed with this kind of naming.

00:58:40.140 | You know, it's a business of ferrets

00:58:42.540 | or what is like a gang of raccoons or whatever.

00:58:45.700 | So if you can tell us what the name is

00:58:48.780 | for the baby armadillos,

00:58:50.460 | as well as what do you call a group of armadillos,

00:58:53.020 | you win the pride associated with being right.

00:58:55.440 | - That's right, right.

00:58:56.540 | One of my favorites is an ostentation of peacocks.

00:59:01.100 | - Amazing. - Or a murder of crows.

00:59:03.260 | - Who comes up with this stuff?

00:59:04.340 | - Yeah, I know, it's a good- - Or a raft of otters.

00:59:06.740 | I think that's correct, but.

00:59:10.100 | - So if you have four newborn identical

00:59:14.420 | nine-banded armadillos,

00:59:15.980 | then this is a great model system

00:59:18.460 | that biologists can use to study

00:59:20.660 | stochastic differences in development.

00:59:24.940 | And sure enough, their brains are wired

00:59:27.420 | slightly differently, their bodies are slightly different.

00:59:30.620 | If you test them behaviorally,

00:59:32.540 | even very, very early in life,

00:59:34.420 | they have different propensities.

00:59:35.980 | Some are bolder and will explore more.

00:59:37.940 | Some will tend to hide in the corner more.

00:59:40.740 | And you know, we know this from the lab.

00:59:43.140 | You get a box of mice that are inbred from the breeder,

00:59:46.660 | and you pluck them out,

00:59:47.580 | and they're not behaviorally identical.

00:59:49.500 | Some might try to bite your hand.

00:59:51.420 | Some will run away.

00:59:52.860 | Some will stand stock still.

00:59:54.940 | Where does this behavioral variation come from

00:59:57.400 | in mice that are nearly genetically identical?

01:00:00.540 | Well, it comes from a bunch of things.

01:00:02.620 | They don't always have exactly equal experience.

01:00:05.500 | But mostly, it comes from

01:00:07.780 | the pseudo-random stochastic nature of development.

01:00:13.060 | I'd like to take a quick break

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01:01:19.320 | - And is the pseudo-random stochastic nature of development

01:01:22.620 | one of the major, excuse me, driving forces for evolution?

01:01:26.300 | Because, you know, we hear about mutations,

01:01:28.780 | and we always think, or people tend to think, rather,

01:01:31.700 | that mutations are bad,

01:01:33.380 | but of course mutations provide the variation

01:01:35.600 | that can also subserve adaptive traits.

01:01:38.820 | I mean, if you're a fan of the X-Men, as I am,

01:01:40.980 | huge fan of the X-Men, the entire series, every single one,

01:01:44.060 | including the Wolverine movies,

01:01:45.540 | you quickly come to learn that genetic mutation

01:01:48.400 | is at the heart of variation,

01:01:49.960 | which is at the heart of individuality,

01:01:51.820 | which is what we're talking about.

01:01:53.300 | - Right, and so genetic variation

01:01:55.240 | is at the heart of individuality,

01:01:57.300 | but there is also, there are also these other things, right,

01:02:02.300 | that we've talked about.

01:02:04.460 | There's the effects of early life experience,

01:02:06.540 | and there is the stochastic nature of development.

01:02:08.900 | Because if you, through the randomness of development,

01:02:12.920 | happen to have like a particularly great liver,

01:02:16.780 | you're not gonna pass that on to your children, right?

01:02:18.780 | That isn't in your germline.

01:02:21.940 | You won't pass that trait along.

01:02:25.360 | - Just a brief insert here on germline.

01:02:27.760 | We had Oded Rajshafi on the podcast

01:02:29.700 | who studies epigenetic transmission

01:02:32.140 | and an inheritance of, it's not Lamarckian,

01:02:37.140 | we have to point that out,

01:02:38.460 | but inheritance of sort of acquired traits does happen.

01:02:42.580 | And the germline is the genes that are present

01:02:45.300 | in the sperm and in the eggs.

01:02:47.860 | All the other cells of your body have genes, of course,

01:02:50.620 | but the best way to put this is simply going to the gym

01:02:54.240 | and getting fit does not make your children more fit

01:02:57.780 | because the germline, as far as we know,

01:03:00.540 | is not modified in a direct way.

01:03:03.000 | In other words, the DNA within sperm and eggs

01:03:06.500 | are not modified according to your behaviors

01:03:08.900 | in most but not all cases.

01:03:10.880 | - That's right.

01:03:11.720 | And as you correctly said about Oded's work

01:03:15.940 | and other people's work,

01:03:17.740 | there is what's called

01:03:19.580 | transgenerational epigenetic inheritance,

01:03:22.380 | which means that you can have traits that are passed

01:03:25.400 | not from one generation to the next,

01:03:26.920 | but even two generations to the grandchildren

01:03:30.500 | that don't require modification of DNA.

01:03:32.660 | But to date, that has been shown very convincingly

01:03:36.420 | in worms and in plants.

01:03:40.680 | The evidence in mammals is really not there yet,

01:03:44.900 | in my opinion.

01:03:46.180 | And most of the claims for that,

01:03:48.460 | and it's a very popular thing to say,

01:03:50.700 | I epigenetically inherited my grandmother's

01:03:53.940 | or great-grandmother's trauma.

01:03:57.580 | The evidence at present is poor, actually.

01:04:02.180 | A lot of it comes from epidemiology,

01:04:05.740 | most of which came from famines

01:04:08.620 | in the Överkallik's region of northern Sweden.

01:04:12.740 | And they had very good medical records,

01:04:14.820 | and they said, oh, well,

01:04:15.940 | if your grandfather went through the famine,

01:04:18.580 | then you're more likely to have this trait if you're male,

01:04:21.180 | or if your grandmother went through this,

01:04:22.980 | then if you're male, you'll have this trait,

01:04:24.500 | and if you're female, you'll have that trait.

01:04:26.100 | And I mean, there are two problems.

01:04:27.900 | One is that there's not a biological mechanism,

01:04:29.940 | but the other problem is that the way these things

01:04:33.860 | were discovered is by something called harking,

01:04:37.240 | or hypothesizing after the results are known.

01:04:41.460 | They did very many statistical comparisons

01:04:46.260 | to try to find something significant.

01:04:48.660 | And you know from your work in the lab

01:04:50.560 | that when you do many comparisons,

01:04:52.600 | you're gonna get some things that look significant,

01:04:55.260 | just occasionally, randomly through luck.

01:04:59.900 | And you have to apply a statistical correction

01:05:02.980 | called a Bonferroni correction

01:05:04.820 | when you make many particularly post hoc comparisons

01:05:08.340 | after the experiment comparisons

01:05:11.240 | to set the bar much higher for accepting that data.

01:05:15.460 | And most of those studies,

01:05:16.820 | they didn't apply that correction.

01:05:19.600 | And I remain unconvinced

01:05:23.060 | of transgenerational epigenetic inheritance in mammals.

01:05:27.620 | Now, let's be clear.

01:05:29.980 | Just because it hasn't been shown convincingly now

01:05:34.300 | doesn't mean that it won't be.

01:05:37.020 | There are some good people working very hard on this,

01:05:40.500 | and they may well describe a mechanism

01:05:45.500 | and show this convincingly in the years to come.

01:05:48.460 | But right now, you may well inherit

01:05:51.540 | your grandma's or great-grandma's trauma,

01:05:53.520 | but you're probably doing it socially,

01:05:56.180 | not through marks on your DNA

01:05:59.340 | that changes how your genes are expressed or not expressed.

01:06:03.760 | - Yeah, so I subscribe to the idea

01:06:05.780 | that there is absolutely,

01:06:07.820 | certainly transgenerational inheritance

01:06:10.540 | of parenting and upbringing, right?

01:06:12.500 | I mean, your grandparents raise your parents who raise you.

01:06:14.780 | Not always people can be adopted.

01:06:16.140 | In fact, I have adopted members of my family.

01:06:19.580 | But if I understand what you're saying correctly,

01:06:22.980 | the evidence that, for instance,

01:06:26.860 | some stress-related gene was modified

01:06:30.140 | during a trauma in my grandparents or great-grandparents,

01:06:35.140 | and the idea that that was passed to me through my parents,

01:06:38.740 | that the evidence there is far weaker.

01:06:41.580 | - Right, and when you think about it,

01:06:42.960 | well, like, how did that happen?

01:06:44.300 | That had to get into your grandparents' sperm or egg cell

01:06:49.620 | and then produce that effect in the brain of your parents,

01:06:53.700 | and then it had to get into their sperm or egg cell

01:06:56.800 | and then contribute to producing it in you.

01:07:00.260 | - But fragmentation of DNA in sperm or in eggs

01:07:03.300 | is a common thing, especially as people age.

01:07:07.660 | DNA, sperm and eggs fragment,

01:07:10.040 | and it's possible that some of those mutations

01:07:14.340 | still allow for viable embryos.

01:07:16.340 | So in theory, the germline could be changed

01:07:18.960 | by environmental events.

01:07:21.900 | - Well, right, but now I think you're starting

01:07:24.760 | to talk about things that are heritable, right?

01:07:27.660 | You're not talking about marks on DNA.

01:07:29.260 | You're talking about the structure of the DNA itself,

01:07:32.040 | and that is its own separate issue.

01:07:36.920 | Now, I think I wanna be really careful about this

01:07:39.500 | because what is now, I think, fairly well established

01:07:44.280 | is that you can transfer things epigenetically

01:07:49.280 | over a single generation

01:07:52.740 | if, as a result of experiences

01:07:56.420 | that the mother has during pregnancy.

01:08:00.340 | So for example, we know

01:08:03.820 | that during the 1918 pandemic flu,

01:08:09.300 | many women were pregnant and got the flu,

01:08:14.280 | and if you look at their children,

01:08:16.800 | you find interesting statistical anomalies,

01:08:20.920 | and those children, for example,

01:08:23.120 | the males wound up going into the army for World War II,

01:08:26.000 | and of course, the army does a complete physical,

01:08:28.400 | and the records are very good,

01:08:29.540 | so you can go into that database,

01:08:31.840 | and you find that the male children

01:08:37.660 | that were in utero during the winter of 1918,

01:08:42.660 | during the pandemic flu,

01:08:44.240 | are on average a millimeter or two shorter.

01:08:47.200 | You might say a millimeter or two, that's nothing,

01:08:49.080 | but in a huge statistical sample of millions of people,

01:08:51.920 | that's enormously significant.

01:08:54.160 | More interesting is that the incidence of schizophrenia

01:08:58.320 | went up about fourfold,

01:09:00.840 | from about 1% to about 4%,

01:09:05.080 | and even though autism wasn't a term in 1918 yet,

01:09:10.080 | I think it came along later,

01:09:12.860 | what we now retrospectively would call autism

01:09:15.620 | also went up by about fourfold.

01:09:18.800 | So there's something about mom being stressed

01:09:23.800 | and carrying the fetus at a particular stage

01:09:28.320 | that seems to impact brain development in a way

01:09:31.440 | that then makes that child more likely

01:09:33.880 | to be schizophrenic or autistic when they grow up.

01:09:37.520 | - Do we know that it's stress?

01:09:38.800 | And my recollection of this,

01:09:40.920 | I believe this was the late Paul Sternberg's work as well.

01:09:44.640 | I maybe have that name incorrect,

01:09:46.900 | but in any event, that it is,

01:09:49.760 | if pregnant mom gets the flu in the first trimester,

01:09:54.760 | you see this higher incidence of schizophrenia

01:10:01.040 | and an autistic offspring.

01:10:04.140 | But do we know that it's stress per se?

01:10:06.500 | Because it's stressful to have the flu,

01:10:07.920 | but the flu is a bunch of other things.

01:10:09.740 | Could be fever, could be some breakdown

01:10:13.380 | in the immune barrier.

01:10:14.260 | I just want to open up the number of variables

01:10:16.360 | that this could be,

01:10:17.200 | or do we know that it's something

01:10:18.320 | in the hypothalamic-pituitary so-called stress axis

01:10:21.940 | that is adrenals,

01:10:23.840 | so hypothalamic-pituitary-adrenal axis,

01:10:26.480 | like is it elevated cortisol,

01:10:28.820 | or could it literally be an immune neural interaction

01:10:32.620 | of some other sort?

01:10:33.660 | - It's probably the last thing you mentioned,

01:10:35.700 | an immune neural interaction.

01:10:37.460 | And the reason I say that is that Gloria Choi at MIT,

01:10:42.460 | together with her collaborators,

01:10:46.760 | has made a mouse model of this phenomena.

01:10:49.540 | So she takes pregnant female mice,

01:10:51.500 | and she injects them with something that,

01:10:54.380 | she doesn't actually infect them with virus.

01:10:56.780 | She puts a chemical in that is on the coat of viruses

01:11:00.280 | that mimics viral infection.

