1
00:00:00,000 --> 00:00:04,000
My guest today is Dr. Hannah Stevens.

2
00:00:04,000 --> 00:00:12,000
Dr. Stevens received an MD and PhD in Neuroscience from the University of Illinois.

3
00:00:12,000 --> 00:00:21,000
Dr. Hannah Stevens leads the Psychiatry and Early Neurobiological Development Lab at the University of Iowa,

4
00:00:21,000 --> 00:00:33,000
Carver College of Medicine. Dr. Stevens is a distinguished professor of psychiatry and holder of the Ida P. Haller Chair.

5
00:00:33,000 --> 00:00:42,000
Her work leads groundbreaking research into the molecular and cellular foundations of early brain development,

6
00:00:42,000 --> 00:00:56,000
and is pivotal in linking prenatal stress, environmental factors, and genetic influences on childhood behavior and the emergence of disorders.

7
00:00:56,000 --> 00:01:02,000
With her focus on the critical periods of pregnancy and early childhood,

8
00:01:02,000 --> 00:01:10,000
her research aims to revolutionize the diagnosis and treatment of conditions throughout the lifespan.

9
00:01:10,000 --> 00:01:18,000
In addition, Dr. Stevens recently published a review paper in biological psychiatry titled,

10
00:01:18,000 --> 00:01:25,000
Developmental Disruptions of the Dorsal Stryatum in Autism Spectrum Disorder.

11
00:01:25,000 --> 00:01:34,000
This is an interesting area in the so-called basal ganglia, an area known for its rosin, various learning methods,

12
00:01:34,000 --> 00:01:43,000
that cognate the functions and motor movements. The dorsal striatum receives inputs for the basal ganglia that in turn

13
00:01:43,000 --> 00:01:50,000
recruits various other subcortical regions used to orchestrate downstream behaviors.

14
00:01:50,000 --> 00:01:56,000
For those roles, this is a region of interest for autism.

15
00:01:56,000 --> 00:02:02,000
And now, my conversation with Dr. Hannah Stevens.

16
00:02:02,000 --> 00:02:07,000
Dr. Stevens, can you start with explaining to me about your medical journey and your background?

17
00:02:07,000 --> 00:02:14,000
Absolutely. Well, let me tell a little bit about my interest in the brain and neuroscience,

18
00:02:14,000 --> 00:02:19,000
and that includes how I was trained medically as well.

19
00:02:19,000 --> 00:02:29,000
So when I went to college, I became fascinated with the idea that all our behaviors have these correlates underneath that occur in our brain.

20
00:02:29,000 --> 00:02:38,000
And chemical signals and electrical signals have the capacity to help us think certain things or move in certain ways and make choices,

21
00:02:38,000 --> 00:02:43,000
which was fascinating to me, and I just couldn't turn away at that point.

22
00:02:43,000 --> 00:02:48,000
So I decided I wanted to learn more about the brain, and I went on to do graduate studies in the brain,

23
00:02:48,000 --> 00:02:54,000
but at the same time, I wanted to be able to apply what I was learning to directly help people.

24
00:02:54,000 --> 00:03:06,000
And I was fortunate to get into a program where you can train in science with a PhD and as a physician with an MD at the University of Illinois.

25
00:03:06,000 --> 00:03:19,000
And I studied their specific ways that the auditory system helps us understand language and the auditory part of the brain, essentially.

26
00:03:19,000 --> 00:03:27,000
And at the same time, I began to be trained as a physician and a doctor in training,

27
00:03:27,000 --> 00:03:42,000
and I began to see that how people develop through their early part of their life is fascinating from just an experiential and how it affects people's lives perspective.

28
00:03:42,000 --> 00:03:50,000
And at the same time, how the brain develops was also beginning to excite me as well and thinking about that.

29
00:03:50,000 --> 00:04:02,000
So I wanted to, when I completed my training there, I wanted to go into a field where I could look at development of people's lives and people's brains.

30
00:04:02,000 --> 00:04:11,000
And for me, that was training to become a psychiatrist and specifically a child psychiatrist.

31
00:04:11,000 --> 00:04:18,000
And at the same time, then continuing to do research in an area that was really relevant to psychiatry and child psychiatry.

32
00:04:18,000 --> 00:04:32,000
And that because there were so many unknowns in child psychiatry about what led people to have the problems they were having, what led children to have emotional or behavioral problems.

33
00:04:32,000 --> 00:04:42,000
I wanted to start early and look very early at formation of the brain and think about how that might set up the brain to not work as well for a person.

34
00:04:42,000 --> 00:04:47,000
And so I began to look at prenatal or embryonic brain development.

35
00:04:47,000 --> 00:05:13,000
And then I've taken that from there, studying both how particular genes and differences in genes affect prenatal and embryonic brain development, but also how different environmental experiences or exposures in the prenatal period can change brain development.

36
00:05:13,000 --> 00:05:25,000
And that has brought us here to this time when I've actually, way back then decided I really wanted to understand the brain.

37
00:05:25,000 --> 00:05:51,000
I've now reached the point where I have gone beyond just thinking of the brain, which is already complex enough to understanding that prenatal brain development involves interaction of the brain with a lot of other tissues, and in particular with the placenta that supports the development of the entire fetus or embryo.

38
00:05:51,000 --> 00:06:00,000
And we think is worth studying for understanding exactly how it influences the development of the brain.

39
00:06:00,000 --> 00:06:09,000
That's not something now that I do as I practice as a physician, I practice as a child psychiatrist. It's certainly not something I do in my everyday life as a physician.

40
00:06:09,000 --> 00:06:38,000
I don't think about the placenta when I'm trying to help children and adolescents with emotional or behavioral problems. But when I try to think about how we might prevent those problems, that's where the science gets me excited to try to think about if we understand the biology that's happening as the brain is forming prenatally, then maybe we can prevent some of the problems for the kids that I see.

41
00:06:38,000 --> 00:06:53,000
I kind of like to rate things. I think I've constantly rate things. And I think for me personally, the number one thing with autism research ought to be the cause.

42
00:06:53,000 --> 00:07:13,000
And there's so much that says the placenta or the embryo is where we need to direct more attention. So I was so fascinating with knowing that you have a history with the placenta.

43
00:07:13,000 --> 00:07:18,000
What is the placenta's role on the embryo?

