Miscarriage Research & the Bruce Effect | Dr. Noam Sobel & Dr. Andrew Huberman

00:00:00.000 | In the Bruce Effect, when you expose a pregnant mouse at an early critical stage of the pregnancy,

00:00:09.640 | I think up to about day three, if you expose the pregnant mouse to the order of what is

00:00:17.360 | referred to in technical terms as the non-stud male, that is a male who did not father the

00:00:22.860 | pregnancy, she will miscarry the pregnancy. She will abort it. Now, that's an insane decision

00:00:29.300 | made by the female here, right? Because she's invested quite a lot in this, right? In biological

00:00:34.500 | terms and in forming this pregnancy and maintaining it. And yet she drops it on the basis of an odor.

00:00:41.120 | And this effect is remarkably robust. And what do I mean by remarkably robust? So this will occur

00:00:49.540 | on about 80% of exposures. Now, as you know, 80% is 100% in biology, right? I mean,

00:00:55.620 | there's nothing that happens at more than 80%. So it's a remarkably robust effect, this dropping

00:01:04.660 | of the pregnancy. And we know it's mediated by chemo sensation through the nose.

00:01:08.740 | For sure. And we know in the following way. So first, it's enough to just bring the odor of the

00:01:14.580 | non-stud male. You don't have to bring the male himself, right? So you just can bring bedding from

00:01:19.460 | a non-stud male and that will induce the Bruce effect. But of course, the most telling set of

00:01:25.380 | experiments is that if in the female mouse, you ablate the vomeronasal organ, you just burn this

00:01:31.300 | tiny structure in the nose, and the effect disappears. So the effect is completely dependent on the former

00:01:37.220 | nasal organ. And I find this utterly a remarkable effect, right? I mean, because again, because of the

00:01:44.980 | extent of cost that the female takes on here, based on this information and smell.

00:01:54.340 | Now, humans, the sort of the going notion in olfaction is that humans don't have a functional

00:02:02.420 | vomeronasal organ. So we don't have that functional organ in our nose. Now I'll point out, we actually do

00:02:09.940 | have the pit. So the structure or the outlining structure is there. But the pit that we have is

00:02:19.940 | considered vestigial and non-functional. And what about this thing I learned about at Berkeley in

00:02:27.220 | integrative biology class that we have something called Jacobson's organ? This is the same organ.

00:02:33.300 | So Jacobson organs is the vomeronasal organ. It's also called Jacobson because I think Jacobson was a

00:02:42.500 | military physician in like the 1800s in Holland or something. And he found it in a soldier he was

00:02:51.220 | operating on or something like that. But the story comes from something like that. But the Jacobson

00:02:56.820 | organ is another name for the vomeronasal organ. These are one in the same, the sensory organ of the

00:03:02.340 | accessory olfactory system. And again, the going notion is that the human Jacobson organ or vomeronasal organ

00:03:09.540 | is vestigial. It's non-functional. Does that necessarily mean that we don't have these pheromone

00:03:14.580 | effects? No, it does not. So first of all, we know that lots of what are considered pheromonal effects,

00:03:19.860 | namely social chemo signaling in rodents, are mediated by the main olfactory system. We know that for sure.

00:03:24.260 | There are several examples for this in mice and rats and rabbits and so on and so forth. So A,

00:03:31.380 | these can be mediated by the main olfactory system. And I'll come back to that in a second. But first to

00:03:38.180 | finish the Bruce effect. And second, and I'm going out on a limb here, but I'm willing to take that risk.

00:03:50.980 | For me, the jury is still out on human vomeronasal organ. The decision or the notion

00:03:59.300 | that it's non-functional relies on about one and a half papers, post-mortem, looking for the nerve

00:04:08.900 | that connects this thing to the brain and failing to find it using staining and so on and so forth. But

00:04:14.740 | staining post-mortem studies in humans are notoriously complicated.

00:04:20.020 | Basically, you know, for many reasons, one of them is that the material is just always

00:04:25.700 | has gone through, you know, it's not ideally set as it is when you sacrifice an animal and

00:04:33.540 | and study its tissue. So based on really, really a paucity of studies that fail to find

00:04:42.820 | this nerve, the notion is that the structure is vestigial in humans. I don't have any evidence that

00:04:51.140 | it's functional, mind you, but I'm just not sure that it's not. But what we do have a suspicion

00:05:00.180 | is that humans may experience something similar to Bruce effect. So, first of all, humans have an

00:05:11.060 | enormous number or ratio of spontaneous miscarriage.

00:05:17.140 | - Are they occurring more often in the first trimester? Because you mentioned that in the Bruce

00:05:22.580 | effect in the mice is in the first three days or so following pregnancy, which in the mouse gestation,

00:05:27.300 | as I recall, is about 21 days in the mouse. You're talking about one seventh of total gestation. So,

00:05:31.300 | I'm not quick enough to, nor is it important to translate, but this would be first trimester.