01:11:02.600 | And then what happens is that in a way

01:11:06.220 | that interestingly is an interaction

01:11:08.140 | with the bacterial content of her gut,

01:11:12.620 | produces a surge of a immune signaling molecule

01:11:17.620 | called interleukin-17.

01:11:21.860 | Interleukin-17 can pass through the placenta

01:11:26.860 | into the fetus,

01:11:28.680 | and if it's present,

01:11:30.500 | just as you said at a particular point in development,

01:11:33.280 | doesn't work anywhere during pregnancy,

01:11:35.660 | but during something that is sort of the mouse equivalent

01:11:38.180 | of the first trimester,

01:11:39.540 | if that occurs,

01:11:41.940 | it causes disordered development

01:11:44.520 | of the layers of the cortex.

01:11:45.840 | Instead of it looking like layers of a cake,

01:11:48.580 | you see balls and clumps of cells.

01:11:51.780 | And parenthetically,

01:11:53.020 | in some but not all post-mortem tissue from autistic people,

01:11:57.420 | you can also see those balls and clumps of cells.

01:12:00.660 | - Are those balls and clumps of cells

01:12:02.240 | thought to reflect alterations in cell migration?

01:12:07.100 | - They are, yes.

01:12:08.840 | I don't know if it's entirely known

01:12:10.780 | how much of it is cell division or migration,

01:12:13.420 | but certainly migration is a part of it.

01:12:16.960 | And it's very likely that that critical moment

01:12:20.240 | to disrupt this ordering of the brain

01:12:23.460 | and produce these increases in schizophrenia

01:12:26.560 | or autism vulnerability

01:12:30.460 | are coming at a point where neurons are migrating

01:12:34.240 | during development.

01:12:36.720 | And so what Choi's group did

01:12:40.120 | is they did all the things you would want to do

01:12:41.880 | as a biologist.

01:12:42.820 | So they gave things to block the function

01:12:45.020 | of this interleukin signaling molecule,

01:12:47.980 | and it blocked the phenomenon.

01:12:49.920 | They artificially injected the signaling molecule

01:12:52.540 | into fetal brain when the mom hadn't been stressed,

01:12:55.240 | and they could reproduce it.

01:12:57.380 | So I'm not saying that there aren't effects

01:13:00.980 | of stress hormones from the hypothalamic-pituitary axis

01:13:05.980 | that are important that you mentioned,

01:13:09.120 | but in this mouse model system work,

01:13:12.520 | it seems that you can produce it

01:13:15.180 | through this immune signaling pathway.

01:13:18.180 | And so then the question is,

01:13:20.100 | well, are these mice autistic?

01:13:23.340 | Well, how do you know if a mouse is autistic?

01:13:25.720 | And the answer is it's actually a little vague, right?

01:13:28.740 | There are behaviors that neuroscientists say

01:13:32.860 | are analogous of human autism.

01:13:36.400 | And one of them is if you give a mouse a marble

01:13:40.820 | in its home cage, it will bury it over and over again

01:13:44.300 | compulsively or bury many marbles.

01:13:46.400 | And people say that that is somehow analogous

01:13:49.160 | to some of the compulsive behaviors you see in autism.

01:13:51.780 | It's a bit of a stretch, right?

01:13:53.460 | I mean, it's a challenge to interpret mouse behavior

01:13:57.320 | in human terms, but it's a reasonable first step.

01:14:02.320 | - Incredible.

01:14:04.940 | And I hope more will continue to be done

01:14:08.960 | as it surrounds the first trimester influenza hypothesis,

01:14:13.500 | 'cause it's been around a while.

01:14:15.940 | And obviously there's a spectrum of what we call autism,

01:14:21.820 | Asperger's, and nowadays people refer to it

01:14:24.760 | as sometimes as neuroatypical.

01:14:26.860 | There's some high functioning people with autism.

01:14:29.540 | There's some low functioning people with autism.

01:14:31.480 | And for that matter, there's some high functioning

01:14:33.240 | and low functioning people who don't have autism.

01:14:35.740 | So, but it is something that I think demands our attention

01:14:40.740 | and that hopefully will be resolved at some point,

01:14:44.680 | because also influenza is but one immune insult.

01:14:50.080 | And presumably pregnant women are being bombarded

01:14:53.560 | with all sorts of viruses and bacteria

01:14:56.360 | and fungal infections and fighting them off

01:14:58.800 | or not fighting them off.

01:15:00.040 | And who knows what the variation

01:15:03.520 | in neuro immune interactions exist in there

01:15:08.520 | that give rise to good variation

01:15:11.680 | and let's call it debilitating variation.

01:15:16.320 | - Well, that's absolutely right.

01:15:17.840 | And so for one example is that we don't know

01:15:22.000 | what the effects are on the children who were in utero

01:15:27.000 | while their mothers were fighting off COVID, right?

01:15:31.960 | We won't know for a while.

01:15:35.160 | - Or the common cold.

01:15:36.180 | - And there might, I mean, there might be nothing,

01:15:38.840 | or there might be something serious lurking there

01:15:42.280 | like there was for pandemic flu.

01:15:44.280 | And it will be very interesting and important to find out.

01:15:49.280 | - Agreed.

01:15:51.400 | I'd love to talk with you about mind body,

01:15:56.600 | but before we do that, I would be totally remiss

01:16:00.480 | if I didn't ask for your broad top contour understanding

01:16:05.480 | of the mini brain, the cerebellum, right?

01:16:11.840 | The so-called mini brain.

01:16:12.960 | And here's why I've been a practicing neuroscientist

01:16:16.100 | for close to three decades.

01:16:18.040 | I know where the cerebellum is.

01:16:19.440 | I've dissected a bunch of them.

01:16:21.280 | I could tell you where a few things are in there.

01:16:25.140 | And I certainly have read about what the cerebellum does,

01:16:28.960 | but whenever I do a PubMed search on cerebellum,

01:16:32.600 | I see an ever expanding set of things

01:16:36.760 | that the cerebellum is implicated in.

01:16:38.740 | Not just balance as most people here, but also timing.

01:16:42.640 | Also cognition.

01:16:44.720 | I hear about timing in particular of motor behavior,

01:16:47.160 | but then I also hear that it's involved in learning

01:16:48.920 | and not just motor learning.

01:16:50.000 | And it certainly is involved in motor learning.

01:16:52.840 | Perhaps that little mini brain is doing 50

01:16:57.260 | or a thousand different things,

01:16:59.120 | but how should we think about the cerebellum?

01:17:02.400 | What is it doing?

01:17:03.780 | And what are some of its core operations

01:17:07.220 | that inform both what it's doing

01:17:09.580 | and perhaps what other areas of the brain are doing as well?

01:17:13.580 | Because I can point to the retinas

01:17:14.920 | or the auditory cortex or the thalamus.

01:17:16.820 | And yes, there's some mysterious nuclei in the brain,

01:17:18.860 | but to me, the cerebellum is one of the most cryptic

01:17:22.320 | and complicated structures to understand.

01:17:25.100 | And I know you spent some time in there.

01:17:26.540 | So what's the cerebellum do?

01:17:29.740 | - Well, cerebellar researchers like to joke

01:17:32.360 | that the cerebellum is a counterweight

01:17:34.220 | to keep your head from falling forward.

01:17:36.340 | - Oh, perfect.

01:17:37.180 | Well, with all the texting nowadays,

01:17:38.240 | people need bigger cerebellums.

01:17:39.600 | - That's right, that's right.

01:17:40.440 | Probably over many generations,

01:17:41.760 | then that will happen along with a expansion of the thumbs.

01:17:44.800 | But of course, everybody's going to text with their minds

01:17:48.720 | in about another 10 years, right?

01:17:50.040 | You'll have Elon's implant

01:17:51.480 | and you won't need your thumbs at all.

01:17:53.560 | - Yeah, or maybe just five,

01:17:55.200 | or my friend Eddie Chang is a neurosurgeon

01:17:57.460 | and works on the auditory system.

01:17:59.680 | He's been on this podcast before.

01:18:00.980 | He was saying that in theory, and actually in practice,

01:18:04.240 | you could just record the neural output

01:18:06.640 | to the muscles of the speech system, essentially.

01:18:10.960 | And you could just amplify that

01:18:15.260 | and you could text without actually speaking.

01:18:18.260 | In fact, when we read, he told me,

01:18:21.440 | we are actually receiving the signals

01:18:24.600 | as if we were going to speak the words we're reading,

01:18:28.200 | but they don't quite arrive at the place

01:18:30.360 | where you could get a full-blown postsynaptic potential.

01:18:33.120 | So you're not actually moving the vocal machinery.

01:18:36.200 | So that means the motor signals are getting sent out there

01:18:38.960 | and so you're speaking what you are reading,

01:18:41.080 | but you just don't know it.

01:18:43.320 | - That's right, and it's very analogous

01:18:44.580 | to what happens during the REM phase of sleep, right?

01:18:47.760 | When you have commands,

01:18:49.880 | your brain is issuing commands to your muscles

01:18:52.920 | to do things like behave in your dreams,

01:18:56.740 | to run away or go here or go there.

01:18:59.880 | But those signals actually are blocked in the brainstem,

01:19:03.440 | prevented from reaching your muscles

01:19:06.440 | because the nerves that don't go through your brainstem,

01:19:11.440 | like the ones that control your eye movements,

01:19:14.960 | aren't subject to that blockade.

01:19:16.400 | That's why you can produce the rapid eye movements

01:19:18.840 | in REM sleep.

01:19:20.760 | But yeah, this is a general theme in the brain.

01:19:22.800 | A lot of times you have the output,

01:19:24.980 | but then you shut it down.

01:19:27.080 | And there are REM sleep behavior disorders

01:19:30.080 | where people thrash and move in their sleep during REM.

01:19:35.080 | And it's because this outflow that's normally blocked

01:19:40.180 | isn't blocked.

01:19:41.960 | - Have you ever had the reverse happen?

01:19:43.400 | I have, where you wake up

01:19:45.120 | and you're still in so-called REM atonia,

01:19:47.120 | you're still paralyzed.

01:19:48.440 | And there's that split second that feels like eternity

01:19:51.040 | where you are wide awake and you cannot move.

01:19:53.360 | And I'll tell you, it's terrifying.

01:19:55.120 | - Yeah, sleep paralysis.

01:19:56.600 | And actually, it's been known forever.

01:19:59.680 | You can actually find ancient Greek depictions

01:20:02.400 | of people lying with a demon on their chest,

01:20:06.120 | paralyzing them.

01:20:07.240 | And that is actually from sleep paralysis.

01:20:10.440 | Later, Hogarth did a drawing of exactly that.

01:20:15.280 | So yeah, this is a well-known phenomenon.

01:20:17.600 | But to get back to the cerebellum as we started,

01:20:21.280 | so the cerebellum is, as you said,

01:20:29.240 | definitely involved in motor coordination.

01:20:33.520 | So people who have damage to the cerebellum

01:20:36.960 | aren't paralyzed, but they tend to be clumsy.

01:20:40.880 | They tend to not coordinate their movements.

01:20:43.120 | They have a disturbed gait.

01:20:45.000 | If they're reaching for an object, they often overshoot it

01:20:48.520 | and have to make successive approximating motions

01:20:51.480 | to get back to their target.

01:20:54.560 | So that's well understood.

01:20:57.000 | But if you look through evolution,

01:20:59.280 | the cerebellum is connected to this brain region

01:21:03.840 | called the thalamus, and it's connected from there

01:21:05.840 | to many regions, including the frontal cortex,

01:21:09.760 | where phenomena like planning and decision making

01:21:14.760 | and moral sense and many aspects of personality

01:21:22.880 | seem to be encoded.

01:21:24.360 | So then the question becomes, well, that's very far away

01:21:27.600 | from being clumsy.

01:21:29.600 | What are these connections doing?

01:21:32.040 | And as time has gone on, I've been in this business

01:21:34.880 | for over 40 years now, I'm an old guy.

01:21:37.960 | And so initially we said, oh yeah,

01:21:39.440 | cerebellum movement control, motor coordination,

01:21:43.360 | that's what it's for.

01:21:45.280 | As time goes on, as you correctly said,

01:21:47.800 | the cerebellum has been implicated

01:21:49.840 | in more and more functions, many of which are far removed

01:21:52.600 | from the motor system.

01:21:54.480 | And if we're looking for a theme about what the cerebellum

01:21:58.960 | does is that it is there to predict the immediate future.

01:22:03.960 | It's trying to determine what's gonna happen

01:22:10.840 | in the next second or two to best guide behavior.

01:22:15.840 | And as you can imagine, this kind of general computation

01:22:21.560 | could be applied very well.

01:22:23.040 | You can see why it's important for motor systems

01:22:25.240 | and doing sports and if you're trying to hit a baseball

01:22:28.200 | and looking at what the pitcher is doing

01:22:29.480 | and trying to anticipate what the pitch is.