44
00:07:18,000 --> 00:07:42,000
That's a great question and a great place to start. So the placenta is really that intermediate structure that is there, that mediates things being provided by the maternal environment for an embryo, and that embryo growing and putting together its brain and of course, all of its other parts that it

45
00:07:42,000 --> 00:08:02,000
has to grow. So the placenta provides nutrients by actively transporting nutrients from a mother, the proteins, the carbohydrates, the sugars that a mother consumes are actively transported to the fetus, so it has the building blocks to actually start to grow and put together

46
00:08:02,000 --> 00:08:24,000
cells. And it also provides a lot of guiding molecules that tell it in part how to put those things together, but that's only in combination with what's already happening in the fetus itself. The fetus has kind of its own blueprint and some molecules coming from the placenta can help guide it.

47
00:08:24,000 --> 00:08:41,000
So things like hormones, things like growth factors. And then the placenta has a big role in modulating the provision of oxygen because all human life needs oxygen and so oxygen exchange is very important in the placenta.

48
00:08:41,000 --> 00:08:59,000
And then the removal of things you don't need. So as anything grows, anything functions, it produces wastes, all the cells of the developing fetus produce wastes and those have to be eliminated through the placenta in part as well.

49
00:08:59,000 --> 00:09:18,000
So the placenta also seems to have come developed to limit the exposure of the fetus to things that wouldn't be good for its growth. And there's interesting active transport mechanisms in the placenta to keep out foreign type molecules, things that aren't natural in the human

50
00:09:18,000 --> 00:09:37,000
milieu, maybe poisons that a person like if we're thinking of way back during evolution, a person might consume poisons from plants or something like that and today, you know, chemicals or medications can be actively kept from the fetus by the placenta.

51
00:09:37,000 --> 00:09:41,000
So that's another very interesting role at place.

52
00:09:41,000 --> 00:09:57,000
Okay. So, explain to me how the placenta from mother to mother is that be different.

53
00:09:57,000 --> 00:10:08,000
Because I'm very fascinated recently over the last maybe three months about even pre pregnancy, the mother preparing for pregnancy.

54
00:10:08,000 --> 00:10:14,000
Absolutely. So the placenta is actually made up in part of mother's tissue.

55
00:10:14,000 --> 00:10:37,000
Part of the uterus actually changes after an embryo implants and becomes part of the uterus so part of, I'm sorry, part of the placenta so part of the placenta is of maternal origin and then part of it also arises actually from the embryonic cells of the embryo initially.

56
00:10:37,000 --> 00:10:49,000
And so it has unique qualities that neither the mother nor the the offspring have in some ways because it's both of their tissues working together.

57
00:10:49,000 --> 00:11:03,000
So it actually is, it's not just that it varies mother to mother but every time a mother has a new offspring or different offspring that placenta will be different that time.

58
00:11:03,000 --> 00:11:26,000
But there are key elements that seem to co occur. So, for example, a problem in pregnancy that can happen to some people is that they'll develop a pregnancy specific disease called preeclampsia which makes the mother have high blood pressure and causes some problems with growth for the fetus and that's thought to the placenta is

59
00:11:26,000 --> 00:11:48,000
a problem to play a major role in that a mother will be at risk if she has preeclampsia the first time she has a pregnancy. She'll be at risk the next time she has a pregnancy so there's some things that are kind of the same as the first time, but she isn't guaranteed to always have preeclampsia the second time

60
00:11:48,000 --> 00:11:59,000
So there are things that are the same and things that are different.

61
00:11:59,000 --> 00:12:11,000
Are you familiar with nerve nerve neuro factor in K no in F KB.

62
00:12:11,000 --> 00:12:19,000
Yes.

63
00:12:19,000 --> 00:12:29,000
Okay, could you tell me a little bit about that because I planned on doing a solo episode. And that might have been a large part of it. But if you can share, then that's data directly to me instead of my interpretation.

64
00:12:29,000 --> 00:12:31,000
Oh, well yeah.

65
00:12:31,000 --> 00:12:34,000
What got you interested in NFKB.

66
00:12:34,000 --> 00:12:51,000
The roles of this time or this little epoch that we're talking about. And the roles with like DHA and omega three kind of maybe rescuing that.

67
00:12:51,000 --> 00:13:09,000
So it was just, I just can't get enough about this air of this timeframe and knowing or trying to understand when does autism actually develop on that timeline from conception to birth.

68
00:13:09,000 --> 00:13:29,000
Yeah, so I mean that's a really like we can step out and take that big picture view first before we go into the details of the molecule but the big picture view being that so everything that people have observed about autism is that as early as we can know what to look for we're seeing the

69
00:13:29,000 --> 00:13:47,000
changes of autism in people who have that and suggesting that you know people used to think well is it a problem that occurs because of something that happens in early childhood and people are becoming more and more convinced that it actually occurs before early

70
00:13:47,000 --> 00:14:03,000
childhood during prenatal development and some of the genes that have been associated with autism have pointed in that direction because they are genes that matter a lot for the development of the brain prenatally.

71
00:14:03,000 --> 00:14:20,000
Not to say they have no role at other times also but that they're just so critical at those early time points that makes it seems like the way that the evidence would suggest it's happening before someone is born and then we start to pick up signs of it as a child develops further

72
00:14:20,000 --> 00:14:28,000
and further skills or or they don't develop those skills sometimes that's what we see.

73
00:14:28,000 --> 00:14:55,000
So, getting at this particular molecule so NFKAP-beta is a molecule that plays a big role in lots of different processes inside cells of all kinds so it plays processes it plays a role in cells of the developing brain, but it also plays a role of cells of the placenta and in fact seems to be one of the major factors

74
00:14:55,000 --> 00:15:15,000
by which placental development itself is regulated so as the placenta develops it, it's a tissue that appears for this limited period of time, the period of pregnancy and it has to develop quickly and build itself quickly and then it's done.

75
00:15:15,000 --> 00:15:38,000
And so it uses molecules like NFKAP-beta to form blood vessels and re-engineer tissue around those blood vessels and monitor the right level of sort of tissue creation and tissue part of development of any kind of tissue destruction because you have to have the right structure

76
00:15:38,000 --> 00:15:46,000
and the right time set means sort of chipping away if you will kind of like that on a on a sculpt on a sculpture or something like that.

77
00:15:46,000 --> 00:16:01,000
So NFKAP-beta through its major regulation of internal cellular processes is really important for all of those structures forming in the placenta.