00:05:36.020 | - Yes, which is indeed when most miscarriage occurs. Now, humans have, again, a huge number of miscarriages

00:05:43.780 | and the numbers, I'll soon share them with you, they sound odd. And the reason they sound odd is because

00:05:50.340 | if you have what's sometimes simply referred to as failed implantation, right, this can occur, you know,

00:05:56.500 | in days one, two, nobody ever knows. Okay, so some papers talk about 90% of all human pregnancies end

00:06:05.140 | in miscarriage. This is counting a failed implantation in day one, two, et cetera. More conservative studies

00:06:12.020 | talk about 50%. Nobody will argue 30%. Okay, so a huge number, a huge number of human pregnancies end in

00:06:21.460 | miscarriage. Now, out of these, there's a portion that are unexplained, right? So nobody knows why.

00:06:30.420 | I mean, there are portions that are explained by all sorts of genetic factors, developmental factors,

00:06:34.500 | and so on and so forth. But there's also a proportion that are unexplained. And so all I'm saying is that

00:06:41.780 | there's a statistical backdrop or setting, if you will, for something like a remnant Bruce effect in humans.

00:06:50.100 | Now, with that in mind, we approached a group of, we enlisted a group of, they're not really patients

00:07:00.020 | and participants in a study of people who couples who are experiencing what is referred to as is

00:07:06.340 | unexplained repeated pregnancy loss. So formally, if you have two consecutive unexplained miscarriages,

00:07:15.620 | then that is sufficient for the diagnosis of unexplained repeated pregnancy loss. However,

00:07:21.700 | in our cohort of 30, we had couples who experienced 12 consecutive unexplained repeated pregnancy losses.

00:07:30.420 | So the two is just the formal, all of our cohort was like 12, five, you know, so this is an emotional,

00:07:38.180 | difficult place to be. And these are couples who are losing their pregnancy for no apparent reason.

00:07:45.860 | So they've gone through all the tests that you can imagine of, you know, genetic incompatibilities and

00:07:50.820 | all sorts of issues, clotting, all the known suspects for pregnancy loss. And the medical establishment remains

00:07:59.540 | totally at a loss as to why these pregnancies aren't holding. And so we hypothesized that,

00:08:06.260 | that perhaps here, there's something akin to a Bruce type effect. Obviously, it's not going to be the same

00:08:11.780 | as in mice, but, but something like a Bruce effect. Now, of course, at that stage, we could not do anything

00:08:17.940 | causal to test this, right. But what we could do is to see, you know, to seek circumstantial evidence to see if,

00:08:25.780 | if where there's fire, maybe there's smoke. And what we did was we tested,

00:08:32.180 | all faction and more specifically, the response to male body odor in, in the couples experiencing

00:08:42.180 | repeated pregnancy loss. And we found a few things. First of all, if you think of the mechanisms behind

00:08:53.220 | the Bruce effect, the Bruce effect implies that the female has to have a very clear memory

00:09:00.580 | of the fathering male, because if she's going to miscarry in response to the nonfather, she has to

00:09:06.980 | know father, nonfather. I mean, that means that there's a pronounced olfactory memory at the moment

00:09:15.140 | of mating. Okay, and in mice, this has been very well characterized and attributed to the anterior

00:09:21.860 | olfactory nucleus structure in the brain. But you'd have to have this memory in order to make

00:09:30.420 | that decision. Now, so to address that, and here you're going to see that you and your childhood

00:09:35.940 | story from before stand out a bit as skillful, is that the first thing we did was just behaviorally test

00:09:43.700 | whether these women and control women could identify the smell of their spouse.

00:09:57.140 | And you might be disappointed or, you know, we would all are probably a bit disappointed to learn

00:10:03.780 | that control women are very poor at this. So you would think that women would be good at identifying

00:10:11.540 | the body odor of their spouse. They're not. They're not far from chance. However, the women who experience

00:10:22.580 | uh, repeated pregnancy loss are more than, they're, they're double, um, at their performance level.

00:10:29.780 | So this is not a nuance effect. Uh, women who, who, who, who experience repeated, uh, pregnancy loss

00:10:36.180 | can identify, uh, their husbands or their spouses, uh, by their body odor.

00:10:42.020 | With much greater acuity than the typical person? Double. A bit more than double. And, and way above

00:10:48.660 | chance. Yeah, no, I, I, sorry, I posed it as a question, but I meant, yes, with much greater acuity,

00:10:54.180 | uh, and double is, is a significant, um, improvement. Are they much better at detecting any odor?

00:11:01.620 | No, they're not. We did the controls and they're not. And then, um, we also measured using fMRI. We

00:11:09.460 | measured their, their brain response to, uh, stranger male body odor. And there, and, and, and this was

00:11:17.620 | quite remarkable because, you know, we approached, so this was a full brain analysis. So without a region

00:11:23.220 | of interest analysis. So it's not as if you're, uh, tweaking your statistics to look at one part of the

00:11:28.580 | brain, you're just looking at the entire brain in the response to male body order and asking,

00:11:33.140 | de novo, is there a difference between these two groups of participants? And there was one huge

00:11:37.380 | difference and it was in the hypothalamus. And so there was a difference in response to stranger male

00:11:43.060 | body order, uh, between the two groups. Um, so, so olfaction is altered in spontaneous, repeated

00:11:52.900 | spontaneous, uh, pregnancy loss. We don't know this is causal, right? Uh, but, but that was enough

00:12:00.340 | for us to approach the ethics committee, um, to run a causal experiment. Um, and we're at the beginning of

00:12:08.020 | that now.

Miscarriage Research & the Bruce Effect | Dr. Noam Sobel & Dr. Andrew Huberman

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