0:00:03 All right. This is super cool. This type of stuff only happens, I think, on MFM. But
0:00:07 here’s the deal. I have a friend named Wade Foster. He started a company called Zapier.
0:00:11 Zapier is a business that was bootstrapped to hundreds of millions in revenue, and it’s worth
0:00:17 $5 or $10 billion. And I had the CEO and founder on, Wade. I had him on MFM. And I said,
0:00:23 look, share your screen and show me how you’re using AI to save 10, 20, 30 hours a week.
0:00:28 It’s pretty amazing. He did it. And he broke down like three or four different ways that he
0:00:33 has automated parts of his life and his business. And it’s really, really cool because this
0:00:38 guy has an incredible perspective because he has such a large company, but because he helped
0:00:43 create this whole automation industry. So if you want to save a bunch of time, this stuff
0:00:47 is not complicated. I don’t know AI that well. And I’m going to implement a ton of the stuff
0:00:52 that I’ve just learned. And by the way, if you’re listening to this with audio only, you
0:00:56 might want to go to Spotify video or YouTube to watch this. It has a lot of visuals. You
0:01:00 can still get a ton of value on audio, but it’s just better, I think, on YouTube.
0:01:04 So give it a watch. Give it a listen. And let me know if you dug it. Talk soon.
0:01:09 I feel like I can rule the world. I know I could be what I want to.
0:01:13 I put my all in it like my days off. On the road, let’s travel.
0:01:20 So I’m thinking about how to introduce you. But basically, I met you in 2016 or 17, something
0:01:25 like that when you spoke at one of my events. And I asked you to speak at one of my events because
0:01:31 you founded and ran a company called Zapier. You know, you guys took off before AI was way
0:01:36 before it was ever a thing. But you basically, if I remember correctly, you only raised at the
0:01:42 time a million dollars, but you got it to nine figures in revenue and then eventually raise
0:01:48 a series A at something like a $5 billion valuation. Is that about those numbers about right?
0:01:55 Close. So the seed round was 1.2. And then the $5 billion number, that wasn’t, that was
0:01:58 all secondary. So none of that stuff went on to the balance sheet of the company.
0:02:01 How much did you guys raise? Was that public?
0:02:02 It wasn’t. We didn’t raise anything.
0:02:04 Well, you took money.
0:02:09 Early investors, early employees, like got some liquidity from it, but nothing came to the
0:02:10 company.
0:02:11 How big are you guys now?
0:02:15 What is the public number? I don’t know the public number. Nine figures is public, though.
0:02:21 You’re at nine figures in revenue. And dude, it’s one of my favorite companies. I never
0:02:25 thought in a million years I’d be fired up about such like a dorky product, like connecting
0:02:31 APIs. But basically my entire company and everyone I know, our entire companies run off of Zapier.
0:02:37 Well, it’s wild. Like the, so the first decade of existence, that dorky company thing, like
0:02:43 100% true. Like no one cares about workflow. Automation is like, like we think it’s cool.
0:02:46 And there’s like definitely people who do think it’s cool, but like the Silicon Valley
0:02:52 wisdom is, you know, raise a bunch of money, throw bodies at the problem, like blitz scale,
0:02:58 go like nuts. And so like people like say they, they cared about automation, but their actions
0:03:03 sort of like betrayed them in a lot of cases, certainly in tech. And so we’re kind of like
0:03:10 a out here doing our thing. Not a lot of people sort of in our space. Now you get into the AI
0:03:16 world and it’s sort of totally inverted where everyone cares about automation. Everyone cares
0:03:23 about AI. Uh, and so the market potential for us has just ballooned enormously. Um, but of course
0:03:29 there’s a lot more players in the space now. Yeah. At the time when I, like when you guys were just
0:03:34 getting going, it was basically you and maybe one other company doing this. Now there’s so many more.
0:03:39 Yeah. And you know, everybody has their angle, their niche, you know, vertical, this vertical,
0:03:44 that, um, you know, more dev centric, less dev centric. Like, yeah. So there’s, you know,
0:03:47 there’s just, everybody’s kind of trying to get a piece of this. What is, you know, going to be,
0:03:50 you know, a trillion dollar opportunity.
0:03:53 In 10 years, how big do you think your company will be in terms of revenue?
0:04:01 10 years. Uh, well, shoot, I think we should be well past, uh, a billion in ARR if we do our jobs,
0:04:01 right?
0:04:05 Dane. And you think you will still not have raised the money?