01:22:31.880 | But it also comes up in a social realm.

01:22:36.200 | If we're trying to read someone and predict

01:22:38.180 | what they are going to do, is this person friend or foe,

01:22:41.080 | which is one of the first things that we try to assess

01:22:43.520 | when meeting someone.

01:22:44.520 | Are they competent, which is the second thing

01:22:46.880 | we try to assess when meeting something.

01:22:50.320 | A lot of this depends upon predictive circuitry

01:22:53.200 | and it depends in part on the cerebellum

01:22:56.640 | and it seems to be at least partially impaired

01:22:59.200 | in people who sustain cerebellar damage.

01:23:02.160 | So it seems as if interestingly, the cerebellum started out

01:23:07.160 | for prediction related for motor control

01:23:10.940 | and through evolution, its basic computation

01:23:14.540 | has been applied to other non-motor behaviors.

01:23:20.460 | Now I'm speaking in generalities

01:23:23.220 | and a lot of the details of this remain to be worked out

01:23:28.020 | and understood, but I would say that is in a nutshell,

01:23:31.900 | the modern conception of the cerebellum.

01:23:34.660 | - Thank you.

01:23:35.580 | Finally, somebody explains to me at a top contour,

01:23:39.220 | but highly informed way what the cerebellum does.

01:23:43.940 | I couldn't be more grateful.

01:23:45.900 | - My pleasure.

01:23:47.100 | In all aspects of biology and life,

01:23:49.900 | the term nature versus nurture is relevant,

01:23:53.320 | but never so much as when thinking about the nervous system.

01:23:58.200 | And I know this firsthand

01:23:59.500 | because I've studied neural development,

01:24:01.420 | both the nature side, the so-called hardwired stuff

01:24:05.700 | that genes just set up, neurons wire up to that neuron,

01:24:10.320 | et cetera, the cerebellum is in the back,

01:24:12.180 | the eyes are in the front, the hardwired stuff.

01:24:15.580 | And then the softwired stuff, the nurture stuff

01:24:20.580 | is the stuff that can be modified by experience.

01:24:23.680 | What are your thoughts on nature versus nurture

01:24:26.180 | and should there even be a versus in there?

01:24:29.500 | - Yeah, I don't think there should.

01:24:31.020 | And I have a lot of problems with nature versus nurture

01:24:36.020 | as an expression.

01:24:38.820 | It was popularized by Francis Galton in the 19th century,

01:24:44.300 | a colleague of Darwin's.

01:24:48.580 | And I think it's wrong in or misleading in a lot of ways.

01:24:53.580 | So of course the nature in nature versus nurture

01:24:57.900 | is meant in this case to mean inheritability, right?

01:25:02.720 | What you inherit in the gene variations

01:25:05.540 | from your mother and father.

01:25:07.460 | And nurture means like how your parents

01:25:11.380 | or your community raised you.

01:25:14.480 | The problem I have with nurture

01:25:16.600 | is that it is too narrow a term,

01:25:20.600 | that really it should be replaced with the word experience.

01:25:24.820 | And experience in the broadest possible sense,

01:25:28.660 | not just social experience,

01:25:32.240 | but the foods your mother ate

01:25:36.340 | when she was carrying you in utero,

01:25:41.060 | the diseases you fought off or your mother fought off

01:25:45.140 | while she was carrying you in utero,

01:25:48.780 | the bacterial population of your guts.

01:25:52.360 | So experience meaning anything that impinges on you

01:25:57.640 | starting from the earliest stages of fetal development,

01:26:02.180 | continuing to the last day of your life.

01:26:04.400 | I think it should be very expansive,

01:26:07.020 | much, much more than social experience in the family

01:26:10.180 | or the community.

01:26:12.500 | And as you mentioned, I have a problem with versus

01:26:15.700 | because there's this idea that these things

01:26:19.060 | are essentially in opposition.

01:26:22.640 | Well, is he that way because of his gene variants

01:26:27.640 | or is that way because of what happened to him?

01:26:31.900 | And I think the thing to realize is that

01:26:37.100 | experience and heredity interact

01:26:40.540 | in all kinds of interesting ways,

01:26:42.860 | some of which are oppositional

01:26:44.620 | and some of which are reinforcing.

01:26:48.420 | A classic one from genetics has to do

01:26:51.780 | with a genetic disease called phenylketonuria or PKU,

01:26:56.660 | which is an inability to metabolize

01:27:01.660 | the dietary amino acid phenylalanine.

01:27:06.420 | And so in order to have this,

01:27:10.460 | you have to inherit broken copies of this gene

01:27:13.540 | from both your mother and your father.

01:27:15.420 | So it's a so-called recessive trait.

01:27:18.380 | And here's where the experience comes in.

01:27:21.640 | It only matters if you eat foods rich in phenylalanine.

01:27:25.060 | If you don't, it doesn't matter

01:27:27.120 | that you inherited these things, right?

01:27:29.480 | So that's a way in which genes and experience interact.

01:27:32.460 | An idea of ways in which then they interact positively,

01:27:37.460 | think about athletic ability, right?

01:27:41.460 | So a lot of athletic ability has a heritable component.

01:27:46.460 | If you are born fast, for example,

01:27:51.280 | then you're more likely to do sports and practice them

01:27:56.300 | and get better at sports as a result of your experience.

01:27:58.780 | So here, genes and experience are feeding back on each other

01:28:03.540 | in a positive feedback loop.

01:28:05.060 | So there really isn't a versus at all.

01:28:09.260 | And then of course, the last thing

01:28:11.060 | is that this isn't the entirety.

01:28:13.500 | So we talked earlier about the pseudo-random nature

01:28:18.500 | of development, stochastic development.

01:28:21.860 | And so if I were to take the phrase nature versus nurture

01:28:26.420 | and reconfigure it, I would change it

01:28:29.660 | to read heritability interacting with experience

01:28:34.660 | filtered through the random nature of development.

01:28:37.900 | Now, that doesn't fall off the tongue

01:28:40.620 | as elegantly as nature versus nurture.

01:28:44.300 | You know, nature versus nurture is like,

01:28:46.540 | if the gloves don't fit, you must quit.

01:28:48.900 | You know, it's got that kinda snappy snare drum beat.

01:28:53.040 | But I think it's a more accurate.

01:28:55.580 | - So heritability interacting with experience

01:28:59.580 | filtered through the randomness of development.

01:29:02.940 | So we can shorten that up

01:29:05.460 | and we'll just call it the Linden hypothesis.

01:29:10.460 | - You know, I don't think I can take credit for that.

01:29:14.580 | It belongs to other people.

01:29:15.740 | - Sure, but there's a long history in science

01:29:18.500 | of things being shortened up and coined

01:29:22.300 | and that's as important.

01:29:24.460 | I'm not, we're not trying to rob attribution here.

01:29:27.720 | And the good news is perhaps you can't call it

01:29:32.820 | the Linden hypothesis, but I can.

01:29:35.220 | And what I've found is as with the Galpin equation,

01:29:37.940 | which is now out there as a hydration,

01:29:40.580 | it's a formula that gives broad

01:29:44.660 | but research-informed parameters

01:29:47.140 | as to how much water one should drink

01:29:49.980 | in order to maintain proper hydration.

01:29:51.800 | For physiologists, Dr. Andy Galpin, who's a PhD in physiology

01:29:56.020 | and an expert in all aspects of exercise science,

01:29:58.620 | there's the Galpin equation, there's the Sobert principle.

01:30:00.500 | So I'm naming these things left and right where appropriate.

01:30:04.200 | And so I'm naming these things sparingly

01:30:09.200 | and where appropriate.

01:30:11.420 | So from here on out, heritability interacting

01:30:14.660 | with experience filtered through the randomness

01:30:17.000 | of development is the Linden hypothesis.

01:30:20.140 | And I'll be damned if anyone's going to rename it

01:30:22.740 | faster than I'm going to propagate it.

01:30:25.320 | - All right, well, I think all the geneticists

01:30:28.300 | will be gnashing their teeth about this being named

01:30:31.380 | after someone who isn't actually a geneticist.

01:30:33.320 | - Quite all right.

01:30:34.160 | And their dentists will thank me.

01:30:35.780 | Let's talk about mind-body.

01:30:38.500 | - Okay.

01:30:39.340 | - I'm fascinated by this for a couple of reasons.

01:30:44.220 | And I promise to keep this brief.

01:30:45.580 | But when I was growing up, I was very interested

01:30:47.700 | in animals and biology and my father's a scientist

01:30:50.300 | and I got very interested in neuroscience early

01:30:52.660 | as people perhaps know.

01:30:55.940 | And so much of neuroscience as I was coming up

01:31:00.020 | through the mid 90s, 2000s, 2010 to 20 stretch

01:31:05.020 | was focused on the brain piece, very little on the body.

01:31:08.860 | There was nothing about gut brain access

01:31:10.460 | in the early discussions and coursework.

01:31:13.000 | In parallel to all of that, I've been interested

01:31:16.140 | in mental health, physical health, and let's just call it

01:31:18.620 | performance and got interested in meditation,

01:31:22.180 | respiration based practices, things like yoga nidra,

01:31:25.340 | things that by way of experience, I understood immediately

01:31:29.580 | had a profound influence on the nervous system,

01:31:32.540 | states of mind and body.

01:31:33.960 | Nowadays, there's an entire institute

01:31:36.460 | at the National Institutes of Health

01:31:38.620 | for complementary health and medicine, essentially,

01:31:42.180 | exploring things like yoga nidra, respiration practices,

01:31:45.660 | even supplements and things of that sort.

01:31:48.220 | And there's this understanding that, oh my goodness,

01:31:51.060 | the nervous system extends into the body

01:31:54.800 | and the body sends neural signals back into the brain.

01:31:57.260 | And so this whole notion of mind body has fortunately

01:32:00.420 | migrated away from kind of California counterculture,

01:32:05.420 | Esalen Institute only, you know, hippie new age,

01:32:12.060 | magic carpet stuff, by the way, that's not what I believe,

01:32:17.060 | but that's often how it was looked at in the past.

01:32:19.660 | And now people at every level of science and medicine,

01:32:23.780 | at every major university and in every scientific journal

01:32:27.440 | are starting to publish papers about the interactions

01:32:29.740 | between bodily organs, like the breathing apparatus,

01:32:33.400 | the diaphragm lungs, the heart, heart rate variability

01:32:37.700 | we hear about, the liver, the gut brain access in particular

01:32:41.900 | and so mind body, the idea that our thoughts

01:32:45.300 | could influence our body and that our bodily state

01:32:48.100 | could influence our thoughts is fortunately

01:32:51.300 | not just understood, but it seems to be both accepted

01:32:56.300 | and appreciated.

01:32:58.380 | So what are your thoughts on mind body?

01:33:01.560 | What does that mean to you?

01:33:03.260 | And what do you think is the potential

01:33:06.160 | of the mind body interaction?

01:33:08.140 | It seems to me we've just barely scratched the surface.

01:33:11.540 | - Yeah, well, I'm glad you asked

01:33:12.940 | 'cause I think it's a really fascinating situation

01:33:17.820 | and where things are changing very, very quickly.

01:33:21.620 | And I think to me, the most important thing

01:33:24.440 | for people to understand is that when you have a hypothesis,

01:33:29.440 | let's say you have a hypothesis

01:33:33.660 | that meditation can attenuate chronic pain.

01:33:39.500 | Attenuate chronic pain, all right?

01:33:42.700 | Well, there is a temptation to think that this operates

01:33:47.700 | outside the realm of science and biology,

01:33:51.660 | that is in some airy-fairy realm in the clouds

01:33:56.100 | that this happens and I mean, for good reason,

01:34:00.260 | there are a lot of people who will describe it

01:34:02.800 | in exactly that way with auras

01:34:05.300 | or they co-opt scientific terms like resonance

01:34:08.560 | and energy but they don't actually use them

01:34:10.600 | in scientific ways.

01:34:11.660 | So there's a lot of very fuzzy language that surrounds this

01:34:16.380 | but it shouldn't obscure the fact

01:34:18.960 | that when you have a hypothesis that say,

01:34:22.060 | some mental state like meditation or guided breathing

01:34:27.060 | affects some process in the body

01:34:33.660 | that you should be trying to understand this

01:34:37.300 | in terms of a biological hypothesis,

01:34:40.180 | not in terms of some indistinct realm that is different.

01:34:45.180 | - Like manifestation.

01:34:51.220 | - Yeah and I really learned this initially from my father.

01:34:55.000 | My father was a psychiatrist, in fact,

01:34:58.280 | kind of a talking cure old-fashioned psychoanalyst

01:35:02.500 | who had his practice in Los Angeles

01:35:06.540 | and we would have dinner together every Wednesday night

01:35:10.020 | and he would always tell me about his patients.

