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Dr. Bradley Cooke: The National Institutes of Health
166 Plays6 days ago
What do the National Institutes of Health (NIH) do, and who works there? Rolf and Joe talk to Dr. Bradley Cooke, who works at the NIH as a Program Director in the Division of Diabetes, Endocrinology, and Metabolic Diseases (located within the National Institute of Diabetes and Digestive and Kidney Diseases). Dr. Cooke talks about the research he conducted when he was in the academic world, including work on the biology of attraction and sex differences in the brain, and then discusses how the NIH monitors and guides the national research agenda, some of the essential and groundbreaking research the NIH has funded, as well as exciting research trends coming our way.
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Transcript
Introduction to Dr. Brad Cook
00:00:10
Speaker
Welcome to Cognation. I'm your host, Rolf Nielsen. And I'm Joe Hardy. And on today's show, we have with us Dr. Brad Cook, who is an n NIH program director and a member of the Division of Diabetes, Endocrinology, and Metabolic Diseases.
00:00:28
Speaker
Great to have you with us, Brad. Thanks, Joe and Rolf. Good to see you and hear you both. Yeah, good to see you, Brad. Yeah, thanks for coming on the show. Yeah, we've known Brad for a long time. We were all in graduate school together back at UC Berkeley more years ago than I would like to count. ah But yeah, it's wonderful to see you. Thanks for being on the show.
Journey from Neuroscience to Cognitive Science
00:00:47
Speaker
I think, you know, yeah, we want to hear a little bit about your background, and your story. I'd love to hear a bit about how you originally got interested in neuroscience. Okay. um You know, when I cast my mind back to the earliest days that I was interested in neuroscience, I think what really fascinated me was the stories of Sigmund Freud and the early days of psychiatry.
00:01:10
Speaker
i was fascinated by the idea of mental illness, of severe mental illness, and I remain to this day fascinated by the ideas of psychosis. And so early readings in Sigmund Freud, Carl Jung um brought attention to the idea of the unconscious. And um through a a deep friendship with a a school buddy, I became even more interested in ah psychology.
00:01:37
Speaker
But my interest somehow sort of organically shifted to the brain itself. And i remember putting together a little plastic model of the brain as an elementary school student and very carefully illustrating it or or or painting it, and putting the labels on it and so forth. so It's difficult to articulate exactly why, but I was always, always fascinated by the brain.
00:02:02
Speaker
yeah Then, you know, my path took me to college, where I originally wanted to be a journalist and a novelist, and had spent a lot of time in high school writing articles for the school paper and volunteering at local newspapers.
00:02:19
Speaker
But I took my first class in cognitive science and, you know, the die was cast. It was it was clear that this was the path I wanted to follow. And so it wast it was a pretty straightforward path from there to to graduate school. I was entranced by scholarship and learning and the empirical sciences.
00:02:39
Speaker
And the multidisciplinary aspects of cognitive science, too, were really interesting. quite entrancing, the idea that you could study linguistics, philosophy, computer science, and neuroscience, and that together they helped form a picture of what the our contemporary understanding of the brain is or should be.
Exploring Sexual Attraction and Orientation
00:03:00
Speaker
And, you know, my I should say that, ah you know, i I recall now that I i formed my scientific understanding critique my particular scientific interest quite early.
00:03:11
Speaker
And that was in part because of the the budding and blooming sexuality of of myself and my classmates there in college. And so I became fascinated with the idea of sexual attraction.
00:03:24
Speaker
and its evolutionary origins. How is it that most people, men and women, find the opposite sex to be attractive? What does that mean to be attracted?
00:03:35
Speaker
And so I tried to sort of problematize that problem down to its sort of neuroscientific roots and realized in college that this is a scientific question that could be studied.
00:03:49
Speaker
Or should say, this is a question that could be studied neuroscientifically. And at that time, I really began to set my sights on figuring out the circuitry of sexual attraction.
00:04:00
Speaker
I also realized that because sexual attraction is usually sexually dimorphic, with most men being attracted to women and most women are being attracted to men, that we could establish brain behavior correlations as well as maybe begin to get at the actual neural circuitry that underlies the sort of sex-specific appraisal of you know visual and other you know other sensory modality stimuli.
00:04:33
Speaker
I really thought we could... sort of begin to break it down in terms of cognitive neuroscience, just how it is that the brain appraises stimuli for its attractiveness and then begins to orchestrate a sort of hormonal emotional response to that.
00:04:50
Speaker
And so that particular question really organized my studies all the way through graduate school and then when I became a professor. So for the first 20 odd years of my scientific career, I was really interested in the neural origins of sexual orientation and sexual attraction.
00:05:11
Speaker
But as you alluded, my path has changed and so I'm no longer in directly in academia. and I'm happy to talk about that transition, but um the scientific path is also interesting. Maybe we could talk about a paper that you did early on in your career, and I hope you're you're not sick of talking about this. This is the famous experiment on sexual orientation and finger length.