78
00:16:01,000 --> 00:16:09,000
So I can't remember his NFKAP-beta been suggested to be an autism linked gene. Is that one of the reasons you're interested in it, Ryan?

79
00:16:09,000 --> 00:16:24,000
I'm pretty confident in saying yes, but I do have a tendency of because of, you know, I don't want to make this sound bad but sometimes we're faced with the different silos.

80
00:16:24,000 --> 00:16:33,000
So this discipline can figure out something, but this one, it doesn't quite conceptualize that or integrate it.

81
00:16:33,000 --> 00:16:40,000
So it might have been from that, but I think it's data does show that it is info.

82
00:16:40,000 --> 00:16:53,000
I think, yeah, it rings a bell for me that it is. And I think one of the interesting things for us to start thinking about a lot of people as we just talked about have been looking at autism genes for how when do they play a role in brain development?

83
00:16:53,000 --> 00:16:58,000
And they pointed towards all these prenatal phases of brain development.

84
00:16:58,000 --> 00:17:09,000
And one of the interesting things since we're on the topic of the placenta that's starting to be discussed is what is the role of these genes not just in the brain?

85
00:17:09,000 --> 00:17:16,000
We think of autism as a brain disorder, but also in structures that support brain development like the placenta.

86
00:17:16,000 --> 00:17:21,000
So does, you know, we just discussed how NFKAP-beta has a very important role in the placenta.

87
00:17:21,000 --> 00:17:40,000
And so one hypothesis that is an interesting one that some people are starting to explore is the risk for autism like problems arising not just from a role of a risk gene in the brain,

88
00:17:40,000 --> 00:17:47,000
but in combination with the fact that that risk gene also affects the placenta, the two things happening together.

89
00:17:47,000 --> 00:17:58,000
We've been doing some work not on NFKAP-beta, but on another autism risk gene or risk genetic risk, which is a copy number variant called 16P11.

90
00:17:58,000 --> 00:18:01,000
Have you heard of that, Brian?

91
00:18:01,000 --> 00:18:06,000
I've heard of 16P11.

92
00:18:06,000 --> 00:18:08,000
Yeah, exactly.

93
00:18:08,000 --> 00:18:09,000
Yep.

94
00:18:09,000 --> 00:18:10,000
That's right.

95
00:18:10,000 --> 00:18:23,000
So that's either a deletion of a part of a chromosome or a duplication, and it's associated with a higher risk of having autism or other neurodevelopmental problems.

96
00:18:23,000 --> 00:18:39,000
And we have worked with a group at the University of Iowa that has a mouse model of that copy number variation and have found that the placenta of that mouse model is not like a typical placenta.

97
00:18:39,000 --> 00:18:45,000
It just seems structurally different, and it seems to be functionally different.

98
00:18:45,000 --> 00:18:50,000
Like it's sending different hormones and growth factors to the fetus.

99
00:18:50,000 --> 00:18:59,000
And one of the most interesting things is that the placenta in general is really different in males and females.

100
00:18:59,000 --> 00:19:11,000
And it seems that this risk gene, at least in this particular instance, seems to affect male placenta more than it affects female placenta.

101
00:19:11,000 --> 00:19:18,000
And so in 16P11, it affects 16P11.2, affects both boys and girls.

102
00:19:18,000 --> 00:19:23,000
They both have a risk for neurodevelopmental disorders if they have that genetic problem.

103
00:19:23,000 --> 00:19:29,000
But there are some problems that arise in that disorder that are more severe for boys.

104
00:19:29,000 --> 00:19:40,000
And so this is one possible source of that difference between boys and girls that might arise from the placenta being different in boys and girls.

105
00:19:40,000 --> 00:19:41,000
Oh, wow.

106
00:19:41,000 --> 00:19:46,000
That's, yeah, that's very fascinating stuff.

107
00:19:46,000 --> 00:19:53,000
Oh, yes, it keeps us, every new discovery just makes us ask even more questions.

108
00:19:53,000 --> 00:19:59,000
Yeah, it just provides information about, you guys have no idea what's happening.

109
00:19:59,000 --> 00:20:02,000
Sometimes it feels that way.

110
00:20:02,000 --> 00:20:03,000
Yeah, yeah.

111
00:20:03,000 --> 00:20:05,000
And that wasn't a shocking issue.

112
00:20:05,000 --> 00:20:10,000
I'm just saying, overall, okay, there's this now.

113
00:20:10,000 --> 00:20:11,000
Yeah.

114
00:20:11,000 --> 00:20:27,000
You mentioned oxygen earlier, and also I wanted to talk about the tissues too, because something else that's, I'm always fascinated with, because if it's autism, there's autism and I call it XYZ.

115
00:20:27,000 --> 00:20:40,000
There's so many comorbids going on with the tissue, something that whenever I saw this data, I was like, oh my gosh, autism and leukocytes.

116
00:20:40,000 --> 00:20:44,000
And I was like, what is, what is the connection there?

117
00:20:44,000 --> 00:20:53,000
And as you described the tissues and so forth, I'm just wondering if, if you have any insight into that, if not, that's fine too.

118
00:20:53,000 --> 00:20:57,000
That's, that's, we could probably talk a lot about that.

119
00:20:57,000 --> 00:21:06,000
I'm wondering, are you wondering, are you thinking about leukocytes during prenatal brain development, or are you thinking about leukocytes in general?

120
00:21:06,000 --> 00:21:20,000
I'm just thinking in general, but everything that I, as, as I discover or come across, I, I bias towards this timeframe that we're talking about.

121
00:21:20,000 --> 00:21:21,000
Yes.

122
00:21:21,000 --> 00:21:35,000
Well, it's interesting because one of the things you might know about pregnancy and prenatal development is that because the tissue of the fetus is different than the tissue of the mother, the immune system of the mother could have a reaction against the fetus.

123
00:21:35,000 --> 00:21:48,000
And one of the major things that sustains pregnancies is that there's an immune shift during pregnancy so that there isn't rejection of the, of the fetus.

124
00:21:48,000 --> 00:22:01,000
And obviously, leukocytes are white blood cells, which are a part of the immune system and allow us to fight disease and clean up stuff that's not supposed to be there.

125
00:22:01,000 --> 00:22:11,000
And they do seem to have, they do seem to function differently in pregnancy and they do populate the placenta.

126
00:22:11,000 --> 00:22:17,000
And they populate the placenta both from the maternal side.