0:04:10 Uh, I don’t think we will.
0:04:14 So you’re going to, you’re going to be one of the largest, one of the larger ever
0:04:19 companies that only, I mean, I don’t know if you still say bootstrap, but you only raise,
0:04:23 um, you turn, uh, you turn a million dollars into something worth tens of billions of dollars.
0:04:25 I mean, that’s going to be one of the more efficient stories ever.
0:04:30 Yeah. You know, this is how they used to do it though. Um, you know, if you look at,
0:04:35 you know, Microsoft’s and how their, uh, fundraising trajectory went, if you look at Amazon and their
0:04:39 fundraising trajectory, now those companies obviously went public much earlier in their
0:04:42 life cycles, but you know, they didn’t raise huge gobs of money.
0:04:48 Yeah. How much did Google raise? I think they raised like, uh, low tens of millions of dollars.
0:04:52 Yeah. I think it was something like that. Google and Google was a lot like Google had a big round.
0:04:56 I think it was their A or their B that was huge. And people were like, Whoa, this is, this is nuts.
0:05:01 And nowadays, like, you know what the, the, the AI companies, the, the foundation model companies,
0:05:08 they’ll do like a billion dollar series. Hey, this is different. So I want to ask you about all of
0:05:16 that, but someone like I’ve noticed that I had better conversations with people while we are doing
0:05:22 stuff. Um, and that doing stuff is this thing where we basically have asked people like you.
0:05:26 So people who run big companies, how many, how many employees do you have?
0:05:29 700 and change.
0:05:34 Okay. So you have 700 employees and you’re trying to get everyone to use AI at your company. And you
0:05:38 guys are an AI company at this point. You were kind of an AI company a little bit for that was really
0:05:44 popular. The thing that I want to do that I’ve loved doing lately is I want you to share your screen
0:05:48 and show me how you’re using AI and really practical use cases. And you said, that sounds
0:05:52 good. And so while you’re showing the screen, I might ask you questions about like the background
0:05:58 of the company and things like that. So I asked you to make a list. You have a list. One of them
0:05:59 stuck out, right? You want to tell me what that was?
0:06:05 Well, so the first one, this is like a pretty basic, like thing that, uh, I use day to day,
0:06:11 which is like a instant dossier, um, creator. So, uh, you know, you can use it for all sorts
0:06:15 of things. Like it’s handy. Uh, it’s particularly handy when you’re sort of like out and about,
0:06:20 like you’re going to a dinner or you’re at an event and you got a list of names or you’re sitting
0:06:24 down and there’s name tags everywhere. And you’re like, okay, who are these people? Uh, and so
0:06:29 that use case, uh, you know, I usually just like feed Claude, uh, some details on the,
0:06:35 the person. And then, uh, Claude will just return like a quick little dossier that includes,
0:06:40 you know, public details about the person, but also like what’s going on. Like, are they a customer?
0:06:44 Is there any details in our HubSpot account? Like, is there anything that ZoomInfo can tell me,
0:06:48 uh, just to kind of just like get some quick hitters to be like, Hey, is there something I can sort of
0:06:53 talk to this person about? It’s sort of like, you know, if you ever watched Veep, uh, uh, Selena has
0:06:57 like, yeah, like has Gary in her ear, like, you know, just saying like these things. And so you
0:07:02 kind of get like your own little version of this. And so do you do a lot, you do a lot of these
0:07:05 dinners with customers and potential investors, things like that. A reasonable amount of them.
0:07:11 Uh, but the cool thing about this one is you can use it in all sorts of ways. So, you know, if you’re
0:07:15 just sitting in your home office and you’ve got a string of meetings coming up, you can do it for all
0:07:21 the people that you’re about to meet that day. If you’ve got, um, leads coming in on your website
0:07:26 and you want to go enrich those and send those over to your sales reps, you can do the same thing.
0:07:32 So like this process works in, is applicable in all sorts of different scenarios. And mostly
0:07:38 what you’re doing is you’re just sort of like amending how you utilize it based on the situation
0:07:38 you’re at.
0:07:44 Cutting your sales cycle in half sounds pretty impossible, but that’s exactly what Sandler
0:07:51 training did with HubSpot. They use Breeze, HubSpot’s AI tools to tailor every customer interaction
0:07:56 without losing their personal touch. And the results were incredible. Click-through rates
0:07:58 jumped 25%.
0:08:03 Qualified leads quadrupled, and people spent three times longer on their landing pages.