00:05:35
Speaker
Of course, I'd be happy to talk about that. um That paper, the the credit for that paper goes to my PhD advisor, Mark Breedlove. Let's see, where to begin? He began with a finding that there is a sex difference in the shape of the fingers and the length of the fingers that's present birth in newborn human infants, male infants,
00:05:59
Speaker
tend to have a shorter index finger than a ring finger. And this is the work of an earlier sort of anthropologist named Manning, I believe. So for whatever reason, Manning had been studying the lengths and probably the length of the fingers and probably other body parts for quite a bit. Anthropometry, I think, is the name of the field.
00:06:22
Speaker
And again, he'd found that in male infants, the index finger tends to be shorter than the ring finger. Whereas in female infant children, the two these two fingers, for whatever reason, tend to be of more equal length.
00:06:36
Speaker
okay So here's a sex difference present at birth. And one of the sort of specialties of the of of Mark Breedlove's research and of the lab that I was in is looking at what's called the organizational effects of gonadosteroid hormones on the brain and the body.
00:06:55
Speaker
And the organizational hypothesis says that male and female typical traits are organized in part by exposure, or the lack thereof, to gonadal steroid hormones like testosterone prior to birth.
00:07:12
Speaker
And so I think Mark realized that, oh, here is another sex difference that may also be affected by the organizational effects of testosterone. because, again, it's present at birth, perhaps reflecting exposure to testosterone during early life.
00:07:30
Speaker
And I should mention that normally the female fetus is not exposed to significant levels of any gonadal steroid hormones. But if she is exposed to high levels of testosterone, then that may very well alter the developmental trajectory of her brain and body and in a more male-typical direction.
00:07:52
Speaker
right So anyway, going back to the story, here we have an apparent sex difference present at birth. And another piece of the puzzle was the belief that sexual orientation in people is something that you're born with, to put it plainly.
Sex Differences in the Brain
00:08:13
Speaker
That it's not a choice, right? That my preference for women and others' preference for the same sex is not something that you choose to have. It may be influenced by your early life, but there isn't much evidence really that you can alter someone's sexual orientation through learning or through reinforcement of one kind or another.
00:08:36
Speaker
So I think the idea that Mark had was to evaluate whether the finger lengths of gay men and women might reflect some might reflect their the people to whom they're attracted. In other words, if gay women are attracted to other women, like straight men are attracted to women, perhaps their finger length ratio reflects this And likewise, too, if gay men are attracted to men, perhaps their finger length ratio is different in some way from that of straight men.
00:09:09
Speaker
So to you know to evaluate this question, we got a portable Xerox machine and created a questionnaire and then took this to gay pride festivals throughout the Bay Area, Oakland, San Francisco, and elsewhere.
00:09:28
Speaker
and offered participants in these festivals, ah you know either can of Coke or ah lottery ticket, for the chance to fill out this questionnaire and to have their finger their hands Xeroxed.
00:09:43
Speaker
okay And we adjusted the contrast on this machine so as to blur out their fingerprints. and The surveys were anonymous. The surveys asked the following questions. What is your gender?
00:09:55
Speaker
What is your so your biological sex?
00:09:59
Speaker
to whom are you attracted? And I think there was a ah rating scale, like what is the strength of your attraction? Strongly attracted to men, strongly attracted to women.
00:10:09
Speaker
Perhaps it was a seven point scale. I don't remember.
00:10:14
Speaker
And then a final question asked the question final question was about the number of biological siblings that the participants had. And that'll be important later on. In later studies, we asked the women participants how they would describe themselves in terms of their sexual orientation, whether they considered themselves to be a very... Well, I should say not so much that orientation, but their gender identity.
00:10:40
Speaker
Did they consider themselves to be a very feminine lesbian or more butch lesbian? and participants were asked to sort of rate themselves on a ah scale.
00:10:52
Speaker
And to my knowledge, everyone agreed to this formulation, this framework, and readily filled out the questionnaires to describe themselves as either being very butch, very femme, or somewhere in the middle.
00:11:07
Speaker
Okay, so now for the results. the The results of the study were interesting, to say the least. And it's been a long time, so I have to i could i may make a mistake, so i beg your pardon if I do.
00:11:22
Speaker
But when we looked at male sexual orientation and the the finger length ratio, okay, so that's an important variable here. We're not looking at the absolute length of the fingers anymore. We're calculating the ratio of the length of the fingers.
00:11:36
Speaker
and men on average have a smaller finger length ratio because their index finger is shorter than their ring finger, whereas women generally have a larger finger length ratio because the two fingers are of more equal length.
00:11:52
Speaker
okay
00:11:55
Speaker
What we found, if I remember correctly, is that gay men tended to have a more male typical finger length ratio. If anything, their finger length ratio was slightly ah smaller than that of straight men.
00:12:12
Speaker
And the ratio was influenced by the number of biological older brothers that they had. With each additional older brother, if I recall correctly, the finger length ratio tended to be smaller.
00:12:26
Speaker
right And so this was a counterintuitive result for us because we expected gay men to have a a larger finger length ratio based on the kind of naive assumption that gay men might be more feminine in some ways.