01:35:14.580 | He was very careful to keep confidentiality,

01:35:16.980 | he wouldn't break confidentiality but I would say,

01:35:20.180 | oh, yes, how's your narcissist?

01:35:21.980 | Oh, he had this dream.

01:35:23.500 | So this was normal conversation

01:35:26.620 | when I was 14, 15 years old with my dad

01:35:29.900 | and one day I said, dad, it's really clear to me

01:35:32.340 | that through this talking cure,

01:35:35.220 | a large fraction of your patients feel better

01:35:37.380 | and they conquer their depression

01:35:39.620 | or their obsessive thoughts

01:35:41.980 | or things that are blocking them.

01:35:44.380 | How do you think it works?

01:35:46.540 | And he says, well, we don't really know the mechanics

01:35:48.900 | but ultimately when it works,

01:35:50.920 | it's not working in some airy fairy realm,

01:35:53.540 | it is working by changing the biology of the brain

01:35:56.220 | and when he said that, it was like a lightning bolt

01:36:01.420 | went off in my head and I thought,

01:36:04.440 | well, I don't have the kind of personality

01:36:07.220 | to be a talking cure psychiatrist,

01:36:10.000 | I'm not nearly nice enough

01:36:12.140 | but I could understand the underlying biology,

01:36:15.540 | maybe I'll do that.

01:36:16.700 | And so as you've correctly pointed out,

01:36:22.220 | when you say the phrase mind body,

01:36:25.320 | you're talking about two directions.

01:36:27.500 | You're talking about mental functions affecting the body

01:36:31.780 | and then you were also talking about how phenomena

01:36:35.140 | in the body affect the mind

01:36:38.980 | and we're understanding so much more

01:36:42.500 | about how that happens

01:36:45.540 | and I think the general thing for your listeners

01:36:49.660 | to appreciate is that we have some culprits here, right?

01:36:56.800 | And generally speaking, there are two classes of culprits.

01:37:01.800 | So if you want to get signals about the body to the mind,

01:37:06.900 | there's two ways to do that.

01:37:08.080 | One of them is through neurons

01:37:10.920 | that reach out into the body and sense things

01:37:13.940 | and this is referred to as introception, right?

01:37:18.240 | So as opposed to extraception, your outward pointing senses,

01:37:22.120 | these are the senses that monitor your own body

01:37:24.480 | and while we can consciously be aware

01:37:27.960 | of a lot of that information,

01:37:29.440 | a lot of it is happening subconsciously.

01:37:31.820 | Like your breathing is happening automatically

01:37:35.020 | most of the time without you thinking about it

01:37:37.080 | and that depends upon sensors about your blood chemistry

01:37:42.080 | and the state of your lungs and a number of other things

01:37:45.480 | that are regulating that process

01:37:48.080 | and it's all happening in the brain,

01:37:49.680 | usually below the level of your conscious attention.

01:37:53.360 | In addition to the neural signals,

01:37:55.920 | there is also a whole realm of hormonal

01:38:00.920 | or diffusible immune signals

01:38:04.980 | and what these are is that these are chemicals

01:38:08.080 | that are released into the bloodstream

01:38:10.040 | and that move throughout the body

01:38:12.160 | and that can activate neurons in the brain

01:38:16.520 | or in other parts of the nervous system

01:38:18.600 | to produce changes in mental function

01:38:23.600 | and I think the real thing that is exciting

01:38:27.800 | a lot of people right now

01:38:29.440 | has to do with immune signaling molecules.

01:38:33.200 | So there's a class of molecules called cytokines

01:38:36.240 | and cytokines are basically the signaling hormones

01:38:39.740 | of the immune system and they can flow

01:38:42.520 | through the bloodstream and through lymphatic fluid

01:38:46.040 | and reach many parts of the body.

01:38:49.200 | We've known for a number of years

01:38:51.160 | that the specialized receptors for these cytokines

01:38:55.440 | are found throughout the brain

01:38:57.600 | and yet we know very, very, very little

01:39:01.320 | about what they do

01:39:03.920 | and that's gonna be an astonishingly fruitful area

01:39:08.920 | of scientific research.

01:39:10.660 | But to give one exemplar,

01:39:15.560 | there are a lot of things these days

01:39:18.160 | suggesting a link between inflammation in the body

01:39:23.160 | whether it be in the gut or in other places to depression.

01:39:28.280 | Well, how might that work?

01:39:31.280 | Well, it could work either through inflammation

01:39:34.280 | sensing neurons sending electrical signals to the brain

01:39:37.160 | or and it's not either or, it could be both,

01:39:39.960 | it could be immune signaling cytokine molecules

01:39:45.140 | produced at the site of inflammation

01:39:47.340 | that then travel through the bloodstream

01:39:50.220 | and the lymphatic system to then reach the brain,

01:39:52.900 | bind receptors and have effects.

01:39:55.840 | And so one of the mysteries about depression

01:40:00.840 | is that it's not that tractable to pharmacological therapy.

01:40:05.900 | So if you look at people who suffer with depression,

01:40:10.800 | about a third of people see significant benefit

01:40:14.280 | from modern SSRI and related antidepressant drugs.

01:40:19.280 | About a third see very tiny benefit

01:40:24.400 | and about a third see no benefit at all.

01:40:27.860 | And part of the reason is because maybe our term depression

01:40:31.140 | is too big a bucket.

01:40:32.580 | Depression is actually many different biological disorders

01:40:35.580 | and only a subset of those are helped by SSRIs

01:40:40.140 | and will need different therapies for the other ones.

01:40:42.600 | That's certainly part of it.

01:40:44.520 | But part of it might actually have to do with inflammation.

01:40:47.980 | So if you think that inflammation

01:40:50.940 | is a risk factor in depression,

01:40:53.540 | well, you could do something very simple, right?

01:40:55.500 | You could gobble an ibuprofen, right?

01:40:59.060 | There's a whole bunch of anti-inflammatory drugs

01:41:01.660 | that are very well understood.

01:41:03.900 | And so, well, what if you just say,

01:41:05.700 | all right, let's have a study

01:41:07.980 | where we have a bunch of depressed people

01:41:09.920 | and we have them all eat anti-inflammatory drugs

01:41:12.380 | for a few weeks and we see if this relieves their depression

01:41:15.280 | and the answer seems to be no, it doesn't.

01:41:19.700 | Well, and that's a little bit hard to understand

01:41:24.200 | because there are definitely links

01:41:26.520 | between inflammation and depression.

01:41:28.640 | So for example, one of the early treatments

01:41:31.200 | for hepatitis C that's since been superseded

01:41:36.100 | by more modern drugs

01:41:37.600 | was a pro-inflammatory cytokine molecule.

01:41:41.800 | And when you gave it to people to treat their hepatitis C,

01:41:44.360 | almost everyone became depressed on this drug.

01:41:48.200 | So you say, oh, well, this really seems like a link.

01:41:52.820 | Likewise, there are certain neurological diseases

01:41:57.140 | like multiple sclerosis.

01:41:58.680 | It turns out the incidence of depression

01:42:02.000 | as a comorbidity in multiple sclerosis is enormous.

01:42:06.120 | And you might think, well,

01:42:06.960 | there's a trivial reason for that.

01:42:07.840 | If you're paralyzed from MS, you're bummed out about life.

01:42:11.360 | And that's the reason.

01:42:12.200 | But if you look at people who have spinal cord injuries

01:42:14.780 | from accidents, they actually have major depression

01:42:18.320 | at a rate from people who are uninjured.

01:42:21.020 | So that doesn't seem to be it.

01:42:22.240 | It's not just that you're bummed out from being paralyzed,

01:42:24.460 | although of course it's reasonable

01:42:25.960 | to be bummed out about being paralyzed, but that's not it.

01:42:28.960 | So what happens in MS?

01:42:31.060 | Well, there's a bunch of cytokines,

01:42:32.720 | including one called interleukin-6, IL-6.

01:42:35.840 | That's elevated massively if you take a spinal tap

01:42:39.560 | and you look at cerebral spinal fluid.

01:42:41.720 | And so that could be causative for depression.

01:42:44.800 | So all these real reasons to think

01:42:46.720 | that inflammation is involved,

01:42:49.400 | but yet the idea is still a little messy.

01:42:51.400 | So now what if instead of looking

01:42:53.280 | at the general population of depressed people,

01:42:55.820 | you look at the subset of people

01:42:58.500 | that don't respond to SSRI antidepressants?

01:43:02.600 | Are they helped by anti-inflammatories?

01:43:05.920 | And there's a bit of a hint that maybe they are.

01:43:09.880 | It's not definitive yet.

01:43:11.240 | There are a couple of studies.

01:43:12.960 | It's right on the edge.

01:43:15.340 | But I think this is a really good example

01:43:19.000 | of how we are gonna see progress very soon

01:43:23.960 | in the body-to-mind part of mind-body medicine

01:43:28.960 | that is going to be of enormous benefit to people.

01:43:35.640 | - So interesting.

01:43:36.800 | Could I get your thoughts on one candidate hypothesis

01:43:40.600 | that I've been thinking about?

01:43:41.720 | I've covered depression on a few episodes,

01:43:44.180 | and I've had Robin Cardart-Harris from UCSF

01:43:48.720 | and Dr. Matthew Johnson from your very own John Hopkins

01:43:52.480 | University, both of whom work, run laboratories,

01:43:54.720 | studying psychedelics for the treatment of depression.

01:43:57.800 | The clinical trials on psilocybin.

01:44:01.800 | And to be clear, psilocybin is still illegal.

01:44:04.560 | It's been decriminalized a few places,

01:44:06.100 | but we're not talking about recreational use.

01:44:07.740 | We're talking about several therapy sessions

01:44:10.280 | and then two, without psilocybin,

01:44:12.200 | then 2.5 gram, approximately,

01:44:15.920 | dosages of psilocybin given separately,

01:44:18.240 | again, with therapists present,

01:44:19.680 | and then follow-up therapy sessions

01:44:20.980 | seem to lead to relief of depression

01:44:24.080 | in approximately somewhere between 65 and 80% of people,

01:44:29.080 | in some cases, total remission,

01:44:30.460 | in some cases, some relief without remission.

01:44:32.840 | Okay, so we can kind of set that result on the shelf.

01:44:36.200 | It's been repeated a number of different times.

01:44:39.160 | Compare that to the results of SSRIs,

01:44:41.240 | which seem to help a third of people,

01:44:42.960 | a third minimally, and a third not at all.

01:44:46.440 | And of course, there's the side effect profiles

01:44:48.460 | of the SSRIs and associated drugs,

01:44:50.400 | not just the SSRIs, but bupren and the other antidepressants

01:44:53.720 | that are taken in prescription drug form.

01:44:55.440 | And then there's this inflammation piece.

01:44:58.740 | So could we hypothesize that relief from depression

01:45:03.740 | has something to do with neuroplasticity,

01:45:06.240 | rewiring of neural circuits,

01:45:08.300 | and that psilocybin, we know, can encourage neuroplasticity,

01:45:13.300 | and that perhaps SSRIs can encourage neuroplasticity

01:45:18.900 | in some people, not all,

01:45:21.220 | and that inflammation is a barrier to neuroplasticity?

01:45:24.480 | To me, this is the only thing that can reconcile

01:45:27.960 | the current status of the results.

01:45:30.640 | And then there's ketamine-based therapies,

01:45:32.160 | and so we have to also kind of set that on the shelf,

01:45:34.040 | but let's set that aside on the shelf

01:45:35.540 | for now to keep it simple.

01:45:36.840 | It seems to me that based on the time course

01:45:41.160 | over which SSRIs work,

01:45:43.100 | the fact that they increase serotonin very quickly,

01:45:45.960 | but the relief from depression comes from much later.

01:45:48.080 | The fact that neuromodulators like serotonin

01:45:50.360 | are intimately involved in neuroplasticity,

01:45:52.560 | they can, in some cases, gate neuroplasticity,

01:45:54.600 | that it all centers back to changing neural circuits.

01:45:57.880 | And so what we're really trying to do,

01:45:59.060 | whether or not it's transcranial magnetic stimulation,

01:46:01.080 | or now we can throw ketamine in there,

01:46:02.440 | or psilocybin, or SSRIs,

01:46:04.960 | that treating depression is about rewiring the brain.

01:46:08.060 | It's not about chemical A or B per se,

01:46:10.520 | although serotonin seems involved.

01:46:12.380 | To me, what I'd love to see are more studies

01:46:17.740 | about the interaction between neuroplasticity

01:46:21.120 | and inflammation.

01:46:22.440 | And are we seeing that kind of work out there?

01:46:24.720 | And because these results sort of sit as disparate,

01:46:28.320 | somewhat conflicting,

01:46:29.360 | but it seems like inflammation is anti-neuroplasticity.

01:46:33.120 | And broadly speaking here,

01:46:34.400 | I realize there are many interleukins.