0:08:07 Go to HubSpot.com to see how Breeze can help your business grow.
0:08:11 So I can maybe do a screen share on this.
0:08:12 Yeah.
0:08:19 You know, Claude, I do a, the thing I love about Claude is Claude has, um, tools connected. And
0:08:26 so, uh, the Zapier MCP server is available here and you can see, uh, you know, if you click
0:08:30 into here, like you can connect all these different things, but you know, with Zapier, you have
0:08:35 access to a 8,000 different tools. And so I can just like turn on all sorts of different
0:08:41 tools to, to use within, um, Claude. So, uh, for example, you can see here, we’ve got eight
0:08:47 tools turned on, but basically these tools are a series of HubSpot, um, capabilities, like
0:08:52 finding contact information, finding company information, finding deal information, and
0:08:57 zoom info in points. So like finding again, contact information and finding company information.
0:09:03 And the other thing you can do inside of Claude is you can make projects. So I don’t know if
0:09:07 you’ve used projects before. So I’ve used it with ChatGPT. It’s like, I have a health project.
0:09:10 I have like a therapist project. I have like a business project.
0:09:16 There you go. So you can assign these tools like to, or you can give these projects like
0:09:22 certain system prompts to like help them do a certain task. And so within one of the projects
0:09:29 I have, it basically sort of coaches it on how to do like, uh, contact information for
0:09:34 me where I’m like, Hey, make these, these dossiers for myself. So, um, we can actually use the,
0:09:39 I actually made a quick one for us, which is this, my first million demo. And I have like
0:09:45 a, I got a buddy who’s going to be cool if I use them, uh, their, their name on this stuff.
0:09:51 So tell me more about Lars from social puppy.
0:09:54 And so what was in that file that you uploaded?
0:10:02 So I didn’t upload any files. Basically what this chat has access to is it’s got access to
0:10:09 the Zapier HubSpot account. And then it’s got access to our zoom info account. And then it knows
0:10:16 my like system instructions, which basically say, Hey, a step one is look up the contact
0:10:21 and company inside of HubSpot. Step two is look up information inside of zoom info. Step three is
0:10:27 go find anything on the web to, to go do this. Now you might’ve seen there were some errors popping up
0:10:34 here. This is one of the, the tricky things about, uh, MCP and Claude right now is that it’s still a
0:10:39 little buggy. Like MCP is technically like a, it’s been out for like maybe, I don’t know,
0:10:45 two or three, or their tool stuff has been out for maybe two or three months. And so it mostly works.
0:10:49 What does MPC stand for? And what is MPC?
0:10:57 Yeah. MCP is called model context protocol. So effectively what this is, is a way for agents
0:11:08 to talk to data. So, you know, in the old world, we would have APIs where, you know, you would say,
0:11:13 Hey, I want to talk to the Gmail API or want to talk to the HubSpot API or the Slack API. And these were
0:11:19 ways for like SAS companies to talk back and forth to each other. And so that protocol works really well
0:11:28 for the SAS tools with agents. They don’t exactly know how to utilize like all those API endpoints.
0:11:35 And so MCP is basically this layer that sits in the middle that helps them go find different tools that
0:11:42 they can go use and then, uh, take advantage of them. So unfortunately right here, you can see this
0:11:49 one is, uh, Oh, it, it worked. Um, but the cool thing you can see is it’s iterating over a bunch of different
0:11:54 endpoints. So it’s saying, Hey, this didn’t work. Um, let me try more director approach. Okay. That didn’t work.
0:12:00 So this is Claude trying to figure out how to go do this task. They’re like, Hey, I, you know, I’m not exactly
0:12:06 sure. I’ve got access to a bunch of different tools. Some of these things might work. Some of these things may not
0:12:12 work. And then at the end, it’ll spit out information on it. So it pulls up, you know, LinkedIn,
0:12:18 URL. You can see that Lars is a product manager at Zapier. Uh, he’s got, you know, he’s hanging out in
0:12:22 Vancouver. You can see all the different things that sort of, we know about them. And then social
0:12:29 puppy happens to be his side gig. Uh, it’s this way for people who own dogs to, to do meetups together.
0:12:34 Of course, he’s not paying for HubSpot. So, you know, they took a look at HubSpot and was like,
0:12:37 yeah, there’s no deal associated with this, um, for, for Lars.
0:12:42 Do you see what it says? It said colleagues describe him. Wait, what was that? Colleagues describe
0:12:45 him at, what is this? It has incredible drive and enthusiasm for the goals.