00:12:42
Speaker
um I think in later papers, we looked at women. I'm not sure we looked at women in this publication that you're asking about, Rolf. The story, though, for women was more straightforward. We found that the finger length ratio in gay women was more masculine than it was first for straight women.
00:13:06
Speaker
And moreover, that the self-description of oneself as either being more butch or femme, that there was a correlation there with women who described themselves as being more butch tended to have more male typical finger length ratios.
00:13:23
Speaker
than women who call themselves more femme. okay So this pose this sort of opened up a lot of questions, of course, among people who hear this story.
00:13:35
Speaker
But the credit goes to Mark Breedlove for including the question about birth order. And the reason is because it had been known for some time, and it remains pretty well established to this day, to my knowledge, that um the number of biological older brothers one has is the strongest predictor of male homosexuality.
00:13:57
Speaker
Okay. And I'll say that again, because it's a bit conceptually hard to wrap your mind around. The number of biological older brothers you have increases the probability of being a gay man yourself.
00:14:10
Speaker
And to my knowledge, nobody's worked out the mechanism for this. But there is some circumstantial evidence that perhaps pregnant women are being inoculated in some way by the male typical antigens that are being shed by the fetus.
00:14:31
Speaker
So every cell in our body is expressing HLA. It's a molecule called HLA, I believe. And HLA bears the mark of either being male or female.
00:14:46
Speaker
It's a reflection of the sex chromosomes you possess. And so the theory is that In some some way, some women are being, again, kind of inoculated is the word I would use, as if they're being repeatedly exposed to an infectious agent, perhaps by the male typical marker on HLA that is being shed by the fetus and entering the bloodstream through the placenta of the mother.
00:15:13
Speaker
And then the theory goes, ah the mother is in some way summoning an immune response that in some way, but we don't know, um influencing the development of the male fetus with each additional son, thus making each additional son more likely to be gay.
00:15:34
Speaker
So so this i mean this is part of your so sort of larger work and interest in thinking about sexual dimorphism in the brain. and Yes. So just in a really, and I don't want to spend too much time on this, but just in a really broad sense, how do we characterize differences between a male and female brain?
00:15:56
Speaker
Well, I guess I would say that the differences are quantitative, not qualitative. And I say this because I spent most of my time as a scientist as a neuroscientist looking through microscopes and counting things, doing quantitative neuroanatomy.
00:16:12
Speaker
And so when I studied sex differences, I always spent time counting. whether was counting neurons or counting synapses or counting dendrites, and thus the connections among cells, things like that,
00:16:27
Speaker
um And so and that's that's really true of the bigger picture as well. When people ah sort of survey sex differences in the mammalian brain, and again, most of this research comes from non-human animals, not from people, what we see are numerical differences.
00:16:46
Speaker
Differences in the number of neurons in a particular brain area, and differences in the and the number and kind of synaptic connections among those neurons. And although many sex differences in the brain and in the spinal cord numerically favor males, if you will, that is to say males male animals tend to have more neurons, more synaptic connections in most areas, there are some important exceptions too.
00:17:15
Speaker
And those are interesting as well. Generally, numerical sex differences are seen in what people call the limbic system. So beginning of the amygdala and then moving to the bed nucleus of the stria terminalis and then into the hypothalamus and midbrain and so on down the spinal cord is where you see the the sort of most outstanding anatomical differences between males and females.
00:17:43
Speaker
And as I had correct like sort of correctly surmised in college, and that these sex differences are a very useful way of establishing brain behavior relationships. Because we can deduce the function and learn about general principles of neural functioning by looking at how numerical differences in the brain relate to qualitative differences in neural network function.
00:18:09
Speaker
right And I'll give a quick example of that. In a region of the hypothalamus that is called the AVPV, it's a very long term, the AVPV tends to have more of a certain neuron type in females than in males.
00:18:24
Speaker
And the synaptic interconnections among these cells has also been characterized in males and females. These neurons produce a hormone called GnRH.
00:18:36
Speaker
And GnRH is involved in the luteinizing hormone surge that induces ovulation. Only females show the luteinizing hormone surge, and only females have a particular oscillatory pattern of these GnRH neurons.
00:18:56
Speaker
The particular connections among the cells and the number of these cells is directly responsible for the production of this functional sex difference. And I think that's really interesting. That that sort of underlines the intellectual value, the scientific value of studying sex differences because they are a window into understanding brain function, brain behavior and sort of functional relationships between brain structure and brain function.
00:19:28
Speaker
Yeah. As you're talking about the different you countings that you're doing and and running correlations and that, you I was thinking about this as when you were talking about the finger length topic.
00:19:43
Speaker
how much, you know, when we talk about these sort of quantitative differences, how, what kind of quantities are we talking about in terms of per percent explained by these different, ah and you know, differences between males and females or between, you know, different sexual orientations and things like that. Say, for example, for the finger length topic, like how much of the differences are explained by the, the,
00:20:11
Speaker
by the by the measurements that you took?
00:20:15
Speaker
Well, let's see. Let me back up and and stay one more one more piece of the rationale that I think Mark Breedlove summoned when he designed this experiment.