127
00:22:17,000 --> 00:22:24,000
So mom has white blood cells that play a role in placenta and regulating the functions of the placenta.

128
00:22:24,000 --> 00:22:36,000
And then the fetal white blood cells also start to develop, not they're not there right at the beginning, but they start to develop and also will play a role on the, on the fetal side of the placenta.

129
00:22:36,000 --> 00:22:50,000
And immune perturbations during pregnancy are thought to be one risk factor for neurodevelopmental disorders, including autism spectrum disorder.

130
00:22:50,000 --> 00:23:02,000
So I think leukocytes, we don't know enough yet, really, about all the ways they could be altering placental function, altering brain function.

131
00:23:02,000 --> 00:23:16,000
But certainly the idea that inflammation is inducing a risk does mean that leukocytes have a role that we need to understand better.

132
00:23:16,000 --> 00:23:19,000
Okay.

133
00:23:19,000 --> 00:23:30,000
And you know, I mean, leukocytes are also a very interesting sort of window into the biology of a person because there's something that we can actually look at from the blood of a person.

134
00:23:30,000 --> 00:23:35,000
We can't like take brain samples from people that just doesn't allow, you know, we can't do that.

135
00:23:35,000 --> 00:23:46,000
But we can take leukocytes and leukocytes are thought to maybe sometimes have biology that allows us to understand other things that are happening in a person's body.

136
00:23:46,000 --> 00:23:54,000
But there are limits to that because leukocytes are white blood cells and brain cells are really, really different than, than white blood cells. So.

137
00:23:54,000 --> 00:23:58,000
Okay.

138
00:23:58,000 --> 00:24:12,000
Do you know much about the brain development and things like cortisol or serotonin from the mother to the fetus?

139
00:24:12,000 --> 00:24:18,000
Oh, yeah, those are two very interesting molecules during pregnancy for sure. Should we talk about those? Yeah.

140
00:24:18,000 --> 00:24:39,000
Yeah, the serotonin one, it really captivates me because of how it's rolled and where it comes from tryptophan and the melatonin and serotonin right there in the biosynthesis and just serotonin is role in developing like the

141
00:24:39,000 --> 00:24:45,000
sensory map of in the central nervous system.

142
00:24:45,000 --> 00:25:01,000
Yeah, yeah, let's get into that. Yeah, absolutely. So as you've already pointed out serotonin plays a big role in putting together a brain that can detect stimuli that matter like sensory information.

143
00:25:01,000 --> 00:25:14,000
Things like, you know, a map of like the where you where on the skin, you know, you might feel a stimulus or something like that.

144
00:25:14,000 --> 00:25:30,000
And, you know, serotonin prenatally, so in general serotonin comes from parts of individuals own brain and can affect our like within my brain, I produce serotonin and it affects my brain development.

145
00:25:30,000 --> 00:25:49,000
But there's a stage of development during prenatal life that the serotonin comes from the placenta. So this is actually one of the best explored aspects of how placenta and brain are connected in their development in that people have actually

146
00:25:49,000 --> 00:26:05,000
manipulated in mouse models where we can understand this biology better placenta specifically in the in the serotonin specifically in the placenta and shown that that basically completely changes how the serotonin system develops in the in the

147
00:26:05,000 --> 00:26:24,000
in the eighth offspring, because it relies on that serotonin from from the placenta. And so some of the idea behind the importance of the placenta for brain development is focused on babies who are born too early.

148
00:26:24,000 --> 00:26:42,000
And then, while we become better and better at allowing and finding ways to support those babies to help them survive after being born early, one of the things we know is that we're missing a lot of the factors that the placenta produces.

149
00:26:42,000 --> 00:27:05,000
While we are supporting their survival supporting their their development in many very, very important and positive ways, they, there are theories that missing things like the source of serotonin and the placenta is affecting the brain development of these prematurely born babies,

150
00:27:05,000 --> 00:27:23,000
which is one reason why neurodevelopmental disorders may be more common in babies who are born prematurely it isn't just that they had a lot of stress because they do have a lot of stress, certainly because they have to be cared for so carefully and there's a lot of risks to them,

151
00:27:23,000 --> 00:27:36,000
but it may be that we're lacking some of the key elements like serotonin coming from the placenta and there's another molecule and I know you had an interest in, in also in.

152
00:27:36,000 --> 00:27:46,000
Oh my gosh I've blanked what was the other one you had said cortisol cortisol yes so you have but I would just want to mention before we get to cortisol that there is.

153
00:27:46,000 --> 00:27:58,000
There's really amazing neonatology researcher at Columbia named Anna Penn, who coined this term neuroplacentology have you heard that before, right.

154
00:27:58,000 --> 00:28:21,000
So, she coined that in the sense of how important the placenta is for the brain neuroplacentology is a field that she is very important and and she has shown that in her lab that another molecule called alopregnanolone is arises from the placenta.

155
00:28:21,000 --> 00:28:34,000
Alopregnanolone is in that category of steroid hormones that cortisol is in and plays a big role in refining brain development, particularly in the cerebellum.

156
00:28:34,000 --> 00:28:55,000
So, she is obviously interested in her and her clinical work she works with prematurely born babies. She's a neonatologist and is interested in the idea that perhaps providing some of the factors like alopregnanolone might assist brain development and that's one of the aspects of the work of her lab.

157
00:28:55,000 --> 00:29:12,000
But it gets us into steroid hormones in general which cortisol is is one of the steroid hormones and steroids are very, very important for normal function. You didn't have steroid hormones, you know, your body really wouldn't function correctly.

158
00:29:12,000 --> 00:29:27,000
But they also signal problems sometimes so cortisol is what's known as the stress hormone it becomes elevated in levels when a person is undergoing a lot of stress and does that so it can signal to the body.

159
00:29:27,000 --> 00:29:42,000
Oh, you should now do the things that would help you deal with some stress you should, you know, release the glucose so we have some energy so if we need to run away we should do that you know it puts your body in a different state so it can it can respond to stress.

160
00:29:42,000 --> 00:30:04,000
Of course too much stress can also be bad we all know that we don't want to experience too much. And during prenatal life, too much stress on the part of the mother, maybe a risk, it seems to be a risk factor through a lot of studies for neurodevelopmental disabilities in offspring.