0:12:47 It’s having incredible drive and enthusiasm for the goals. Yep.
0:12:53 Okay. And he’s known for being fun and energetic. That’s cool. Okay.
0:12:57 And I would say that that’s, knowing Lars, I would say that’s accurate. Yeah.
0:13:04 So when you’re going to, uh, let’s say you have a work dinner, let’s say you’re, you’re flying
0:13:09 like, uh, to a different city and you want to meet with like 10 customers and just like host
0:13:11 like a cool hang with them to get to know them. Let’s say they’re big customers.
0:13:17 Would you just upload all six of the names and then just tell it like, make this in note
0:13:19 card format or, I mean, how would you do it?
0:13:24 Well, okay. So, uh, I want to show off something separate. So if I was doing that,
0:13:32 I would actually do this as an internal tool that we built now, this that I was just showing
0:13:37 off, this is kind of for like basic on demand stuff. Yeah. So you can see like it did a good
0:13:43 job, but you know, if I’m trying to show up to like a dinner and I know who’s going to be
0:13:50 there in advance, I want to come in well equipped. Like I don’t want to do this sort of like on the
0:13:56 fly sort of thing. I want to come in having done my research. So we built an internal tool. This is
0:14:00 a company brief generator. Now it uses Zapier interfaces. So this is like a pretty easy thing
0:14:06 to build. And then what it does is you put in a domain name. So you could put in Netflix or Shopify
0:14:12 Slack or whoever, you know, you’re meeting somebody from this company. And then what this does is it
0:14:20 goes and retrieves information from three sources. So one, it pulls from a web search. So it just goes
0:14:26 and finds like, what, what do we know about this company based on what’s on the internet to it does
0:14:33 a glean search. So we use this tool called glean internally, which is like, uh, an internal, like
0:14:38 Google, you can think of it. It’ll go search all your sort of like internal stuff.
0:14:45 Glean is basically, I’ve been trying to use it. It’s you just log in to everything and then it makes,
0:14:50 yeah. Okay. And so it’ll search like Slack and Google drive and you know, all the tools you give
0:14:57 it access to. So we’ll do a glean search. And then the third thing it will do is it will hit our actual
0:15:03 customer database. Well, a replica of it in Databricks and help understand like what
0:15:09 usage is going on inside the company. Then on the other side, it spits out a report.
0:15:14 And so I actually did Hampton before this call. Oh my God. Let me see.
0:15:18 All right. You want to see it? And who’s going to be using this? And at your company,
0:15:24 what roles are using this? Everybody uses this internally. So if you’re customer facing at all,
0:15:30 you will do this. So it doesn’t have like a crazy amount of information on, on Hampton,
0:15:37 but you can see here the company summary. So this is like public pulling a bunch of like public
0:15:45 data on it. Now I did some like research on it and it’s, it’s sort of correct. Like I’m betting
0:15:48 you’re spotting things here that you’re like, Oh, that’s not quite right.
0:15:51 I think the goal of having this, if, if you’re, if your intention is to connect with me at a dinner
0:15:54 or something like that, like you have ammo there.
0:15:59 Exactly. And that’s what I’m getting out of this. I’m not, you know, like, uh, like I looked up before,
0:16:04 like, it doesn’t look like Jordan is the CEO anymore. Right. So that’s a thing where I’d be like,
0:16:07 okay, you know, I probably don’t want to talk about that, but there’s, you know, this, Oh,
0:16:11 it’s a membership community. It’s in New York. Like, you know, here’s some things that I can,
0:16:15 you know, riff with you on, you know, it pulls up a bunch of information. Then you can see,
0:16:21 here’s our glean summary where it’s got, you know, more issues about like what’s going on with the
0:16:26 account and things like that. And so, you know, maybe there was a payment issue with you all at
0:16:32 some point in time. Yeah. And so I can be prepared where I’m like, if you come up to me and you’re
0:16:38 like, wait, like you really screwed me over in 2024. Like, uh, I can be like, yeah, Hey, I’m really
0:16:42 sorry about that. Here’s what we did to fix this. We did this, this, this, and this. And all of a
0:16:47 sudden you’re like, okay, Wade’s really on top of it. Like I feel better about, you know, Zapier as a,
0:16:52 as a vendor, uh, versus like, you know, if I didn’t have this and you were just like, Wade,
0:16:58 I’m still pissed about what happened in December in 2024. And I’m like, um, what happened? I don’t,
0:17:02 I don’t know what happened. And so now you’re like, man, he doesn’t even know what’s going on
0:17:08 in his own company. And so you have a tool like that. And then lastly, it didn’t actually pull much.