00:20:27
Speaker
And this this will become important in a minute. The finger length ratio, is it's almost impossible to conceive of a way in which one's behavior could influence the finger length ratio.
00:20:40
Speaker
right it's It's impossible, really, to think of ah of a way in which behaving like a gay man or behaving like a gay woman or a straight man or a straight woman could possibly affect the ratio of your finger lengths.
00:20:53
Speaker
That's important because nearly every sex difference in the brain that we look at is potentially influenced by behavior. So this is correlation causation issue. so yeah Yeah, exactly. It's only through experimentation that we can really begin to establish causal connections between numerical differences in the brain and qualitative differences in behavior. right Yeah. I mean, that's that's sort of what was behind my question a little bit in the sense, yeah both the correlation causation thing, but also...
00:21:26
Speaker
you know ah the idea that there's a lot of individual variability. I'm trying to get at that sense. And indeed there is. And yeah you know I think as we get further and further away from the sort of core regions of the limbic system and hypothalamus that regulate sexual behavior,
00:21:44
Speaker
I would bet that there is more and more variability in the human brain in terms of these numerical sex differences.
00:21:56
Speaker
right um that's That's a hypothesis, that's a prediction that is in principle testable, but I'm sure i'm pretty sure nobody's ever looked at that.
00:22:09
Speaker
it is It is a fact, though, that in non-human animals... It's fairly, you know, finding sex differences in these brain regions that I studied so much, it's pretty reliable. And the and although definitely there is a you know normal distribution in terms of these quantitative parameters, you can reliably find statistically significant differences.
00:22:32
Speaker
But then when you go outside those areas and look at, say, the cerebral cortex, that's where it gets a lot harder to find reliable sex differences in non-human animals, and I think also in humans.
00:22:44
Speaker
Yeah, that makes sense. Yeah, I mean, I guess I'm just trying to just to drive home the point also that, you know, while you know there are statistically significant differences You couldn't necessarily pick out from any given count of one of these metrics that a particular sample was a male or female because they're they're overlapping. I completely agree.
00:23:06
Speaker
No, I completely agree. That's right. There are very few sex differences that are so categorical that you can reliably identify one sex or the other.
00:23:17
Speaker
Yeah. Yeah, cool. Well, so I mean, so how did you then like that, that interest in it? So did that interest kind of carry you through your your time as a professor? And do you want to talk about like, yeah, I did not along the way that you found especially interesting?
00:23:32
Speaker
Sure. um Let's see. So I had a lot of different interests as ah as a professor. I was sort of like a kid in a candy shop. So one of the first projects that I started was looking at the different ways that male and female rats responded to something called social defeat.
Gender Differences in Neural Networks
00:23:53
Speaker
And so my graduate students and I um adopted a technique used and developed by others in which young male and female pre-pubertal rats were exposed to a bully, a large, aggressive male or female rat who would be introduced into their cage and would sort of beat them up for a few minutes. I don't think it was more than like five minutes and then be removed.
00:24:21
Speaker
And then we would look at the behavioral and neural consequences from that. And this was line of experiments was based on the sex differences in the prevalence of mood disorders.
00:24:35
Speaker
So on average, girls and women are more likely to have anxiety and depression than males are. And the underlying reasons for this are not well understood.
00:24:47
Speaker
But one possibility is that sex differences in gonadal steroid hormones contribute to that. And so that was the goal of this line of research, was to begin to dissect the kind of biopsychosocial and neural origins of sex differences and depression and and anxiety.
00:25:07
Speaker
And so we would, when these young rats who had been socially defeated grew up as adults, we would then test them for depression and anxiety-like behaviors.
00:25:18
Speaker
And we did find that female rats were more likely to display ah depression and anxiety-like behaviors if they'd been subjected to social defeat. They males if they had been subjected to social defeat.
00:25:30
Speaker
And we began to explore the role of a ah stress hormone receptor in the brain and how it was differently expressed in males and females and how that expression was affected by puberty and the rising levels of gonadal steroid hormones that occur during puberty, as well as how social defeat itself influenced the expression of those receptors.
00:25:56
Speaker
And is this is this something you see a parallel in people? Well, you know, I'm not an expert on the latest research on on people, but there is, as I said, that that sex difference in the prevalence of mood disorders.
00:26:13
Speaker
That's pretty well established. I believe also it's been found that there is a sex difference in the levels of the stress steroid hormone called cortisol.
00:26:25
Speaker
So women tend to have higher levels of cortisol overall. And we know that that level of cortisol is influenced by estrogen. So changing levels of estrogen influence cortisol levels.
00:26:37
Speaker
That doesn't mean that females are more stressed or women are more stressed or experience more stress subjectively. It just means that their cortisol levels are higher. And the underlying effect of that is not clear.
00:26:51
Speaker
I'll mention another line of research that I got into. And this is because this was, but so I was ah appointed a professor at Georgia State University and I had a visiting professorship at Georgia Tech.