01:46:36.180 | There are many, you know, some of which are inflammatory,

01:46:38.520 | some of which are anti-inflammatory,

01:46:40.260 | but is that a meaningful hypothesis?

01:46:43.040 | And do you think there's any hope whatsoever

01:46:47.140 | to actually cure depression

01:46:48.560 | if we sort of start to unify the results

01:46:53.680 | in these different camps?

01:46:55.080 | - Yeah, I think it's a completely reasonable hypothesis,

01:46:57.640 | and I would be broader.

01:46:58.680 | And I would say, honestly,

01:47:00.440 | the relief of any neuropsychiatric condition ultimately

01:47:04.520 | is from neuroplasticity in some form or another.

01:47:07.160 | And I think it's worthwhile to step back a bit

01:47:10.700 | and talk about what neuroplasticity means.

01:47:14.240 | To date, there has been a focus on synapses,

01:47:19.240 | on the contacts between neurons

01:47:21.560 | as the site of neuroplasticity.

01:47:23.640 | And that's warranted.

01:47:25.920 | Synapses are plastic.

01:47:27.200 | They change as a result of experience,

01:47:29.380 | as a result of hormone changes,

01:47:31.760 | as a result of exercise,

01:47:33.360 | as a result of lots of things.

01:47:35.920 | But synapses are not the be all and end all

01:47:39.280 | of neural function.

01:47:40.820 | So for example, neurons work by sending electrical signals

01:47:45.200 | along their lengths and between neurons

01:47:49.400 | and interconverting those with chemical signals.

01:47:51.840 | And the processes of generating those electrical signals,

01:47:56.320 | the ion channels that are involved,

01:47:58.640 | that are embedded in membranes,

01:48:00.320 | that are involved in that are also plastic.

01:48:03.040 | They can also change as a result of experience.

01:48:06.360 | That's what we call intrinsic plasticity

01:48:08.920 | as opposed to synaptic plasticity.

01:48:12.000 | In addition, there are literal morphological changes.

01:48:15.840 | So when we talk about the wiring of the brain,

01:48:19.660 | sometimes we're talking about literal wiring,

01:48:21.940 | like cell A wasn't connected to cell B

01:48:24.380 | and now it is and that changes.

01:48:26.700 | And then sometimes, well actually cell A

01:48:29.220 | was connected to cell B but cell B wasn't responsive enough

01:48:32.220 | and now there's a change in cell B,

01:48:33.720 | so now cell A can fire cell B.

01:48:35.940 | And that could have been a result of a change in its synapse

01:48:38.420 | making it more receptive to a transmitter release from cell A

01:48:42.460 | or it could be something intrinsic in cell A

01:48:44.580 | that makes it fire its electrical signal,

01:48:47.060 | let's spike more easily.

01:48:49.840 | I think that one of the key cell types

01:48:54.840 | that's going to be important for your hypothesis,

01:49:00.140 | linking inflammation to synaptic plasticity

01:49:06.220 | is going to be a cell called the microglial cell.

01:49:09.700 | And microglial cells are non-neuronal cells in the brain,

01:49:12.840 | they're motile, they can crawl around,

01:49:15.420 | they have long processes and they can gobble things up.

01:49:20.420 | They can literally sort of chew away

01:49:23.520 | and digest bits of the extracellular scaffolding

01:49:27.740 | that surrounds neurons and synapses

01:49:30.740 | and thereby renders them plastic.

01:49:32.900 | They can destroy synapses and there is a lot of indication

01:49:37.900 | that certain disease states may involve

01:49:40.620 | over exuberant microglia pruning synapses

01:49:44.940 | to a degree that they shouldn't.

01:49:47.580 | And we know that microglia are chock full

01:49:52.020 | of cytokine receptors and so are responsive

01:49:56.860 | to inflammatory signals.

01:49:59.560 | When we're talking about inflammation

01:50:01.620 | and we're talking about drugs,

01:50:03.240 | it's worthwhile to mention that there are a lot

01:50:05.820 | of behavioral things that also can influence the signaling.

01:50:10.060 | So we know, and I know you've discussed on your program,

01:50:13.820 | the incredibly salubrious effects of physical exercise

01:50:17.740 | on mental function.

01:50:19.260 | So exercise is about as good an antidepressant

01:50:23.620 | as SSRIs are and the side effects are only good side effects

01:50:28.620 | as opposed to the bad side effects of SSRIs.

01:50:32.500 | And again, this isn't working through some airy fairy realm.

01:50:36.340 | The reason that exercise works to relieve depression

01:50:40.060 | and the reason that exercise works

01:50:41.980 | to maintain your cognitive function as you age

01:50:46.260 | is because of biological pathways

01:50:49.020 | that we are now uncovering,

01:50:50.500 | some of which will involve microglial cells and neurons

01:50:55.380 | and other types of cells in the brains,

01:50:57.020 | some of which will involve not the neurons

01:51:00.980 | in the brain at all, but the brain's vasculature.

01:51:03.780 | So we know that exercise is very salubrious

01:51:07.460 | for keeping blood flowing to the brain.

01:51:10.060 | And when you're young, you have a super abundance

01:51:12.820 | of blood flowing to your brain.

01:51:13.980 | So it doesn't matter if it's reduced,

01:51:16.220 | transiently, you're fine.

01:51:18.380 | But as you get older, your blood vessels become more occluded

01:51:22.740 | and less elastic and you're closer to the trouble spot.

01:51:27.740 | And if you exercise regularly,

01:51:32.260 | you can dilate and make your blood vessels,

01:51:35.580 | including those in your brain, more elastic.

01:51:37.860 | And that is almost certainly protective

01:51:41.220 | against both depression and cognitive decline as we age.

01:51:46.220 | - Well, I am a fan of exercise,

01:51:50.480 | but I'm fortunate that I enjoy running

01:51:52.720 | and some forms of resistance training.

01:51:55.560 | So I always assumed that the good side effects

01:51:59.020 | were just the positive mood effects

01:52:00.820 | until the recent literature that, as you mentioned,

01:52:04.320 | improve vasculature blood flow and reduced inflammation,

01:52:09.320 | if not during the exercise

01:52:10.780 | when inflammation actually increases,

01:52:13.320 | decreases inflammation.

01:52:15.440 | I'm delighted to hear you say the word microglia.

01:52:18.280 | And my postdoc advisor, the late Ben Baras,

01:52:21.520 | would be especially delighted.

01:52:22.880 | People can look up Ben.

01:52:23.840 | I'll provide a link to his biography

01:52:27.240 | in the show note captions,

01:52:28.200 | because he really championed, to the point of,

01:52:32.880 | I don't know if champion's even a sufficient word.

01:52:34.600 | I mean, Ben was beating the drum saying,

01:52:35.940 | "We have to pay attention to glia.

01:52:37.220 | We have to pay attention to glia."

01:52:38.400 | For the longest time, glia were relegated

01:52:41.720 | to these other journals.

01:52:42.920 | They even had their own journals.

01:52:44.060 | And in the last, what is it, 10 years,

01:52:45.880 | there's been a kind of explosion of research

01:52:48.840 | exploring the role of microglia in other glial cell types.

01:52:51.580 | And it's really fantastic to see that this,

01:52:56.200 | actually the most abundant cell type in the brain

01:52:58.360 | is the glial cell,

01:53:00.440 | are getting the attention they deserve.

01:53:02.960 | - It's absolutely true.

01:53:04.920 | And, you know, we scientists like to think

01:53:08.880 | that we're very rational creatures

01:53:10.360 | and we're not subject to fads,

01:53:11.960 | but we totally are, right?

01:53:14.300 | When I started out in this field in the early '80s,

01:53:18.580 | everything was about opioid peptides.

01:53:21.440 | And then there was a period where gaseous neurotransmitters

01:53:24.120 | like nitric oxide were all the rage.

01:53:27.160 | And, you know, right now glia are in the spotlight,

01:53:29.820 | for a good reason.

01:53:30.660 | I'm not trying to say that it isn't worthwhile.

01:53:33.500 | But there is this phenomenon of things being faddish

01:53:37.580 | and people jumping on bandwagons.

01:53:40.140 | And it happens both in terms of the subject we study,

01:53:43.840 | but also in terms of the techniques we use.

01:53:48.200 | And right now, the technique that is most faddish

01:53:53.200 | involves single cell expression profiling.

01:53:59.680 | That is, creating a list of what genes are turned on

01:54:02.880 | and how strong they're turned on in single cells

01:54:06.020 | and seeing how that changes in different cell types

01:54:08.680 | and with experience.

01:54:09.940 | And it's a very valuable technique,

01:54:13.140 | but one could argue that it is perhaps a bit overused

01:54:18.140 | in that 15 years from now, people will go back and say,

01:54:21.500 | "Gosh, those folks in 2023 were really overdoing it

01:54:24.940 | with the single cell profiling."

01:54:27.040 | - Yeah, and if anyone's thinking about getting into

01:54:29.220 | the field of neuroscience or another area of biological

01:54:32.020 | or other research, I can just tell you that

01:54:34.020 | if you're starting your PhD or your postdoc,

01:54:36.140 | take a look at whatever fad is happening now

01:54:38.540 | and just know that in five years,

01:54:39.940 | it will be something different.

01:54:40.940 | And it takes you about five years to finish your PhD

01:54:43.540 | or postdoc, so pick something different

01:54:45.620 | than what's faddish now and you'll land right on the money.

01:54:49.500 | - There's always a lot to do.

01:54:50.760 | You don't have to do what everyone else is doing.

01:54:52.900 | - And indeed, the deletion test becomes relevant here.

01:54:56.740 | The deletion test, as it was described to me

01:54:58.900 | by my colleague, E.J. Cichulinski at Stanford is,

01:55:01.980 | if you look around and you see one or more groups

01:55:05.980 | doing what you want to do very well,

01:55:07.900 | just pick something else.

01:55:08.860 | Your life's gonna be a lot more pleasant.

01:55:10.900 | - Absolutely, I agree with E.J. on that entirely.

01:55:15.980 | - Let's get back to mind-body.

01:55:18.340 | There are a bunch of different domains of mind-body

01:55:21.860 | as you so aptly pointed out, it's bi-directional.

01:55:25.020 | Mind informs the body, body informs the mind.

01:55:28.500 | But we could probably break this down into respiration.

01:55:32.800 | So breathing, conscious patterns of breathing,

01:55:37.060 | emphasizing inhales or emphasizing exhales,

01:55:39.380 | cyclic hyperventilating, et cetera.

01:55:41.720 | Could also be thought patterns.

01:55:44.980 | A little bit harder to break those down,

01:55:46.300 | but many, not all, but many forms of meditation

01:55:50.340 | involve having a very still body, not all,

01:55:53.400 | there's walking meditation, et cetera,

01:55:54.780 | but still body focused mind.

01:55:58.420 | Kind of a, not a state that we are in a lot of times

01:56:01.820 | unless we direct that state.

01:56:03.220 | There are still other mind-body patterns of communication

01:56:08.940 | through very still body, deep relaxation,

01:56:12.260 | things like yoga, nidra, non-sleep, deep rest.

01:56:14.880 | There's hypnosis, there's touch-based

01:56:18.720 | body-mind communication.

01:56:20.940 | If we're gonna talk about mind-body,

01:56:22.740 | also we should refer to as body-mind,

01:56:26.820 | how do we dive in and think about this?

01:56:28.900 | Because this is involving clearly

01:56:31.020 | a thousand different neural pathways,

01:56:32.540 | not just the vagus nerve.

01:56:34.620 | Typically people just kind of hang their hat on.

01:56:36.180 | Mind-body must be vagus nerve,

01:56:37.540 | and of course it involves the vagus,

01:56:38.820 | but the vagus is an extensive set of pathways.

01:56:42.260 | So how do you like to frame up mind-body?

01:56:45.860 | And what's most intriguing to you

01:56:47.100 | about mind-body communication,

01:56:49.700 | both in terms of the biology and its practical applications?

01:56:53.260 | - Well, I think just as we talked about

01:56:55.700 | how there are two potential pathways

01:56:57.980 | in conveying signals from the body to the mind,

01:57:00.560 | there are also two potential pathways,

01:57:03.060 | at least two potential pathways

01:57:04.780 | to conveying signals from the brain to the body.

01:57:09.780 | And they are the neural signals

01:57:14.060 | that are conveyed by neurons that actually get there.

01:57:16.540 | And they are hormones and neurotransmitters

01:57:20.500 | and cytokines that are released from the brain.

01:57:24.100 | I should mention that hormones

01:57:26.020 | are actually produced by neurons,

01:57:28.140 | including, for example, some of the hormones

01:57:30.640 | that you think about as being produced as sex hormones,

01:57:34.440 | like estrogen is produced by neurons

01:57:36.960 | in your brain, for example.