0:17:12 So I don’t know how much usage is going on here, but for companies that are really using Zapier,
0:17:18 the visualizations area pulls up a whole bunch of metadata about how their account is being used.
0:17:24 So I can see like, Oh, you know, they use Slack and HubSpot and Google, and they’re using AI or not
0:17:28 using AI in the account. Here are the users that are using it, all that sort of stuff.
0:17:29 Well, who built this?
0:17:34 I think it was like one of our, uh, data analysts built this tool.
0:17:35 On like Replay or something?
0:17:44 Uh, no, this is mostly just a Zap. So it hits, you know, a Zapier interface. So you put in a domain
0:17:51 name, then there’s a Zap that goes out and it hits those three areas. So it hits, uh, does a web search,
0:17:56 probably a step one. It does a glean search, a step two, and then it does an internal search on
0:18:01 our Databricks instance at step three. And then the output is an HTML file.
0:18:04 What would I Google to find the landing page that allows me to make this?
0:18:13 So we have, uh, a bunch of templates that you can check out. So zapier.com, uh, templates slash
0:18:19 use cases. This has like a bunch of places where you can go figure out how to do versions of this
0:18:25 for yourself. So like anything under lead management is going to give you like great examples for ways
0:18:29 to like build a version of this for yourself. And then the second place you can check out is we have
0:18:34 this, this project that’s product called agents, which is in beta, but it has its own templates,
0:18:39 which these are pretty slick as well too. So you can, you know, company research is the number one
0:18:44 thing here. So you can go build a version of this to, to help you with company research.
0:18:50 Have you seen, uh, on the office, they, um, they show like, uh, I guess Michael stole Dwight’s notes
0:18:54 on his customers, but he forgot how to like, he didn’t know how to like read them. And he’s like,
0:19:02 Oh, uh, I see you, uh, are Eric from a PA. Right. And, uh, you have a gay son, right? Uh,
0:19:08 like, well, they’re like weird. It’s like green is color coded. Green is color coded to mean this,
0:19:10 to mean this, which means stop. You’re just like, Oh man.
0:19:17 Hold up. Just a really quick break. I know you’re watching this and you’re thinking this
0:19:22 is a ton of information. Our producer Ari, she just listened to the entire episode and she wrote
0:19:27 out all the important stuff. So if you want to go and implement a lot of these workflows or whatever
0:19:31 you want to call them, she wrote them all out. And so you can use the QR code on the screen,
0:19:37 or there’s a link below in the description. You can click that and you should still watch and listen to
0:19:42 the rest of the episode. But the thing that she made, it’s a PDF and it has everything written
0:19:46 out. So you just click and link off to all the important, great stuff. All right, back to the
0:19:52 episode. Oh, what’s the second one? Cause you have a bunch here. Yeah. So, um, we could go to the agents
0:19:56 manning the inbox one, or there’s another even more basic one. Like how basic do you want to get?
0:20:03 You drive baby. I like I’m basic. I’m pretty, I, I, I’m a, I’m a, I’m a huge noob when it comes to this.
0:20:11 All right. So here’s one that I do all the time. All right. So what’s this use case? I, you know,
0:20:17 if you’re, if you run a company, you probably get like a Google doc, like of a business review or a
0:20:24 strategy memo or something like that shared with you all the time. And you’re trying to figure out like
0:20:30 what’s going on in this thing. And you know, the use case that I like to do is I like to just talk
0:20:35 to like, just go back and forth with chat GPT to try and better understand this. So I didn’t want
0:20:41 to share our own internal stuff. So I actually pulled the, uh, some of you might’ve seen this,
0:20:46 like Mr. Beast put out this, like, uh, leaked, had this leaked memo of like how they do their
0:20:51 production stuff. So I figured we could just try it for the viewer. Um, about a year ago, Mr. Beast,
0:20:57 the famous YouTuber, he has a production company. He has like a 50 or a hundred page document that
0:21:01 sort of breaks down how he wants his team to behave in different situations. So like,
0:21:05 yeah, for example, one famous thing is he was like, I want you to hire a consultant.
0:21:08 Consultants are amazing. They’ll like save you time, whatever. I want you to post this many
0:21:12 videos. So he like had the outline for the company processes and culture.