00:27:03
Speaker
And there I really pursued my interest in computational neuroscience. And so together with my colleague, Steve Potter, who had developed these amazing neural robot hybrid preparations in which primary neurons were grown on top of a multi-electrode array, and then the collective activity of these neurons could be recorded through the array, and the neurons themselves could be stimulated via the array as well.
00:27:35
Speaker
The notion there was to harvest neurons from fetal male and female rats and dissect them, disassociate them, and then grow them on top of these 64 multielectrode arrays and characterize the collective activity of these neurons as they grow and form neural networks.
00:28:03
Speaker
and evaluate whether we could see sex differences in the collective activity of these of these networks, and also what the effect of acute exposure to gonadal steroid hormones would be. And unfortunately, this work never was published, but we did find some interesting things about the sort of qualitative aspect of the way these neuron neural networks would oscillate.
00:28:23
Speaker
So we found that estrogen, which of course comes from the ovary, but is also produced within the brains of male and female animals, tended to have an excitatory effect on the networks, making them much more likely to get into a kind of seizure-like oscillatory state.
00:28:41
Speaker
a kind of runaway excitation. And that resonated with and was sort of consistent with work I did as a postdoc where we looked at the effect of estrogen on the susceptibility of human women and female rats to have seizures.
00:28:58
Speaker
So I was in a lab that that studied epilepsy and seizures, and we you know I contributed to research there that we looked at how the hippocampus is affected by estrogen and how the the hippocampus under the influence of estrogen can promote seizure activity.
00:29:16
Speaker
So... Yeah, those are two projects that I that i spearheaded at when I was a professor. One was this behavioral neuroscientific thing looking at sex differences in anxiety-like behavior, and the other was this much more wild and woolly experiment with multi-electrode arrays.
00:29:34
Speaker
Both were a lot of fun. But I'll just ah' segue to you know the the new career in
From Academia to NIH: A Career Shift
00:29:41
Speaker
government. And so after about 10 years of being a professor, i was I got kind of tired of it, and I just wasn't really good at getting grants. And I found myself to be sort of all left thumbs in the lab. I just wasn't very...
00:29:54
Speaker
good of an very good of an experimentalist, I think. And so I i sought out something different and applied for and and received a fellowship from an organization called AAAS, which is the American Association for the Advancement of Science. They publish Science Magazine, for example.
00:30:11
Speaker
And they have ah an annual fellowship for people seeking to transition out of academia into government. And being a native of Washington, D.C., I knew a little bit about government. And so I began, i think, in 2017 with this fellowship. And ah for folks who are considering transitioning out of academia that are listening to this, I could not recommend this fellowship more highly.
00:30:35
Speaker
It begins with a summer-long sort of workshop and classroom sessions on how government works and how government shapes scientific policy and how science policy affects the scientific enterprise in the United States.
00:30:52
Speaker
um And at the conclusion of that, most people ah move into jobs in the U.S. s government, which is what I did. I started at the National Science Foundation, where I was for a year, and then I moved to the National Institutes of Health, which is where I am today.
00:31:08
Speaker
And as Rolf said, I'm a program director in a division called um Diabetes Endocrinology and Metabolic Diseases. And there, I oversee the portfolio on neurobiology, basically the the relationship of and the the study of obesity and metabolic diseases using non-human animals through the framework of neuroscience and neurobiology.
00:31:37
Speaker
I also have another bucket in which another... aspect of my work is in a complication from diabetes called diabetic neuropathy. And that also, you know, employs or calls upon my training as a neuroscientist.
00:31:54
Speaker
Diabetic neuropathy is a horrible complication that affects about 50% of people with diabetes. And it leads it leads to a permanent loss of sensation in the hands and feet, as well as autonomic neuropathy in some people that causes...
00:32:09
Speaker
gastrointestinal, blood pressure, cardiovascular, urinary, sexual dysfunction, also irreversible. And so, you know, I can talk, if you'd like, about what my what my role is and responsibility and what everybody does as program directors. So it's not just me. I'd love to i'd love to hear, too, um maybe about whether you think your career path is typical. Are there a lot of other people who have similar sorts of trajectories that you work with? And even just a sense of what's the size and scope of...
00:32:44
Speaker
the NIH and you know what other sorts of people you interact with because I don't sure know that I have a great sense of that. I'm not sure most people don't. I'm not sure I did either. um and that's ah That's an interesting way of looking at it.
00:32:57
Speaker
I'd say that roughly maybe o 60% of my colleagues had careers in academia before they moved to the NIH.
00:33:07
Speaker
The remainder usually transitioned from their postdoctoral fellowship into a program officer type role. So all scientists, PhDs who had some significant research experience.
00:33:21
Speaker
Yeah, exactly. ah Many of those who transitioned from their postdocs had been postdocs at the NIH itself. okay And so let me take a step back and tell your listeners that the n NIH, the National Institutes of Health, um is importantly called the National Institutes of Health in the sense that it is a...
00:33:41
Speaker
a body with 27 individual institutes and centers, each of which is focused on a particular dimension of public health, the sort of biomedical dimension of public health.
00:33:54
Speaker
So I'm in the division of diabetes, digestion, and kidney diseases, okay which is called NIDDK. The neuroscientists in your audience, myself included, would be most familiar with neurological disorders and stroke, NINDS, as well as the National Institute of Mental Health.