01:57:38.360 | So let me give an example that I think is a bit out there,

01:57:44.740 | but I think is really, really fascinating.

01:57:48.780 | And this comes from the cancer world.

01:57:54.220 | And so melanoma is a bad cancer.

01:57:59.220 | It kills a lot of people.

01:58:00.780 | It can spread.

01:58:02.100 | It's highly metastatic.

01:58:04.580 | And we know that melanomas often become innervated.

01:58:09.580 | That is to say, they become contacted by neurons

01:58:13.680 | and are wrapped and receive signals from them.

01:58:16.300 | And we also know that if a melanoma becomes innervated,

01:58:20.220 | then the prognosis for that patient is worse.

01:58:25.220 | It's more likely to grow.

01:58:27.500 | It's more likely to spread.

01:58:29.740 | Well, how does that happen?

01:58:31.220 | Well, recently, there have been some reports

01:58:35.160 | that show that neurons that innervate the melanoma

01:58:40.160 | don't act directly onto the tumor cells.

01:58:45.740 | Rather, what they do is they secrete a signaling molecule

01:58:49.980 | that has a receptor on immune cells

01:58:54.820 | that are patrolling the edges of the melanoma tumor

01:58:59.160 | and nibbling away at it.

01:59:02.220 | And when that signaling molecule is released from the neuron,

01:59:07.220 | it shuts down or reduces that immune patrolling function.

01:59:15.060 | And then as a consequence, the tumor can grow and spread

01:59:20.060 | and butt off more readily.

01:59:22.820 | - So the signal that comes from neurons

01:59:24.740 | is sending the ambulances home, so to speak.

01:59:27.620 | - Yeah, exactly.

01:59:29.060 | And the signal is something called

01:59:31.020 | calcitonin gene-related peptide or CGRP.

01:59:35.720 | - I'm familiar with CGRP from the domain of touch

01:59:40.240 | and its involvement in, I think like itch perception.

01:59:44.580 | - Pain perception and itch perception, right.

01:59:47.300 | - Interesting.

01:59:48.140 | - Yeah, and so, all right.

01:59:49.980 | So if neurons can affect the progression of cancer

01:59:54.980 | through their activity, and these neurons in the periphery

02:00:03.340 | are ultimately connected to the brain

02:00:05.420 | through a couple of different hops,

02:00:08.580 | then is it reasonable to hypothesize

02:00:14.260 | that mental processes could affect cancer progression?

02:00:19.260 | So let's say we have a hypothesis

02:00:22.860 | and it's a wild hypothesis and I want to just emphasize

02:00:25.980 | that there is not evidence for this,

02:00:28.360 | but let's make the hypothesis that says

02:00:31.180 | that through meditative practice,

02:00:34.180 | you can slow the progression of certain tumors

02:00:42.220 | that tend to get innervated, right.

02:00:45.360 | Well, right now, this is just kind of a wild idea,

02:00:49.540 | but I think the important thing, as I've said before,

02:00:53.020 | that this is a wild idea with a biological substrate.

02:00:57.540 | It's not like you meditate and magic happens

02:01:00.380 | and force fields open and the angels sing

02:01:04.100 | and then your tumor shrinks.

02:01:07.620 | This is, we are saying that activity in certain areas

02:01:11.760 | of the brain is increased by this meditative practice

02:01:15.020 | and that this sends signals to this neuron

02:01:17.380 | and this neuron that actually go to the tumor

02:01:19.440 | and make something happen through this biochemical pathway

02:01:22.640 | that we have defined, right.

02:01:25.220 | And to me, this is speculative,

02:01:27.940 | but it's also extraordinarily exciting, right.

02:01:32.940 | It opens a kind of investigation

02:01:38.720 | of mind to body signaling

02:01:41.920 | that has received very little attention up to now.

02:01:46.920 | - Incredible, and I say incredible

02:01:49.780 | because while you're giving an example of CGRP

02:01:54.680 | and nerve innervation and metastatic tumors,

02:01:59.300 | I absolutely love the idea that a phenomenon

02:02:05.680 | involving some practice that could be put under the umbrella

02:02:09.300 | of mind-body or body-mind

02:02:10.820 | becomes something entirely different

02:02:14.860 | when we're trying to hang that

02:02:17.300 | on the hook of a biological process.

02:02:19.820 | It's like something fundamentally changes there, right.

02:02:22.620 | It's amazing to me, for instance,

02:02:27.240 | that early on, psychedelics and breath work,

02:02:30.620 | conscious breath work, were lumped together,

02:02:33.420 | cost people their jobs at major universities.

02:02:35.800 | I won't name the universities

02:02:36.940 | 'cause you work at one, I work at another,

02:02:39.020 | and there's a third one called Harvard.

02:02:41.320 | I guess I just named them.

02:02:42.580 | But nowadays, there are laboratories

02:02:45.000 | at every single one of those institutions

02:02:47.280 | studying deliberate respiration on health,

02:02:50.240 | as well as psychedelics and meditation for that matter

02:02:55.240 | with the goal of understanding what cytokines,

02:02:58.560 | what neurotransmitters, et cetera,

02:03:00.560 | change through defined pathways, including vagus,

02:03:04.080 | but phrenic nerves and frontal cortex

02:03:07.520 | and all the stuff that is considered

02:03:10.520 | classic rigorous neuroscience.

02:03:12.160 | So I do think we've entered a new era.

02:03:14.880 | So it's not costing people their jobs anymore,

02:03:17.280 | it's actually giving people their jobs.

02:03:20.440 | And it's federally funded,

02:03:21.960 | which itself is also fantastic, in my opinion.

02:03:25.240 | So we are in a new era.

02:03:28.060 | - What do you think needs to be done

02:03:31.040 | to really nail down the idea

02:03:35.040 | that how we think influences our biology,

02:03:38.020 | even though it's a total duh,

02:03:39.680 | because everyone knows that chronic stress, for instance,

02:03:42.800 | can be detrimental.

02:03:44.040 | Short-term stress can actually be beneficial.

02:03:47.100 | And stress is a mental process

02:03:48.960 | that essentially deploys chemicals in the body

02:03:52.260 | that then create other issues in the body

02:03:55.320 | that then create shifts in mental processes.

02:03:58.820 | It's so obvious when it's spelled out,

02:04:01.840 | but it's just remarkable to me

02:04:03.720 | how this has just been lumped in the category

02:04:05.700 | of like woo science.

02:04:08.280 | And I can't quite figure out what needs to be done

02:04:11.900 | in order to convince people that their nervous system

02:04:14.180 | includes stuff outside the skull and spinal cord.

02:04:16.520 | And of course, of course, of course it would work this way.

02:04:20.000 | - Well, right.

02:04:20.840 | I think it is the job of biomedical researchers right now

02:04:25.840 | to reclaim a lot of this from the realm of nonsense.

02:04:32.880 | And the problem is there has been a lot of nonsense.

02:04:39.600 | And, you know, there's sort of a visceral reaction.

02:04:44.040 | You know, when someone says, oh, yeah,

02:04:46.680 | well, you can do breath work and it'll realign your chakras

02:04:50.920 | and that is, you know, what will reduce your anxiety

02:04:55.920 | or your gut inflammation.

02:04:59.040 | And I'm tempted to just go, oh, shut up.

02:05:01.020 | - But what if the chakras are collections

02:05:02.680 | of nerve innervation, of bodily sphincters,

02:05:05.320 | and, you know, it could make sense.

02:05:06.760 | - Right, it could, but there's gotta be some biology.

02:05:10.720 | In some cases, these analogies are rooted in something real.

02:05:15.040 | And in some cases, they're just made up bullshit, right?

02:05:20.040 | And I think the challenge is to have really rigorous

02:05:25.200 | scientific tests of these things to take it back

02:05:31.200 | and to be willing to say, all right,

02:05:33.400 | there have been a lot of claims, for example,

02:05:36.120 | made about how mental processes can influence the body.

02:05:39.960 | And only a subset of those are gonna be true.

02:05:43.120 | And of that subset, it is our job to understand

02:05:48.120 | how they work, both to rationalize them,

02:05:51.080 | but also to optimize them and make them better.

02:05:55.040 | I mean, there's no question that mental processes

02:06:00.000 | affect the body.

02:06:01.240 | I mean, we know, for example, that if we just keep you awake

02:06:05.480 | and don't let you sleep long enough, you'll die.

02:06:08.240 | And what will you die from?

02:06:09.320 | You'll die from sepsis, because the barrier between

02:06:13.000 | your gut contents and your peritoneum will break down.

02:06:18.000 | Right?

02:06:20.960 | Well, so how does that happen, right?

02:06:24.280 | We're just starting to understand.

02:06:26.120 | There's a really dramatic example,

02:06:29.280 | but there are gonna be many more subtle examples.

02:06:32.480 | So you've mentioned breath work a couple of times,

02:06:35.520 | and I think this is really interesting.

02:06:38.680 | My colleagues who are interested in respiration

02:06:43.680 | tell me that you can record in many different places

02:06:49.240 | in the brain, many different places in the neocortex

02:06:51.880 | and in other regions, and find a signature

02:06:55.520 | of the breathing rhythm sort of as a background

02:06:58.520 | to neural activity.

02:07:00.920 | You can find it in the cerebellum.

02:07:02.320 | You can find it in the frontal cortex.

02:07:04.760 | You can find it in the habenula, which is implicated

02:07:09.320 | in many things, including depression.

02:07:11.320 | You can find it lots of places.

02:07:13.520 | So the idea that conscious modulation of your breathing

02:07:18.520 | could have manifold effects on neural function,

02:07:24.600 | I think is reasonable, given that kind of observation.

02:07:29.600 | Here, here.

02:07:32.800 | Let's talk about you a bit more.

02:07:36.920 | You've been so gracious in covering this wide array

02:07:41.360 | of topics and with such eloquence.

02:07:43.560 | And I must say, I've been delighting in all of it.

02:07:46.400 | You are in a unique position these days,

02:07:50.440 | because if I understand correctly,

02:07:53.440 | you've been diagnosed with a fatal illness.

02:07:57.560 | I suppose we've all been diagnosed

02:07:58.840 | with a fatal illness of sorts,

02:08:00.200 | because we're all going to die sooner or later.

02:08:03.080 | If you're willing, could you tell us the story

02:08:06.720 | of how that diagnosis came to be,

02:08:09.760 | what your initial reaction was, and where things stand now?

02:08:14.760 | And then perhaps we can explore some of the,

02:08:18.840 | well, let's just say pleasant surprises that have emerged

02:08:22.360 | since that initial diagnosis.

02:08:24.280 | - Well, sure, I'd be happy to.

02:08:26.600 | So in the summer of 2020,

02:08:31.600 | in the dark days of COVID,

02:08:34.560 | when things were looking really bad,

02:08:37.640 | I developed profound shortness of breath.

02:08:41.640 | I couldn't get up a flight of stairs

02:08:43.600 | without huffing and puffing.

02:08:47.080 | And I thought, oh, well, I've got COVID,

02:08:48.440 | but I took COVID vests and they were all negative.

02:08:52.520 | I thought, oh, I must have COVID.

02:08:53.920 | I've got the symptoms of COVID.

02:08:55.760 | I have respiratory issues.

02:08:57.360 | I'm feeling weak.

02:08:58.200 | It's gotta be COVID.

02:08:59.920 | And after a while, when this didn't go away,

02:09:01.600 | my wife said, you gotta go into the doctor.

02:09:03.560 | This is crazy.

02:09:04.720 | You gotta find out what's going on.

02:09:06.480 | And I did.

02:09:07.320 | And they hooked me up to an electrocardiogram.

02:09:10.800 | And they said, oh, you've got atrial fibrillation,

02:09:15.000 | meaning that your heart is doing two beats

02:09:18.040 | every time it should do one.

02:09:19.920 | So I have a very high heart rate.

02:09:21.640 | And when the heart beats that fast,

02:09:23.440 | it can't work very effectively.

02:09:24.920 | It earns enough time to recharge before the next beat comes.

02:09:28.760 | Now, it turns out that there is

02:09:31.760 | a very straightforward therapy for this.

02:09:35.640 | Atrial fibrillation comes from electrical signaling

02:09:39.480 | in the heart sort of swirling about in a circle

02:09:42.480 | and reactivating part of the heart muscle

02:09:45.320 | faster than it should.

02:09:46.520 | And so if you thread through a catheter

02:09:49.920 | in your groin up through blood vessels,

02:09:54.920 | you can put in a little needle and use that

02:09:57.280 | to cauterize and to ablate a tiny little strip of cells

02:10:01.000 | in the heart that will produce a barrier

02:10:03.480 | that will prevent that aberrant return

02:10:06.920 | of electrical activity and will cure atrial fibrillation.

02:10:10.280 | So I had that process, that ablation surgery.

02:10:13.680 | And sure enough, it cured my atrial fibrillation.