161
00:30:04,000 --> 00:30:23,000
That's not to say that the system hasn't attempted to, you know, I'm making it sound like an active player here but you know perhaps through evolution the system seems to develop so that too much stress hormone can't affect the offspring there are active functions in the placenta to

162
00:30:23,000 --> 00:30:43,000
monitor how much stress hormone, how much cortisol is coming from the mother and convert it into things that aren't as that aren't going to cause problems for the fetus, but there are points at which that system is not as good it doesn't function as well.

163
00:30:43,000 --> 00:30:53,000
And also stresses that cause so much of that activation and so much of that cortisol that likely it supersedes it overcomes those barriers.

164
00:30:53,000 --> 00:31:12,000
And that's something my lab studies a lot of is the impact of stress on the developing offspring brain and we have found in fact that, you know, these studies in humans have suggested it's a risk factor for neurodevelopmental disabilities and we among other labs

165
00:31:12,000 --> 00:31:18,000
have shown in fact that it causes specific developmental delays in the brain.

166
00:31:18,000 --> 00:31:26,000
The first one that we had studied was a delay in the migration of cells that have to travel long distances in the brain.

167
00:31:26,000 --> 00:31:42,000
And now we're interested in looking at other ways of understanding whether the brain gets delayed and and maybe stays in a period of growth for a longer period of time.

168
00:31:42,000 --> 00:32:04,000
As perhaps one way of responding to cortisol or other factors that happen in stress so stress is a complex state and involves inflammation it involves cortisol, it involves changes in your cardiovascular function all of which might be part of the reason it is a risk factor.

169
00:32:04,000 --> 00:32:06,000
Okay.

170
00:32:06,000 --> 00:32:19,000
Cortisol. It often gets a bad it's a bit of a misnomer I think, because true we associated with stress so much but naturally it's what wakes us up in the morning.

171
00:32:19,000 --> 00:32:30,000
So something is telling me that it's actually a good thing. We just maybe as modern humans kind of just don't know what it's supposed to be doing.

172
00:32:30,000 --> 00:32:41,000
I think you're right. Yeah, exactly. I mean, then, you know, even at the, the phenomenological level we know that having absolutely no stress in your life isn't a good thing.

173
00:32:41,000 --> 00:32:47,000
So even if we want to always put it together with stress, it would be bad for it to be gone entirely.

174
00:32:47,000 --> 00:33:15,000
Yeah. And where it's cleared from in the hypothalamus is very telling. It's very fascinating, I should say, from pom-C, the ACTH, you know, the hypothalamus cleaves and then from the pituitary, the ACTH, but the ACTH in the clip hormone and then below that in this biosynthesis is a malano site.

175
00:33:15,000 --> 00:33:27,000
So it's like, whenever we were discussing the leukocytes, I'm thinking about the aphomalano site as well, because of its role in leukocytes.

176
00:33:27,000 --> 00:33:41,000
And these things are kind of like connected or are we just not doing what we're supposed to be doing with these molecules in these biosynthesis, because autism just kind of shows up in the 1930s.

177
00:33:41,000 --> 00:33:46,000
So what really happened? What's changed?

178
00:33:46,000 --> 00:34:07,000
Oh, that's such a good question. So many people are interested in understanding why we are describing more children now and maybe even beginning to describe them only 100 years ago or in not just children, people throughout their lifespan having these particular problems.

179
00:34:07,000 --> 00:34:18,000
As with anything, I think there's a role for better understanding, leading people to recognize it more, right?

180
00:34:18,000 --> 00:34:29,000
That the more we understand something and the more we feel like we have something that we can say about it or do about it, we will tend to notice it more.

181
00:34:29,000 --> 00:34:46,000
But there's also the possibility that the rates have also changed. And that's, and it's hard to understand exactly why that would be. We know for sure that genetics plays a huge role in autism.

182
00:34:46,000 --> 00:34:58,000
So, is it something that interacts with genetics? Is it something that's adding to genetics? These are all great questions that I don't think we have all the answers for.

183
00:34:58,000 --> 00:35:07,000
And I don't know that much about melanocytes and leukocyte interaction. So I don't know that I can comment on that.

184
00:35:07,000 --> 00:35:11,000
Yeah, yeah. Sometimes I just get excited.

185
00:35:11,000 --> 00:35:16,000
Yeah, no. That'll be the next podcast.

186
00:35:16,000 --> 00:35:18,000
Yeah, yeah.

187
00:35:18,000 --> 00:35:22,000
There's always good to have more and more topics coming.

188
00:35:22,000 --> 00:35:25,000
Yeah.

189
00:35:25,000 --> 00:35:33,000
Let's talk about, well, there's two items here while we're on the placenta in this prenatal timeframe.

190
00:35:33,000 --> 00:35:39,000
I'll just mention them both. But placenta's role in gene expression and DNA methylation.

191
00:35:39,000 --> 00:35:46,000
And then also if you know anything about cell proliferation, then the differentiation and then you mentioned migration earlier.

192
00:35:46,000 --> 00:35:48,000
You can just.

193
00:35:48,000 --> 00:35:51,000
Sure, sure. Absolutely.

194
00:35:51,000 --> 00:36:07,000
So placenta in terms of methylation. Well, so, I mean, in case your listeners aren't up on methylation, that's a way that the genes that are the same in everything.

195
00:36:07,000 --> 00:36:17,000
Well, not every single, you know, in most of the cells of my body, I have the same genes, but they're doing very different things in different cells and they do very different things at different ages as well.

196
00:36:17,000 --> 00:36:33,000
And we think that a lot of that regulation for how does the gene, the set of genes I have do something different in different scenarios comes from whether they're methylated or other modifications that are similar to methylation.

197
00:36:33,000 --> 00:36:46,000
So not to put it all in the back of methylation, but it's not that methylation reflects developmental stage so that there's like normal changes in methylation that occur.

198
00:36:46,000 --> 00:36:54,000
Like when are when we make gametes that are going to produce like an embryo when they when they join an egg and sperm.

199
00:36:54,000 --> 00:37:03,000
There's methylation changes that occur through the division of the earliest cells of a of a of an embryo blastocyst stage.

200
00:37:03,000 --> 00:37:21,000
And then there's also methylation that's thought to reflect exposures and sort of keeping almost like a way of the cell of keeping track of things that have happened to it historically.

201
00:37:21,000 --> 00:37:37,000
And then there's and then there's also at a completely different level of the role of methylation is in the brain, very rapid changes in methylation, like when we're sitting here talking to each other are probably part of what's allowing us to build memories of what we're doing.