00:34:15
Speaker
There's hearing disorders and so on. So the n NIH covers all of neuroscience, and it supports the scientific enterprise in two ways.
00:34:25
Speaker
One is by hosting labs within the walls of the and NIH itself, and we call that the intramural program. So many researchers have fellowships, or they become faculty within the NIH and spend their whole careers there studying an important problem related to public health.
00:34:45
Speaker
But the NIH also supports almost every biomedical researcher in the United States who's working at a college or a university. So if you're interested in visual perception and seek out research funding, a researcher will apply, write a a grant proposal, and receive grant money from the and NIH if they if they are selected for funding.
00:35:08
Speaker
So that's the part of the and NIH that I'm part of, the extramural side. And this is where science policy and science itself, where they really meet.
00:35:20
Speaker
Yeah, so the idea is that like most of the research that's being done at universities and that's related to health is being funded by the and NIH in some capacity. absolutely Absolutely. I couldn't quote number for you. but Yeah, I'd love to hear the numbers. i mean But all these amazing discoveries, both of the basic research side that then lead to ultimately ah solutions to help people with their health, but then also you very direct studies of applications that help people live better, longer lives comes through research done but that is supported by the NIH, either intramurally or extramurally.
00:35:56
Speaker
That's exactly right. and let me let be Before we go on, I want to say that mike the opinions I express and have expressed are those of my own, not those of of my employer the and NIH. right so I'm speaking as a private citizen.
00:36:11
Speaker
And yeah, you should take my opinions for what they are, just my opinions. But no, you're right, Joe. All of us, I think all of us on this call and many folks who've been listening were perhaps inspired by a professor of of science in one way or another.
00:36:27
Speaker
And chances are very good that they, those people were supported by the and NIH in some way. And I should add that the n NIH supports, you know, i guess the the metaphor we use is that of a pipeline.
00:36:40
Speaker
So we support people who are in college, who go to who are then in graduate school, who then become postdocs, who then transition from their postdoc to becoming an assistant professor, and all the way through their scientific career. So there are grant mechanisms, they're called, that support undergraduate research and support professors who are at undergraduate-focused institutions, like Wheaton College, for example.
00:37:07
Speaker
And then there are grants that go to professors at big schools like UC Berkeley.
00:37:12
Speaker
Undergraduates and graduate students can get fellowships. Most of our money goes to fellowships of of graduate students, not undergraduates, but graduate students get can get fellowships from the NIH.
00:37:24
Speaker
Postdocs can get fellowship fellowships from the NIH that support their salary as they do important research. And then, of course, there's the the research the research grant program, I think, RPG, is the grant award that's given to individual researchers via their university to support their research.
00:37:46
Speaker
So my PhD advisor, your PhD advisors probably had grant awards from the NIH that supported their very important research into sexual differentiation or visual perception or how the eye works.
00:38:01
Speaker
You name it, the NIH supports it in terms of biomedical research. Yeah. And how do you think that compares to the interest in terms of how much funding the and NIH is putting out there compared to other big countries, like, i don't know, like compared to the EU or compared to China, for example?
00:38:20
Speaker
I don't think it's it's possible to compare. i think the I mean, you can compare it, but historically, the United States has had an overwhelming presence in terms of funding.
00:38:32
Speaker
Vastly more dollars go to basic and applied research via the NIH and other federal agencies than any other country. We probably dwarf the top you know five in terms of dollars spent.
00:38:49
Speaker
And that's why so many people want to come to the United States to do research from Europe, from China, from Japan, from all over. People come to the United States so that they can contribute to the scientific enterprise via the funding that is available through the NIH.
00:39:07
Speaker
That's, that's, yeah, that is, it's just really important that in terms of our leadership as a country in science is driven so much by these governmental organizations that fund this research and then the, all of the infrastructure that's built around that. So I just, yeah, ah to me, it's right it's something that I think, you know, a lot of people probably don't know if if you haven't been involved in academia or if you haven't been involved in scientific research, just something that's not apparent to you or,
00:39:35
Speaker
you know you don't think about on a day-to-day basis. so yes I agree. i agree and and Let me add one more thing, which is that the National institute Institute of Health is by far and away the largest funder of basic research in the United States.
00:39:46
Speaker
But every single project that is funded must have some public health-related purpose. it must it It exists only so that the researcher kit can contribute in some way to improving public health.
00:40:01
Speaker
And that is not just some arbitrary evaluation or opinion on the part of of someone like myself. No, grant ah grant proposals are reviewed by you know by their peers in the scientific community.
00:40:17
Speaker
And there is an extraordinarily arduous process through which grants are evaluated and critiqued and revised so that the very best science is funded.
00:40:28
Speaker
It's not something that anybody takes lightly and people take it very seriously. And I'm really proud to say that I'm a part of it. It feels patriotic to be contributing to the scientific enterprise in this country.