02:10:19.560 | I was feeling terrific.

02:10:21.640 | And they said, oh, as a follow-up,

02:10:23.720 | come back a few months later and we'll do an echocardiogram

02:10:27.320 | to see how your heart looks.

02:10:29.560 | And they did, and they went, oh my God,

02:10:32.240 | there's this huge mass pressing against your heart.

02:10:35.560 | It's like the size of a Coke can.

02:10:37.960 | Oh, here's what we think it is.

02:10:40.960 | We think it's a hiatal hernia.

02:10:42.760 | We think your stomach is poked up through

02:10:44.560 | the diaphragm muscle and it's nestling next to your heart.

02:10:47.800 | So the way we diagnose this, it's kind of humorous.

02:10:50.280 | They say, chug this can of Dr. Pepper

02:10:54.240 | and then quickly get up on the table

02:10:56.960 | and we'll do the echocardiogram.

02:10:59.920 | And in the echocardiogram, we can see a signature

02:11:02.320 | of the popping CO2 bubbles in your soda.

02:11:06.240 | And if we see those in the mass,

02:11:07.760 | then we know it's your stomach.

02:11:09.400 | So I did it, I chugged it, I got up there,

02:11:11.040 | oh, nope, it's not your stomach.

02:11:13.640 | They said, oh, okay.

02:11:15.040 | Well, what we think this is is a teratoma.

02:11:20.040 | And a teratoma is a developmental anomaly

02:11:24.960 | that you carry usually from fetal life

02:11:27.520 | where there's a group of different cells

02:11:29.640 | that gets in a place where it shouldn't

02:11:31.160 | during development and then grows.

02:11:33.000 | You've probably heard about people

02:11:34.280 | who sometimes get like a tooth

02:11:36.160 | that grows hair in their abdomen.

02:11:38.280 | Sometimes women have these around their ovaries.

02:11:40.480 | And they're not malignant, they don't spread.

02:11:43.440 | It's a fairly easy thing.

02:11:44.440 | But I had this enormous Coke can pressing on my heart.

02:11:47.280 | It may have, we don't know, have been the source

02:11:50.480 | of my atrial fibrillation to start with.

02:11:52.680 | But in order to deal with this,

02:11:55.120 | I had to have open-heart surgery.

02:11:57.000 | So I had the surgery and it was a big, hairy deal.

02:12:02.000 | I was told it would last about five hours.

02:12:05.680 | It turns out it lasted two days.

02:12:07.680 | - Wow.

02:12:08.940 | - They had me on the heart-lung bypass machine

02:12:11.180 | longer than you're supposed to

02:12:12.740 | because you're very likely to throw a clot and get a stroke.

02:12:15.720 | Fortunately, that didn't happen.

02:12:17.300 | I had very skilled surgeons at Johns Hopkins.

02:12:20.480 | It was bleeding so much that they couldn't close the chest.

02:12:23.560 | So they had to do all the surgery

02:12:24.620 | and then just leave me anesthetized with my chest open

02:12:27.780 | until the bleeding stopped.

02:12:29.520 | So the surgery was a bear.

02:12:31.700 | And then I'm waiting to get the pathology report

02:12:35.480 | back on the tissue they removed.

02:12:36.980 | And it came back and it was bad news.

02:12:38.780 | Sorry, it's not a teratoma, it's not benign.

02:12:42.360 | It is a kind of cancer called synovial sarcoma.

02:12:45.760 | And synovial sarcoma is a moderately rare cancer

02:12:48.960 | and it usually affects the synovium,

02:12:52.240 | which is the lining of the joints or some other places.

02:12:56.080 | It's pretty rare to have it happen in the heart.

02:12:59.880 | There are a few examples.

02:13:01.380 | If you look in the biomedical literature

02:13:03.460 | for common cancers like testicular cancer or breast cancer,

02:13:07.920 | there are huge tables of statistics

02:13:09.840 | from millions of patients on what's been tried

02:13:12.520 | and what works and what the prognosis is.

02:13:14.760 | For synovial sarcoma of the heart,

02:13:16.940 | there are only individual case reports.

02:13:18.680 | Oh, there's a guy in Kenya and he got him, is what happened.

02:13:21.520 | There's a woman in Minnesota

02:13:23.960 | and this is what happened with her, right?

02:13:25.800 | There are no statistics because it's that rare.

02:13:29.200 | And the oncologist said,

02:13:31.660 | "Well, I think you've got six to 18 months to live."

02:13:37.840 | Now, this was about now 27 months ago.

02:13:42.840 | So I've fortunately exceeded that lifespan estimate.

02:13:51.120 | And I think we gotta be clear also that, you know,

02:13:54.320 | being an oncologist has gotta be a terrible job

02:13:56.360 | for many reasons.

02:13:58.120 | But one of them is that you gotta give a lifespan estimate

02:14:00.500 | even if you really don't have the data to do it

02:14:03.080 | in a very informed, you can't just say I won't do it, right?

02:14:05.240 | You gotta do it, people expect it.

02:14:07.200 | So, you know, I'm not saying like,

02:14:08.680 | oh, the oncologist was incompetent

02:14:10.440 | because I've outlived my estimate.

02:14:12.220 | You know, he was trying to do something

02:14:13.800 | based on very little information, made his best guess.

02:14:16.640 | So, you know, I got this information and I was furious.

02:14:22.800 | I was so angry.

02:14:28.320 | Heart cancer, who the hell gets heart cancer?

02:14:31.280 | Is that even a thing?

02:14:32.240 | Have you ever heard of somebody with heart cancer?

02:14:34.040 | - Not until now. - No, heart cancer.

02:14:36.480 | What the F?

02:14:37.760 | I've got heart cancer, this is crazy.

02:14:40.560 | Time I was 59 years old, I was like, I got a lot to do.

02:14:42.960 | I can't have heart cancer.

02:14:45.000 | And what was I think transformative for me

02:14:50.000 | is that at the same time that I was feeling white hot angry

02:15:00.160 | with the universe, I was also feeling a deep sense

02:15:06.280 | of gratitude for what I've had.

02:15:08.280 | I've had a terrific life.

02:15:11.300 | I'm not that young, I've had a lot of it.

02:15:13.720 | And I had great parents, wonderful friends growing up.

02:15:18.480 | I've had a good career.

02:15:20.940 | It's been a fairly easy run of it.

02:15:24.940 | And I think the ability to have a job

02:15:31.760 | where you follow your own curiosity every day,

02:15:36.100 | there's nothing like that.

02:15:37.100 | So few people in the world get to live that way.

02:15:41.220 | I feel incredibly grateful.

02:15:43.960 | And I feel incredibly grateful for my family.

02:15:45.620 | And I have a wonderful wife named Dina

02:15:47.320 | and she's just the best.

02:15:49.160 | How do I deserve this?

02:15:50.140 | I don't deserve her, honestly.

02:15:52.660 | So in neuroscience, we often think,

02:15:57.440 | oh, well, you have a state, you have a set point.

02:16:01.180 | Are you anxious or are you relaxed?

02:16:04.280 | Are you fleeing or are you approaching?

02:16:07.200 | It's like a single axis.

02:16:09.000 | Well, but it isn't.

02:16:11.060 | And I think most people understand that.

02:16:12.640 | But me, I didn't until that moment really understand

02:16:16.900 | that I could feel profoundly grateful

02:16:20.040 | and profoundly angry in the very same moment.

02:16:25.040 | And having cancer and getting the kind of treatments,

02:16:33.000 | the chemo, the radiation, it's famously deeply unpleasant.

02:16:37.400 | And I had all that and it was just as unpleasant

02:16:39.480 | as anyone's cancer story that you've heard.

02:16:43.640 | The radiation burned my esophagus.

02:16:45.520 | I couldn't eat for weeks.

02:16:46.960 | It was months.

02:16:48.100 | It was painful to swallow.

02:16:49.800 | Bad stuff.

02:16:50.640 | Lots of people have had to have bad stuff like this.

02:16:55.040 | And what I realized,

02:16:59.720 | this is, it's a deeply unempowering situation

02:17:04.720 | to be a medical patient,

02:17:08.000 | particularly when there's something serious.

02:17:09.760 | You have a limited sense of agency.

02:17:12.440 | Things are being done to you.

02:17:14.880 | Drugs go in you that make you feel really bad.

02:17:18.320 | And there isn't that much to do.

02:17:21.600 | And I realized that for me,

02:17:25.640 | the sense of agency came from being curious,

02:17:30.640 | from being a total nerd about things.

02:17:35.400 | And part of what it made me curious about

02:17:40.360 | was my own mental processes as they related

02:17:44.240 | to my cancer and my cancer diagnosis.

02:17:47.740 | So for example, I'm getting the chemo

02:17:51.720 | and I should just say as background, I'm fortunate.

02:17:55.760 | I don't have a tendency for depression.

02:17:58.980 | I'm a pretty upbeat guy.

02:18:00.600 | I don't take any credit for that.

02:18:02.060 | I think I was just born lucky and raised lucky, right?

02:18:07.060 | But day after day of feeling bad in your body from chemo,

02:18:12.560 | boy, it's hard to be positive.

02:18:15.340 | It really is.

02:18:16.180 | I could not overcome it.

02:18:17.440 | My mood got really, really low.

02:18:20.600 | And I could tell myself, this is gonna be over.

02:18:23.840 | It's not gonna go on forever.

02:18:25.280 | You won't feel this way forever.

02:18:27.760 | And you would think that as a rational person,

02:18:30.200 | I could talk myself out of that mood, but I couldn't.

02:18:33.280 | Probably because my brain was awash in interleukin-6

02:18:36.920 | and I couldn't overcome it.

02:18:38.840 | I felt really low.

02:18:39.680 | But at the same time, I was sort of out of remove

02:18:41.960 | being a nerd about going like, huh,

02:18:43.620 | I bet these cytokines are messing me up right now.

02:18:46.160 | I bet that's what's going on.

02:18:47.400 | And that gave me some sense of agency in a time

02:18:50.920 | where otherwise I really wouldn't have it.

02:18:54.360 | Another thing it really brought home to me

02:18:56.200 | is this issue that we were discussing earlier

02:18:59.000 | about how malleable perception is

02:19:02.680 | and perception of time in particular.

02:19:05.560 | If someone had said to me, when I was healthy,

02:19:08.200 | before I was diagnosed, you're gonna die in five years,

02:19:11.960 | I would have gone, oh, no.

02:19:13.920 | No, no, no, no, no, I'm 59 years old.

02:19:15.520 | I should get way more than five years.

02:19:17.080 | I got a lot of things to do.

02:19:18.480 | Professional things, personal things, family things,

02:19:23.000 | I got a lot of things to do.

02:19:24.040 | No, that wouldn't be right.

02:19:25.080 | I'd be very upset.

02:19:27.160 | But if you told me after my diagnosis of six to 18 months,

02:19:32.160 | oh, you get five years, I'd be like, five years?

02:19:36.240 | Yeah, that's pretty good.

02:19:37.640 | I can do a lot in five years.

02:19:39.520 | I can finish up in the lab and I can do some good work

02:19:43.960 | and I can spend time with my family and travel

02:19:46.200 | and savor life's pleasures and do all kinds of things.

02:19:49.560 | Five years, great.

02:19:50.720 | And of course, it's the same five years, right?

02:19:53.840 | The only thing that's different is the context.

02:19:57.000 | But I think the thing that really I realized the most

02:20:03.680 | is that I really couldn't and still can't

02:20:12.000 | engage with the idea of myself being gone.

02:20:16.560 | So yeah, I can do practical things.

02:20:19.640 | I can update my will.

02:20:21.360 | I can write letters for my people in my lab.

02:20:24.360 | So if I kick off, they've got that

02:20:27.420 | to take to their next job.

02:20:28.760 | I can do all these nuts and bolts things.

02:20:31.520 | But in terms of genuinely engaging with my own demise,

02:20:37.680 | I really find that as much as I try, I really can't do that.

02:20:42.680 | And at first I thought, well, that's just your own

02:20:46.680 | lack of imagination, Linden.

02:20:48.800 | It's just because you're not very good at this.

02:20:53.300 | But the more I thought about it, I thought,

02:20:56.480 | actually, no, this is a human thing.

02:21:00.220 | This is a fundamental human thing.

02:21:02.600 | And one of the things, when I look back

02:21:05.580 | on the 40 plus years I've been doing neuroscience

02:21:08.100 | that's different is that when I was first trained,

02:21:11.600 | the brain was really described as a reactive structure.

02:21:14.340 | Something happens in the world.

02:21:16.060 | You know, it comes to your sense organs,

02:21:17.380 | your eyes, your ears.

02:21:18.300 | It goes into your brain.

02:21:19.260 | It triggers some things.

02:21:20.740 | You think, you make decisions, and then you make an action

02:21:23.780 | that goes out to your muscles, and that's the loop.