0:21:17 So here’s what I like to do. I like to give it to chat GPT, basically tell it what it is.
0:21:25 I like to say it’s a rough draft and then I want it to, uh, succinctly describe back to
0:21:32 me what is in the doc. So I mostly just don’t want it to, I don’t want it to like put its
0:21:36 opinion on it. So, you know, you’ll do that. And then, you know, it kind of describes back
0:21:43 to you like, okay, here’s what it is. You know, the core philosophy, what makes a YouTube video
0:21:49 go viral. You know, it kind of just goes through the doc a little bit, but it’s kind of, it’s kind
0:21:54 of generic. So I’m like, Hmm, like, I don’t, I don’t know that I love this. So then I might just
0:22:03 say like, Hey, be a hundred X, you know, more specific. And I stole that from this woman who’s
0:22:08 the runs product at whoop Hillary. Uh, I saw a YouTube video where she did this and I found that
0:22:14 to be like, okay, now you start to get like, all right, a lot of really good nitty gritty details
0:22:21 inside of this where you can see what’s going on. And all the while, you know, for Zapier internal
0:22:27 stuff, I, I’m able to now try and get a better sense of like, what is this team trying to tell me?
0:22:33 So when would you use this? So you’re using the Mr. Beast one as an example, but give me a realistic,
0:22:39 uh, Zapier, like, so you’re within your company, we’re trying to decide, you know, uh, maybe I’ll
0:22:46 give you an example. Like we’re trying to decide, should we launch a voice agent or not? Right.
0:22:51 Okay. Hypothetical thing. And some product team will say, Hey, I want to go make a case for it.
0:22:55 And they’ll write up a strategy memo to say, here’s why we should or shouldn’t do this stuff.
0:23:03 Now, if they’re like really good at making their case, they’ll have, you know, qualitative data to
0:23:08 support their evidence. They’ll have quantitative data to support their evidence. They’ll have
0:23:13 multiple options for like how to go tackle this. And, you know, we could go route a, we could go route
0:23:18 B, we could do, you know, a hacky version. Here’s what like the all in version looks like. And then
0:23:22 they’ll have their like strong recommendation for how to go do this stuff. Yeah.
0:23:30 That’s like what I great like strategy memo looks like to me, but not everyone like sort of comes in
0:23:35 and does that. And they don’t always tee up the information in the way that like I am best at
0:23:42 interpreting it. And so I will usually start by reading the raw document myself. So that way I like,
0:23:49 okay, I, I understand what the team is trying to say in their own words. Then I’ll upload it like this
0:23:54 to chat GPT and start going, okay, what does chat GPT think about this stuff to start to augment it and
0:24:00 get like a thought partner on what am I going to sort of try and what types of questions should I ask
0:24:05 the team? You know, what types of things am I trying to get out at the end of the day?
0:24:06 Got it. Okay.
0:24:12 So that’s how I end up using this. But the, the interesting question is like, you kind of ask it
0:24:17 a couple of questions like this. And so chat GPT starts to get a warmup and then
0:24:24 you ask it like the real questions, the 100 times more specific one. That’s a really good hack.
0:24:30 Another good hack that I use is I will tell chat GPT the problem I’m trying to solve and what I think
0:24:34 the prompt should be. And then I just say now write the prompt for me.
0:24:38 Totally. Yeah. Meta prompting. Right. You’re like, I need a prompt to do X.
0:24:45 Yeah. Yeah. And so this is like the, the, the way that I see like some of the, the people that I’m
0:24:50 like, Holy cow, you’re like really using chat GPT or like using these tools exceptionally well
0:24:57 is they don’t just like ask their question right away. They usually ask like these warmup questions
0:25:02 where they’re trying to like gather a bunch of contacts, get a bunch of specific information
0:25:10 going. And then once they sort of have enough of like things in memory for chat GPT, then they start
0:25:14 asking like the real things they want to know, which is like, where are my blind spots?
0:25:20 But the blind spot question is, uh, so let’s say that you’re using the voice AI. So you’re saying
0:25:24 where are Wade’s blind spots and deciding if this is a good idea? Is that what you’re saying?
0:25:30 Well, basically, you know, because I’m presenting it as my own idea, uh, it, and then when I ask,
0:25:33 where is the blind spots? Sorry, I’m scrolling really fast. I’m probably making people go nuts.