00:40:40
Speaker
so So just to drill a little bit into some of the things you might be doing on a day-to-day basis, the sort of things that you might be advancing. So one of the things you might be doing, if I'm thinking about this right, is is shaping research priorities. So um the kinds of things that might b funding might be allocated more to and also determining some of that funding to, maybe not...
00:41:06
Speaker
directly for all of it, but the sort of guiding the direction that research might go in your particular areas of expertise. Yeah, that's exactly right, Ralph. So one of my responsibilities, one of our responsibilities is to talk to scientists and get their opinions about what the big sort of gaps are in our understanding.
00:41:27
Speaker
And we evaluate and seek out those gaps through surveys of the literature as well. So when I go to a scientific meeting, I'm there to hear and listen to people as they talk about what their obstacles are and what the frontier that they see is in science.
00:41:44
Speaker
And there's also some of our judgment that comes into into it too, like what what do we perceive as being a gap? And so ah when I started at NIDDK, one gap that I perceived was in what I call neuroplasticity, the capacity of the brain to change as a result of experience, hormonal exposure, any number of different things.
00:42:07
Speaker
And so with my colleagues, we put together a workshop in which scientists converged to give talks and to talk to one another over the course of a couple of days on the subject of neuroplasticity.
00:42:20
Speaker
And it was agreed at the end of it that, yeah, there is a gap in our understanding of how the neural circuits that control appetite, eating, metabolism, how those circuits change over the course of one's lifetime, how they're affected by the food we eat, by obesity and other and hormones that ah regulate appetite, that sort of thing. so So that's one example of finding a gap and promoting research in that area.
00:42:51
Speaker
Another gap is that i that others and myself have noticed is in this scourge of diabetic neuropathy. It's, ah again, a very common complication, particularly among people with type 2 diabetes.
00:43:05
Speaker
And um we currently don't really have a treatment for it. We can relieve the pain of of diabetic neuropathy, but there's no intervention that can reverse or even stop the continued degeneration of sensory axons from the hands and feet.
00:43:24
Speaker
And that eventually, by the way, turns into motor degeneration as well. So it's a devastating complex. That sometimes leads to people having amputations as well, right?
00:43:37
Speaker
Absolutely. and And the reason for that is because when you can't feel your hands or feet, um you're much more prone to injure them. And if you, again, if you and if you injure them and you can't take care of the wound, um it can turn into a disaster.
00:43:53
Speaker
And once a limb has been or a foot or a hand has been amputated in a person with diabetes, I think the the mortality rate after amputation is higher, is like close to 50%. Wow.
00:44:04
Speaker
So it's it's terrible. And believe me, I'm not just the only i'm not the only one NIDDK who's concerned about this. it's a It's a well-recognized issue that many folks, including myself, are concerned about and working on.
00:44:19
Speaker
Another another area that you mentioned as something that you're that you're seeing coming through is related to GLP one drugs.
Innovations in Obesity Treatment
00:44:31
Speaker
That's like a big area of interest right now. I'm curious to hear a little bit about what kind of research you're seeing coming down the pike there and and also just maybe hear a little bit more about how those drugs work.
00:44:43
Speaker
Sure. So GLP-1 receptor agonists, as they're called, include drugs that um everyone's seen advertisements for, like Ozempic, Mongiorno, Wegovi.
00:44:55
Speaker
um And these are all in the same class of of drugs. They include... GLP-1 receptor agonist. And in layman's terms, what that means is that it's a a drug that activates a receptor in the body and in the brain called GLP-1 receptor.
00:45:13
Speaker
An agonist means that it activates the receptor as opposed to turning it off or inhibiting it. GLP-1 itself is produced by the brain and by the body.
00:45:24
Speaker
But normally it's has a very short half-life in the body because circulating enzymes in the blood digest it very quickly. So the great innovation of these drugs, like Ozempic, has been to modify the molecule in such a way that they resist enzymatic degradation.
00:45:43
Speaker
and so that their half-life is much more prolonged than it would be normally by the GLP that is is produced by the body. And so when I started NIDDK, there was no effective treatment for obesity.
00:45:57
Speaker
But now, five years later, there is. And so these medicines are... I can't overstate how important they are for public health, because obesity is a terrible problem, and it affects about 40% of Americans, of adults,
00:46:12
Speaker
But that number is increasing. And the health consequences of severe obesity are really quite serious. There are cardiovascular issues. There are musculoskeletal issues.
00:46:24
Speaker
The quality of one's life is severely affected by severe obesity. And so any medication treatment that can make an impact on that is a good thing. Let me just briefly explain or tell you what the way these with the way these drugs seem to work. okay So they seem to have three ways or three basic mechanisms or ways of working.
00:46:46
Speaker
The first way is by increasing the amount of glucose-stimulated insulin release. That's a mouthful, but um when we consume food, the glucose from that food enters our bloodstream and activates insulin-producing cells in the pancreas.
00:47:03
Speaker
As far as I know, what GLP-1 does is it boosts the production of insulin when it's stimulated by glucose.
00:47:12
Speaker
It may also directly cause the release of insulin as well. I'm not sure. GLP-1 also slows the movement of food from the stomach and through the intestine.