202
00:37:37,000 --> 00:38:00,000
And so that's another place that DNA methylation plays a role but in the placenta. It is interesting how, just like with any cell the methylation pattern might be able to tell us something about how the system was functioning as well as what the system had experienced before and that's becoming a way for us to

203
00:38:00,000 --> 00:38:16,000
possibly look at function of the placenta, but also sort of the history of the placenta because it's a tissue as we talked about earlier that has a role for the period of pregnancy and then it has another you know then we're done with it.

204
00:38:16,000 --> 00:38:36,000
And like, and but some researchers are starting to collect samples of placenta from lots of different pregnancies so that we could maybe look at methylation among other things to understand better does the methylation of the placenta differ between people who eventually are diagnosed with autism

205
00:38:36,000 --> 00:38:56,000
eventually diagnosed with ADHD, or, you know, anything else like perhaps even understanding other diseases such as obesity just because the placenta plays a role in so much. I mean, it's intimately involved in all of fetal development when some of these problems may begin.

206
00:38:56,000 --> 00:39:04,000
So, I'm not sure if there was anything particular about about methylation that you had been thinking about Ryan.

207
00:39:04,000 --> 00:39:14,000
I mean, anything in particular, I just know that it's pretty common in the literature. So, yeah, yeah.

208
00:39:14,000 --> 00:39:28,000
About the only thing I really know about it is it takes a donor from methionine. It's, you know, often things in their biology have those cycles, and then it gets the donor to folate and then on from there.

209
00:39:28,000 --> 00:39:52,000
Yeah, and so you're basically in part pointing out that methylation can't just happen just because we sell wants to have methylation has to have the right co factors there to actually make the methylation happen and that can also be a way that you can know if, you know, there's been perhaps a limitation of certain nutrients by virtue of methylation patterns.

210
00:39:52,000 --> 00:40:00,000
But, but something else you said earlier.

211
00:40:00,000 --> 00:40:06,000
Maybe Oh, we were talking about developmental processes of things like migration and proliferation.

212
00:40:06,000 --> 00:40:29,000
And so, so, so in placenta, the cell, you know, making that tissue informing that tissue rapidly does involve those normal processes of cells dividing proliferating and cells migrating to where they need to go including cells that contain particular nutrients who that have to locate themselves

213
00:40:29,000 --> 00:40:53,000
particularly in certain parts of the placenta so that they can provide the nutrients to the fetus. But the, I had referred to some processes like proliferation and migration with respect to the fetal brain, because the fetal brain has a very also very systematic way that it gets put together and that

214
00:40:53,000 --> 00:41:13,000
involves cells being rapidly produced you have to produce thousands, tens of thousands of cells very quickly. And in fact, we don't produce really, for the most part, any more neurons after the prenatal period not to any large extent in very small numbers is there are

215
00:41:13,000 --> 00:41:32,000
new neurons produced. So we get all of the neurons we're ever going to need to do all the stuff we're doing talking the thinking all this stuff, what in the prenatal period, and those cells are all born in sort of the, if you think of the developing brain, this is maybe

216
00:41:32,000 --> 00:41:52,000
very, very simplistic, as sort of a donut shape it has a hole in the middle, and it's sort of a donut, and that hole in the middle is sort of the fluid filled space and all the cells that are born are born right along the edge of that hole and then they have to migrate away from that edge of the hole into

217
00:41:52,000 --> 00:42:16,000
the rest of the donut. And so cell migration is a major phase of brain development that requires a lot of energy, because the cells have to move, and, and requires very, very specific guiding signals so the cells know where to move.

218
00:42:16,000 --> 00:42:29,000
And some of those things we think were in the models that we looked at the migration of cells seem to be the cells weren't getting the right cues on where to go.

219
00:42:29,000 --> 00:42:53,000
When they were in the presence of, of stress, maternal stress I should say. And we actually think that another way of describing another way of using the word stress is in a cellular context is oxidative stress and in first cells that's not the same as the kind of stress you and I as

220
00:42:53,000 --> 00:43:18,000
people experience it's like a cell experiences an imbalance in the level of like damaging molecules, it gets exposed to, and we think that oxidative stress is playing a role in misdirecting some of that migration during prenatal brain development that that might also contribute to neurodevelopmental disorders.

221
00:43:18,000 --> 00:43:28,000
The source of the oxidative stress is that from the mother or is that in the womb itself.

222
00:43:28,000 --> 00:43:52,000
Yeah, I think it's, I think it's getting focused on the, it originates probably in some of the very specific aspects of maternal physiology that change in certain circumstance. Like we talked about maternal stress can involve cortisol, it can involve inflammation and those processes.

223
00:43:52,000 --> 00:44:15,000
When directed at particular cells like the cells of the placenta the cells of the fetal brain can actually then secondarily induce oxidative stress so it's, it sort of originates in the mother but it's filtered through the placenta and the fetal tissue response to those things that are happening from the mother.

224
00:44:15,000 --> 00:44:35,000
And so we, we have found in some of our models that in part those effects can be blocked by antioxidants so people have heard of that probably because we hear about antioxidants in our diet and antioxidants are molecules that can combat oxidative stress.

225
00:44:35,000 --> 00:44:58,000
And we have provided that in our models where we think there's a high level of oxidative stress occurring and this is causing a disruption of brain development we've found correction of some of those processes when the mother is given antioxidants to wall wall also experiencing the

226
00:44:58,000 --> 00:45:23,000
risk of the risky condition that the stress condition. So, so that we do think that it's not at the level of an exact dose or an exact guidance in diet but we do think that it's good to have a good level of antioxidants in your diet during pregnancy just because it can help regulate some of the

227
00:45:23,000 --> 00:45:37,000
keep in line in the normal range of operations the levels of, of, you know, oxidative stress, not allowing it to get to out of control.

228
00:45:37,000 --> 00:45:56,000
I've seen some data saying that autism and mitochondria, there's about 80% implicated with mitochondria, but I'm like, I think that's highly misrepresented. I think it's closer, probably to 100% or maybe even 100%

229
00:45:56,000 --> 00:46:13,000
Yeah, yeah, I don't I don't know about the percentages but I mean there are some theories that part of the problem is in mitochondrial regulation of providing energy and then cleaning up the byproduct of producing that energy which is cleaning up the oxidative stress so

230
00:46:13,000 --> 00:46:29,000
I mean it is a very interesting idea and there are some there are some very specific genetic deficits in that process that are that cause neurodevelopmental disabilities.