0:25:37 I understand what you’re saying. So where am I blind? You’re really saying the author of
0:25:39 Where’s the team’s, yeah. Where’s the team’s blind spots? I got it. Okay.
0:25:46 Yeah. And you know, as you read through this now, so like if I was, you know, uh, Mr. Beast
0:25:51 and I was going through the blind spots, you would say, Oh, okay. Interesting.
0:25:54 Role specific guidance. Yeah. There are different roles inside the team.
0:25:59 So should I add like, you know, training that’s specific to different roles or should
0:26:05 I not? You know, there’s no feedback system for creative feedback. Do I care about that
0:26:10 or not? And now when I asked this blind spot question, I’ll find that like, there’s usually
0:26:14 one or two things that chat GPT will catch where I’ll go, Oh yeah, that’s a good one.
0:26:19 And then there’ll be a bunch of things. We’ll be like, nah, I I’m good. Like that, that’s
0:26:23 not an actual blind spot. Like that’s not real. Like we’ll, we’ll be fine with that. And so
0:26:30 it’s like, I find this just like simple back and forth to be like good at just catching stuff.
0:26:35 Like it just catches like simple errors that are obvious. Um, it doesn’t do the work for
0:26:39 me. It doesn’t do the thinking for me, but it just, it augments it. It’s like just having
0:26:44 a thought partner there that can help you navigate any of the sort of tricky decisions
0:26:48 that you’re there. You’re talking to. What are some other good warmup questions?
0:26:54 You had, you had a good one, which was the meta prompt. The second thing that you can do is
0:27:03 just blab a bunch of context to it. So a lot of folks use things like a super whisper or whisper
0:27:09 flow. You talk to it. You talk to it. Yeah. I love that. So yeah, my co-founder goes
0:27:14 on like long walks with his dog and he will literally just talk back and forth,
0:27:21 back and forth, back and forth. And then he’ll take the transcript of that and then input that
0:27:28 and say, Hey, based on all of this, now I want you to go write a strategy memo on XYZ thing
0:27:31 versus saying, Hey, just write the strategy memo on this.
0:27:35 Can you actually walk, walk me through that? You know, I, I take, I’m like a history buff and
0:27:40 I like go for walks with AI with chat GPT and like, we’re just conversing about world
0:27:47 war two. Uh, and like, it’s so funny that like I, it’s great. Like I’m like, wait, so why
0:27:51 do they do this? And how did these people react to that? Like, that’s like, I have my, I have
0:27:56 like a historian who I have conversations with obviously using it this way is significantly
0:28:02 more productive. Can you walk me through, uh, his conversation with that? Like, is it on chat
0:28:06 chat GPT? And then does he say like at the end now transcribe all of this?
0:28:12 He, I see, I’m trying to think how he does it. So you, if you talk to chat GPT, it does give you the
0:28:17 transcript. And so I suspect he’ll just take the transcript out of it. I, maybe he, uh, he might
0:28:22 have it. He might actually just tell it like, Hey, give me the whole transcript of this conversation
0:28:26 in JSON format or something like that, because he’s an engineer and he likes stuff in JSON format and
0:28:33 he’ll be able to do something more sophisticated with it and then upload it back into the next
0:28:34 prompt.
0:28:41 Got it. Okay. This is awesome. So good ways to, um, warm up questions. So, uh, I like the meta
0:28:48 prompt. You like, um, be a hundred X more specific. Another one that I like to do that. I think people
0:28:48 don’t do a lot.
0:28:50 Describe it back to me.
0:28:55 Oh, that’s a good one. So you’ll say, describe it back to me. I like to say, before we get
0:29:01 into it, if there’s any questions that you think you need answered, so you have full context,
0:29:03 please ask them now.
0:29:08 Yep. I do that as well. That’s a hundred percent. A great one. Like I, I have a really long running
0:29:17 chat GPT project around like my personal health and wellness. And so there’s a whole bunch of stuff.
0:29:25 I don’t know in health and wellness space. And so I’ll just take exports of like, I have a workout
0:29:30 app that I have and I’ll just like upload the outputs of that. I have like a sleep app and I’ll
0:29:38 upload that. And I’m like, here’s a bunch of stuff data on me. You know, I want to know how to improve
0:29:44 my overall health and wellness, but tell me if I can give you more information that gives you better,
0:29:45 better suggestions for me.
0:29:50 Dude, this is awesome. So you basically like this whole episode, it’s turning into like a thing
0:29:56 where it’s like, how can you save me 20 or 30 hours per week? You’ve done a good job so far of saving
0:30:00 time. What are a few other ways that you’re using this stuff?