02:21:28.780 | And that's what the brain does.

02:21:30.820 | And what we have known in more recent years

02:21:34.020 | is that actually when the brain is waiting

02:21:36.340 | for something to happen, it's not just idling

02:21:38.860 | and spacing out, that the brain is at every moment

02:21:42.540 | subconsciously trying to predict the near future.

02:21:45.380 | Predicting the near future is predicated on the idea

02:21:51.180 | that there will be a near future.

02:21:54.220 | That is to say that you won't be dead and gone, right?

02:21:56.900 | That there'll be a future for you.

02:22:00.180 | And so I think that my ability, which I think is actually

02:22:05.180 | a human, I mean, not my ability, my failure,

02:22:09.740 | which I think is actually a human failure

02:22:11.400 | to truly engage with my own demise, is a feature.

02:22:15.300 | It is a side effect of the fact that the brain

02:22:20.300 | is always trying to predict the future.

02:22:23.540 | And so that was interesting to me just as a way

02:22:28.700 | that my illness was revealing something about the brain.

02:22:32.160 | But it also made me think a lot

02:22:34.060 | about the world's religions, right?

02:22:37.020 | Religion is everywhere in the world.

02:22:38.580 | If you ask anthropologists, is there any society

02:22:41.820 | that doesn't have religious ideas, they'll say no.

02:22:44.980 | They say they don't always have the word religion.

02:22:46.580 | They might just say, well, yeah, in this place,

02:22:48.420 | everybody knows that the world's on the back of a turtle,

02:22:51.220 | and this and this happened, there are these rules.

02:22:53.980 | They may not call it religion, but every place

02:22:56.860 | in the world has religion, not everyone is religious,

02:22:59.900 | but it is a cross-cultural universal.

02:23:03.500 | And most religions, not absolutely every single one,

02:23:06.900 | but almost every single one, has stories of afterlife

02:23:11.460 | or reincarnation in which your consciousness endures.

02:23:15.580 | Well, why would that be?

02:23:16.840 | And in many religions, they've got a deal, right?

02:23:20.260 | Follow these rules in life, and then you'll be rewarded

02:23:23.140 | in the afterlife, and that's a very general idea.

02:23:28.060 | - Or punished in the afterlife.

02:23:29.220 | - Or punished in the afterlife, right.

02:23:31.580 | And in some religions, you meld with the divine.

02:23:36.580 | In other religions, you're reincarnated as this or that.

02:23:42.220 | Heaven or hell, right?

02:23:43.140 | There's variance, but they share

02:23:45.780 | that your consciousness endures.

02:23:48.180 | And so why is this so popular all over the world?

02:23:51.220 | Well, I would hypothesize that it is a side effect

02:23:56.220 | of the fact that the brain can't help

02:24:00.140 | but always trying to predict the future.

02:24:02.620 | When we can't imagine the world without us in it,

02:24:07.620 | then we are forced to concoct stories of the afterlife.

02:24:13.000 | - Fascinating.

02:24:16.920 | - And makes me want to ask about this feature

02:24:21.180 | of time perception.

02:24:22.480 | My undergraduate, graduate, and postdoc advisors

02:24:28.840 | all sadly died early, really, by pretty much any standard.

02:24:33.840 | And I was fortunate enough to be in communication

02:24:38.900 | with the last two as they were going through that process.

02:24:43.460 | Both of them described a heightened sense of gratitude,

02:24:48.460 | especially for things that previously

02:24:51.920 | they had not paid attention to.

02:24:54.700 | So we call this noticing the little things.

02:24:57.300 | But that makes me conclude that something

02:25:02.300 | about the knowledge of one's impending death,

02:25:06.020 | however far off that might be, shifts our attention,

02:25:12.160 | at least temporarily, leads to this sense

02:25:15.100 | of slowing down a bit.

02:25:17.060 | Because in order to shift our attention

02:25:18.820 | to quote unquote the little things

02:25:21.600 | or things that we previously overlooked,

02:25:23.600 | there's this sense of slowing down.

02:25:26.140 | And we know from basic videography, photography,

02:25:30.180 | that slowing down means an increase in frame rate.

02:25:33.380 | Shooting at strobe frame rates

02:25:38.900 | gives you the perception of a strobe.

02:25:41.600 | Shooting at very high frame rates

02:25:42.980 | allows you to see things in very slow motion.

02:25:44.940 | You're noticing subtle variations

02:25:46.820 | that normally you overlook.

02:25:48.180 | I'm not trying to be overly reductionist

02:25:51.960 | about this process of enhanced gratitude

02:25:56.080 | that you described and how it was alongside intense anger.

02:26:02.620 | But have you noticed a shift in your perception of time

02:26:07.420 | because you were given initially this,

02:26:09.860 | okay, X number of months.

02:26:12.220 | And then now with the, you're still here, fortunately.

02:26:17.220 | And with this kind of open-ended,

02:26:20.700 | well, it wasn't the prediction

02:26:23.020 | that was given to you by your oncologist,

02:26:24.620 | but it's unclear how long you're going to be here, right?

02:26:28.060 | Which is how most of us exist.

02:26:31.240 | You have the sense that it's sooner rather than later,

02:26:34.020 | but you don't really know.

02:26:35.600 | So I'm curious as to how the idea that,

02:26:38.300 | okay, you have 12 months more to live

02:26:40.380 | versus more than 12 months, but not infinite.

02:26:44.540 | But of course I know that I have,

02:26:45.960 | hopefully I have more than 12 months, but it's not infinite.

02:26:49.060 | So this idea of the finish line, the cliff,

02:26:54.060 | leaving aside whatever might happen afterwards,

02:26:57.780 | I don't know, haven't been there,

02:26:59.380 | it changes what we notice

02:27:03.360 | by way of changing our perception of time.

02:27:06.800 | I mean, this is a profound tuning of our perception.

02:27:11.780 | What are your thoughts on that?

02:27:13.280 | And do you notice that each sip of coffee,

02:27:16.240 | you probably don't notice each step

02:27:17.620 | across the kitchen floor in the morning,

02:27:19.580 | you're probably paying attention to your lovely wife

02:27:22.500 | and kids and things that day,

02:27:24.260 | but presumably it's dynamic,

02:27:28.340 | but what is your perception of time like now

02:27:31.700 | with the understanding that yes,

02:27:33.040 | you made it through the past the gate that was predicted,

02:27:35.360 | but what lies ahead is uncertain.

02:27:39.340 | - Yeah, so that's really interesting.

02:27:41.260 | And I would say definitely my perception of time is slower

02:27:46.260 | and it seems like an age since I was diagnosed.

02:27:50.840 | But I think part of that is because it's been action packed.

02:27:55.840 | In other words, since I was diagnosed,

02:27:59.580 | so many emotionally salient things, non-trivial things

02:28:04.960 | have happened.

02:28:06.580 | So many intense discussions with my wife and my friends

02:28:10.980 | and the people in my lab.

02:28:12.840 | My wife and I have taken a lot more vacations

02:28:15.860 | than we normally do, so we're running all over the world

02:28:19.140 | and there's a certain sense of packing it in

02:28:22.500 | that I think influences time perception.

02:28:25.560 | But I would say actually for me personally,

02:28:29.580 | the gratitude isn't about the little things.

02:28:32.940 | The gratitude is about the very biggest things.

02:28:37.940 | The gratitude is gratitude for being a sentient being

02:28:43.200 | and having that blessing.

02:28:46.980 | The gratitude is for being able to have a life

02:28:53.060 | where I can follow my own ideas and creativity

02:29:00.120 | and my gratitude is for, choke up,

02:29:03.840 | the profound love that I've felt from my wife

02:29:10.960 | and my children.

02:29:11.800 | You know, it's not the little stuff.

02:29:15.400 | It's the big stuff that I think about

02:29:19.720 | when I think about gratitude.

02:29:21.000 | It's not noticing the sip of tea, it's the big issues.

02:29:26.780 | And for me, I want to delay my death

02:29:31.780 | as much as possible, of course.

02:29:37.740 | But when I think about it,

02:29:43.800 | the part that makes me upset is leaving people behind.

02:29:50.240 | It's not for myself.

02:29:55.340 | I've had a great life.

02:29:57.120 | I've had a lot of it.

02:30:00.720 | I'm 61.

02:30:02.400 | I'd like to go longer, but that's a pretty good run.

02:30:05.160 | I've gotten to do lots of things in those 61 years

02:30:08.520 | and have wonderful, loving, interconnected experiences.

02:30:13.440 | And so the negative part is about what I leave behind.

02:30:17.440 | - Certainly what you've left behind is enormous.

02:30:25.040 | And has been the consequence of actions

02:30:29.360 | long before your diagnosis,

02:30:31.260 | which I think is a clear lesson to everyone.

02:30:34.340 | I can't speak for you, but don't wait for the diagnosis.

02:30:38.540 | You've mentioned the sense of agency that you felt

02:30:44.040 | by being able to pay attention to

02:30:48.100 | and explore your experience of,

02:30:49.880 | let's call it what it is, impending death.

02:30:53.980 | And at the same time, as you mentioned,

02:30:57.660 | you've amplified and accelerated the number of things

02:31:02.080 | that you've put into the world recently,

02:31:04.120 | writing incredible articles about your experience

02:31:08.300 | of life and death.

02:31:09.640 | And we will, of course, link to those

02:31:11.520 | so people can read them.

02:31:12.760 | I've read them all and they are profound

02:31:16.620 | and they don't just feel important.

02:31:19.440 | They clearly are important.

02:31:22.300 | So very few people have your insight

02:31:26.260 | into the nervous system at the mechanistic level,

02:31:29.520 | but also at this more holistic level

02:31:31.440 | that you've clearly displayed to us here

02:31:33.760 | and in your research and in your book writing

02:31:36.100 | and public speaking.

02:31:37.320 | I think it's a risky thing to ask somebody for advice,

02:31:44.580 | but I can't help myself

02:31:47.340 | because I think it's a real opportunity

02:31:52.220 | if you had advice to give to any and all of us

02:31:58.340 | based on the whole experience,

02:32:02.620 | all of it from go, as they say.

02:32:06.480 | If you're willing and feel free to pass,

02:32:09.920 | but if you're willing, what is your advice?

02:32:13.760 | Well, I would say the advice that is really universal

02:32:18.760 | is what everybody already knows and is a bit trite,

02:32:23.840 | but I'll say it anyway.

02:32:26.440 | And that is appreciate what you got while you got it.

02:32:29.840 | And this isn't any big secret and everyone knows it.

02:32:34.840 | I would say for a subset of people,

02:32:39.220 | the way of the nerd is very empowering.

02:32:42.240 | I don't think that's the case for everyone.

02:32:46.200 | I think for a subset of people

02:32:50.120 | who are deeply curious as their nature,

02:32:55.120 | turning that curiosity to your own mortality

02:33:00.200 | and your own medical situation

02:33:03.700 | can be empowering and useful.

02:33:10.860 | But I don't think that should be broad advice.

02:33:14.240 | I think that's only, for a fraction of people,

02:33:16.220 | that's probably the worst thing they could do.

02:33:18.560 | And there's nothing wrong with that.

02:33:20.720 | Everybody's different, right?

02:33:23.780 | Not everyone should adopt the way of the nerd,

02:33:26.520 | but for a fraction of people,

02:33:28.680 | it's a really, really good thing to do.

02:33:32.240 | - This is normally the portion of a conversation

02:33:35.720 | with a guest where I list off the many, many things

02:33:39.000 | they've done and how grateful I am

02:33:40.800 | and all of that is absolutely true

02:33:43.500 | in the case of you being here today

02:33:45.460 | and the work you've done.

02:33:46.400 | But I think it's self-evident

02:33:48.400 | how much you've not just accomplished,

02:33:51.420 | but how much knowledge you've put into the world

02:33:54.940 | and not just scientific knowledge,

02:33:56.840 | but knowledge about the human experience

02:34:00.300 | of others and of yourself.

02:34:02.680 | And so I just want to extend a giant thank you

02:34:07.680 | on behalf of the listeners and viewers

02:34:10.480 | and myself, thank you for coming here today.

02:34:13.680 | Thank you for doing what you do.

02:34:15.420 | And so great to still have you here

02:34:19.240 | and to have this conversation.

02:34:21.060 | And I hope it goes longer and no matter when it ends,

02:34:26.060 | you've done an enormous service to humanity.

02:34:29.120 | - Well, thank you, that's very kind.

02:34:30.440 | It's been a pure pleasure to have this discussion with you.

02:34:34.320 | - Thanks, David.

02:34:35.600 | Thank you for joining me today

02:34:36.960 | for this discussion with Dr. David Linden.

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02:36:34.860 | Thank you once again for joining me

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02:36:42.140 | [upbeat music]

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Dr. David Linden: Life, Death & the Neuroscience of Your Unique Experience | Huberman Lab Podcast

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