231
00:46:29,000 --> 00:46:44,000
It does show us that for sure that problem can result in in, you know, a problem like autism, but you know I don't know the extent of it across all different people who have autism.

232
00:46:44,000 --> 00:46:51,000
Yeah the mitochondria. It's a bit of a bad word right now, but it's for a good reason I think.

233
00:46:51,000 --> 00:47:06,000
It's important. So, yeah, there's so many of them though. So it's kind of hard to dial in. It's easy to look at the role of one, but like the cell nucleus there's so many. How many does it take.

234
00:47:06,000 --> 00:47:14,000
How many abnormal mitochondria in a cell, nucleus does it take for the cell to kind of underperform.

235
00:47:14,000 --> 00:47:30,000
Very good question and it really probably depends on what the cells trying to do. Stage of development, all the other things going on at the same time that's why biology so interesting yet so confoundingly complex.

236
00:47:30,000 --> 00:47:38,000
Yeah, whenever you mentioned oxygen earlier I instantly went to mitochondria.

237
00:47:38,000 --> 00:47:50,000
And Richard Fry was on and he said this nonchalantly say the whole reason we breathe is so oxygen can function into cytochrome c-oxidase.

238
00:47:50,000 --> 00:47:55,000
I love that. I love that. That's a great one.

239
00:47:55,000 --> 00:48:02,000
I would never thought what we breathe so that reason in the mitochondria.

240
00:48:02,000 --> 00:48:17,000
With even what we know about melatonin being produced in the mitochondria during the day. And then that maybe being, if we were to subordinate them, melatonin being our number one antioxidant.

241
00:48:17,000 --> 00:48:22,000
Of course there are other crucial ones, but it's something like that.

242
00:48:22,000 --> 00:48:33,000
The daytime environment, maybe even like as being removed from the sunlight now. And because of the electrons.

243
00:48:33,000 --> 00:48:38,000
Are we deficient on electrons.

244
00:48:38,000 --> 00:48:47,000
Oh, so you're thinking about like changes in modern life as we have and the rates of autism going up and less sun exposure.

245
00:48:47,000 --> 00:48:56,000
That's interesting. That's interesting. I would now would say that like there's so many things contributing to

246
00:48:56,000 --> 00:49:08,000
changes in the provision of certain molecules. I, you know, modern diet major major shift right like we eat so differently than we did 100 years ago.

247
00:49:08,000 --> 00:49:15,000
So that's another one but yeah that's a very interesting hypothesis.

248
00:49:15,000 --> 00:49:27,000
I'm, I'm, I'm hitched on it though Dr Steven so I just have to caution you that autism predates all of these other environmental toxins that are discovered now.

249
00:49:27,000 --> 00:49:33,000
I'm not saying that they're not important, but the artificial light predates autism.

250
00:49:33,000 --> 00:49:41,000
And then light is, if we think about quantum physics, light is electrons.

251
00:49:41,000 --> 00:49:52,000
It doesn't have it hits matter. And then you know it, this causes so much energy to come about that.

252
00:49:52,000 --> 00:50:02,000
And we've neglected ourselves and I think maybe that's why autism shows roughly two generations after artificial light.

253
00:50:02,000 --> 00:50:19,000
That's interesting. There is, there is a field of biology called quantum biology. I don't know if you've heard of that where people try to understand the role of quantum particles in the processes of cells which is really a, I starts to blow my mind

254
00:50:19,000 --> 00:50:22,000
even more than most biology does.

255
00:50:22,000 --> 00:50:44,000
Yeah, this is as far upstream in the cell as you can go is quantum biology because it's what drives biochemistry biochemistry doesn't work without those that the quantum physics the signals from the environment is, is what I'm taught.

256
00:50:44,000 --> 00:50:45,000
Yeah.

257
00:50:45,000 --> 00:50:48,000
Yeah, but

258
00:50:48,000 --> 00:50:52,000
Big ideas. Wow.

259
00:50:52,000 --> 00:51:10,000
I can't comment. I don't think autism or origin. It originates in the 1930s and the rates also follow us, removing ourselves more from the sun and introducing artificial light and the types of artificial light, because light has a wavelength.

260
00:51:10,000 --> 00:51:19,000
I wonder how, you know, with these disorders that are that are so modern that have modern definitions.

261
00:51:19,000 --> 00:51:29,000
I wonder if we, how we would ever be able to determine if people did have these problems before.

262
00:51:29,000 --> 00:51:48,000
You know, you do see characters in literature that was written hundreds of years ago that appear to have some of the issues of modernly defined neurodevelopmental problems, particularly think about ADHD in that way.

263
00:51:48,000 --> 00:52:02,000
And in historical record, there's quite a bit of reference to people who struggle with attention and control of movement and things like that but we, you know, getting a rate would be so hard, a real rate.

264
00:52:02,000 --> 00:52:21,000
It's always going to be a bit of a mystery to know how much it was, you know, happening 100 years ago and then, you know, the social, the cultural response to it too is like, maybe people were even, you know, there's more stigma maybe in the past.

265
00:52:21,000 --> 00:52:29,000
So maybe people didn't even have a chance to know people who might have had autism. I don't know.

266
00:52:29,000 --> 00:52:41,000
Yes, to think about ADHD goes back a couple of hundred years, 17th century maybe. And our modern environment environment doesn't do it any favors.

267
00:52:41,000 --> 00:52:49,000
So that's true. All the distractions are pretty tough. Yep. Yeah. Yeah. Yeah.

268
00:52:49,000 --> 00:52:53,000
For sure.

269
00:52:53,000 --> 00:53:00,000
We haven't even talked about the dorsal striatum. I know we haven't, but we've already been talking a long time.

270
00:53:00,000 --> 00:53:07,000
Yeah, that's okay. But I do have a couple of questions for you before we wrap up. Sure.

271
00:53:07,000 --> 00:53:20,000
I love the dorsal striatum so much. But I realize we're not going to get into it but I am very curious about what are you recently most excited about?

272
00:53:20,000 --> 00:53:23,000
Are you personal or professional in your research?

273
00:53:23,000 --> 00:53:31,000
Yeah. So we, you know, well, since you've alluded to the dorsal striatum, I will say we have some really interesting data.