00:47:23
Speaker
And so GLP-1 increases or prolongs the sensation of fullness by slowing down the movement of food through the gut. And the third thing it does is it acts on the brain to directly affect those regions that are involved in appetite.
00:47:40
Speaker
And it seems to suppress neurons that code for hunger through ah an interesting synaptic mechanism. So I'll say one more thing about GLP-1, which is that it's produced in the gut by the distention of the intestine.
00:47:56
Speaker
And it's also produced in the brain, in a region of the brainstem called the nucleus of the solitary tract. Neurons there project into the hypothalamus, where they release GLP-1 and through a synaptic mechanism, again, as I said, influence the activity of these neurons that code for hunger.
00:48:12
Speaker
this is a major This is a major success in science, I think. I mean, you know this has been touted as a real miracle. um So to what extent um to what extent could this have happened without an NIH funding source?
00:48:29
Speaker
That's a good question. And I don't know the full story of how the and NIH supported all of the research on GLP-1. But what I do know is that basic research into, um i believe it's the the Gila monster, ah produces a substance in its saliva that slows the breakdown of GLP-1.
00:48:51
Speaker
It inhibits this enzyme that's circulating in our blood. And I believe with fairly low confidence that that research was supported by the National Science Foundation, that the discovery of this compound in the saliva of the Gila monster, which eventually led to the modification of GLP-1 so that we can have drugs like Ozempic, that was originally funded by the National Science Foundation.
00:49:12
Speaker
So a lot of the basic science that sort of led to led to the discovery of this came from... Exactly, exactly. Basic curiosity-driven research, which has been seen as the jewel of the United States.
00:49:29
Speaker
you know the The public funding of research is, in my mind, one of our highest achievements as a society. um Holding up science as something that we collectively value.
00:49:42
Speaker
you know I don't think I would have become a scientist if it hadn't been for the public support of it. Yeah, and it's it's you know that that exploration into you know some lizard and its you know saliva that could never have been predicted that that would lead to this absolutely blockbuster class of drugs that helps people you know not be obese.
00:50:06
Speaker
it's you know It's only through exploring the space of what's possible that you can find these discoveries. that's That's the nature of discovery, right? You don't know where to look. If you knew where to look, everyone everything would already be known.
00:50:20
Speaker
So it' it requires that exploration. Exactly. And I will add that no CEO of a company ever looked at a lizard and said, there's profit to be had in that there's saliva. yeah It was curiosity-driven.
00:50:34
Speaker
i don't know what possessed the researcher to look at the saliva of the Gila monster. But um that they did, and I'm glad they did it. And that just basic, pure curiosity has been supported by the United States pretty much since the end of World War II, and i'm I'm really glad that they have.
00:50:54
Speaker
Carl Sagan said that science is like a candle in the darkness. And I couldn't agree with that sentiment more. It is... you know it it is a light that keeps the sort of forces of darkness, of ignorance at bay by training people to think rationally and to ask systematic questions about reality that simply can't be done by any other method.
00:51:21
Speaker
And so I'm a big fan of science for its own sake because it helps young people and the adults that they turn into look at the world in a rational way.
00:51:34
Speaker
And we need that so badly. It's so important in this day and age that we have folks who look at the world objectively and and systematically objectively.
00:51:48
Speaker
What are you, you know one of the last things we like to ask is kind of like a last question is, what are you excited about going forward like ah
Future Directions in Obesity and Neuropathy Research
00:51:57
Speaker
research-wise? like What are you seeing out there that you're excited about? Are you are you looking at different areas of emphasis that you're new calls or things that you're especially excited about?
00:52:09
Speaker
Yeah, I can think of two things. One is based on this premise that obesity begets obesity. And by that I mean it tends to run in families, right?
00:52:21
Speaker
And there's undoubtedly a hereditary component. We know that there's a hereditary component to obesity and metabolic disease. However, there's also good evidence that the intrauterine environment and the food that the mother is eating when she's pregnant may contribute to the development of neural circuitry that regulates appetite and metabolism.
00:52:45
Speaker
And I'm extremely interested and very, very curious in the factors that may pass from the mother to the growing fetus that in turn influence her brain development, that in turn regulate her appetite and body corpus and her body habitus.
00:53:06
Speaker
And so this is this particular question gets at the very heart of what I find so exciting about neuroscience and and behavioral science, which is the sort of nature-nurture question, the intertwining of development and experience to form a unique individual.
00:53:24
Speaker
The second thing I'm excited about is this initiative on neuropathy. And I'm excited about that because the facts of diabetic neuropathy, as you alluded to, Joe, for example, the horrible prevalence and and outcomes related to amputation profoundly tug at my heartstrings. And so I'm emotionally motivated to help the n NIH find a cure and or a treatment for diabetic neuropathy.
00:53:54
Speaker
And so that is a long-term project, but one I feel very good about pursuing for the rest of my career at the NIH. Well, that's great, Brad. that the Great places to end it, I think.
00:54:06
Speaker
Dr. Brad Cook, yeah, thank you so much. You're welcome, guys. That's a lot.