274
00:53:31,000 --> 00:53:45,000
So one of the things to think about if we're trying to understand how prenatal events and brain development influence the risk for neurodevelopmental disorders,

275
00:53:45,000 --> 00:53:53,000
the major factors that happens is determining the right size of a structure and the right cellular population that goes into that structure.

276
00:53:53,000 --> 00:54:03,000
And so we've been interested in that from the sake of the dorsal striatum. Many, many people have focused on that question from the standpoint of the cerebral cortex.

277
00:54:03,000 --> 00:54:26,000
So there's been a huge range of literature going back 20 years on what regulates the right number of cells populating the cortex and people have studied genetic factors and they've studied environmental factors and have, you know, emphasized the role of these wonderful cells, the microglia in regulating those processes,

278
00:54:26,000 --> 00:54:45,000
but not as much as really been done about how do we regulate the right size of the dorsal striatum. And because of evidence in the literature that autism seems to have enlarged dorsal striatum from the earliest time point that people look at brain imaging studies of people with autism,

279
00:54:45,000 --> 00:54:59,000
we wanted to understand what if we try to manipulate the size and the cell population that goes into building the striatum. And so we have really new data that we're just going to present this coming week and is still really being collected,

280
00:54:59,000 --> 00:55:12,000
showing that if we use a modulator of cell proliferation in mice while their brains are developing in utero,

281
00:55:12,000 --> 00:55:33,000
we actually seem to be able to increase the size of the striatum and disrupt some of the kinds of problems that are some of the kind of behaviors that are also disrupted in neurodevelopmental disorders including things like habit learning or procedural learning,

282
00:55:33,000 --> 00:55:43,000
which the striatum plays a huge role in is allowing us to learn how to do things in a very regulated patterned way just so we don't have to think about it every single time we do something.

283
00:55:43,000 --> 00:56:02,000
So we have new data suggesting that when we, when we manipulate this and grow the striatum beyond the point where it normally will grow that we see this disruption of these procedural learning behaviors in the animals after they grow.

284
00:56:02,000 --> 00:56:21,000
And that they're the one thing we really want to understand is, what is that what happens when we increase that growth early, does it stay increased, does it actually get even larger over time because one of the other phenomena in autism is that the

285
00:56:21,000 --> 00:56:41,000
dorsal striatum doesn't just begin larger, it actually seems to grow faster through childhood. And so we will, we want to look at this model, if we really have been successful in creating it and understand how it tracks over time and how it changes with development because we think

286
00:56:41,000 --> 00:57:02,000
that might help us understand some of the places where you could, maybe you can't change the initial events that occur prenatally because you don't yet know that you have the issue, but could we find out how it tracks with time, and then find ways to, you know, if a person is having a big problem because

287
00:57:02,000 --> 00:57:18,000
of the symptoms, find ways to modify the stradle, the stradle cells, the stradle structure in ways that would be beneficial. So that's that's really an exciting thing for us right now.

288
00:57:18,000 --> 00:57:29,000
That is exciting. Do you know if it's the larger sizes, increased amounts of dintrites and axons and even the morphology of it.

289
00:57:29,000 --> 00:57:45,000
Yes, that's one of the questions we want to find out. So thus far we've really been, we've been focusing on creating more of the cells that build the structure, because we see those differences in people with autism.

290
00:57:45,000 --> 00:58:06,000
And it seems to just that it's an early fundamental problem like the cell population, but it might lead to this to what you're saying also that you have alterations in dendrites and synaptic structure and that would be something we have to explore after we after the next stage of the study, it's coming right up.

291
00:58:06,000 --> 00:58:10,000
So yeah, hopefully we'll be able to answer that question soon.

292
00:58:10,000 --> 00:58:22,000
Yeah, I'm looking forward to that. It makes kind of makes sense because it's, then those areas become preferred because our central nervous system just wants to respond. It doesn't like to work.

293
00:58:22,000 --> 00:58:25,000
It just wants to respond based off of what it knows.

294
00:58:25,000 --> 00:58:46,000
Right, right. Yep. Yep. Yeah, and I mean that would suggest, you know, we know that even if we don't necessarily see increased structure in people with autism, we know that straddle connectivity to the sensory cortex is also more than in people in people who don't have autism.

295
00:58:46,000 --> 00:59:02,000
So we have like the cells not only maybe in some people there's more of them but maybe in other people it's not that there's more cells is that they're just more active. And, you know, understanding why that would be would be another would be another goal.

296
00:59:02,000 --> 00:59:14,000
Maybe that's you know, when we see these things happen in people we don't know for sure if it's like a, that was part of the thing that caused the problem or is that actually what the person is doing to try to deal with the problem.

297
00:59:14,000 --> 00:59:20,000
You know, that's still up for interpretation but certainly worth exploring.

298
00:59:20,000 --> 00:59:28,000
Yeah, that's awesome. Well, Dr. Stevens, I just loved our conversation and I thank you for your time.

299
00:59:28,000 --> 00:59:34,000
I'm looking forward to the data you just explained and I'll be looking out for it.

300
00:59:34,000 --> 00:59:37,000
Oh, fantastic. Well, I'll keep you updated for sure.

301
00:59:37,000 --> 00:59:38,000
Yeah, please do.

302
00:59:38,000 --> 00:59:55,000
That would be great. That would be great. Well, thank you so much for all your interest in the in the placenta. I, you know, I'm really hopeful that the big take home point is I'm just hopeful that we can do the right thing to support healthy brain development as much as

303
00:59:55,000 --> 01:00:10,000
possible as early as possible and that really all starts by, you know, making sure we know what goes into a healthy brain in the earliest time points so that's my that's my goal.

304
01:00:10,000 --> 01:00:22,000
That's awesome. That's my number two on my list number one's cause and number two is identification and early biomarkers because this is undisputed that the earlier the better.

305
01:00:22,000 --> 01:00:32,000
Well, thank you. Have a great weekend and thank you so much. Yeah, take care.

306
01:00:32,000 --> 01:00:40,000
If you're listening to the podcast or listening to the episode, please feel free to leave a review or ratings.

307
01:00:40,000 --> 01:01:01,000
In podcasting, review and ratings are crucial. And I very much appreciate your feedback. You can contact me on X at RPS 47586 or click on the hop link so you can have links to all the show platforms and contact information.

308
01:01:01,000 --> 01:01:15,000
You can email me info.fromthespectrum at gmail.com. And thank you for listening to From the Spectrum podcast.