0:30:07 So Zapier Agents is another one that’s interesting to go give a try to. So most people, when they talk
0:30:14 about agents, they are usually talking about like chat agents, where you’re going back and forth with
0:30:20 chat GPT or you’re going back and forth with Claude. What’s different about Zapier Agents is these are
0:30:26 fully automated agents. Like these are things where you can say, hey, I want you to just go do this job
0:30:35 for me always. So for example, let’s make an agent that replies to your email. And actually, I don’t want it to
0:30:41 reply to my email because I’m a little scared that it might reply in a way that is not up to my
0:30:48 standards. So what I actually want you to do is make drafts for my emails. So I’m just going to do like
0:30:53 a really basic thing here, which is let me start from scratch here. So you can just do like new agent
0:30:57 agent here. And we’re just going to do a custom agent. We’re just going to like do like just kind
0:31:06 of blab into this box here. So what is this? This is Zapier. This is Zapier Agents. And so it has access
0:31:14 to all of Zapier’s tools. And it has access to Zapier’s trigger infrastructure, meaning these agents wake up
0:31:19 based on all the events that might happen in your world. So you get a new email, you get a new lead,
0:31:24 you get a new customer, you have a new project come in, like all the things that you can think about
0:31:30 that happen in all the SaaS tools you use in your software, you can use that to wake up your agent and have
0:31:36 the agent go do something. So in this case, we’re going to use Gmail anytime you get a new email to wake
0:31:43 this agent up, because then we want that agent to go reply to the email. So we’re going to just do some
0:31:47 a really basic prompt. This is not a prompt you would actually use, but I want to show off how this
0:31:58 works. So you would say, hey, anytime I get a new email, write a draft reply for me. So this is like
0:32:07 super basic. And we’re going to see what this thing goes and does. So you can see, you know,
0:32:13 building these agents takes a little bit of effort to do it. But you get this co pilot that starts to
0:32:19 like suggest, like, okay, we’re getting ready to go build this agent with you. I’m going to I’m going
0:32:25 to help you make this workflow. But I need some more details. So that question you were saying, Sam,
0:32:29 which is like, hey, ask me more quick questions to help me make this better. Like it’s baked into
0:32:34 the experience here. Because we know that like, when you say, hey, anytime you get a new email,
0:32:38 write a draft reply for me, if that’s what you’re going with, like, you’re probably not going to
0:32:43 actually have a great agent. Like you need to provide these agents with tons of details
0:32:49 to actually make it good. So, you know, it’s asking me like, what email service do you use? I’m like,
0:33:04 oh, I use Gmail for my email. Two, I want you to save it as a draft reply inside Gmail. And then reply
0:33:12 content, what should the draft reply include? You know, it should, you know, it’s like, hmm, I don’t
0:33:16 know, like, what should it include? Like, I get a lot of different types of emails. That’s interesting.
0:33:20 It’s like email filtering. Should this apply to all new emails, only emails from specific? So it
0:33:25 starts to ask you questions that start to make you think. Yeah. So maybe like, uh, only internal,
0:33:31 only my coworkers or something. Yeah. Well, so I was thinking, actually, I don’t want it to draft a
0:33:38 reply to every email. What I really want it to do is, uh, reply to everyone that is asking about a job
0:33:44 at Zapier. Uh, cause I get a lot of people that are emailing me and saying like, I’d love to work
0:33:50 at Zapier. Uh, this would be an amazing thing. Uh, it’s basically just like a, like a super smart
0:33:55 vague, like, um, uh, responder. Yeah. Like when I go on vacation. Yeah. Yeah. You used to have like
0:34:00 these autoresponders, but they were like, all those autoresponders were like pretty dumb, dude. And this is
0:34:05 great because like we get, you know, for MFM, we get dozens a day of people wanting to come on the
0:34:13 podcast and totally ruins my inbox. Yeah. All right. Okay. So now here we’re going, right? So
0:34:19 it’s starting to build the actual prompts for the agents. You know, when a new email is received in
0:34:23 Gmail, analyze the content. It’s Herman. If the sender is asking about a job or a career opportunity,
0:34:28 look for keywords like job, career, position, hiring, application, blah, blah, blah. So like we’re making
0:34:34 it, it’s actually making a really good prompt for ourselves. So now I start to go, ah, this is
0:34:39 interesting. So I can come in and edit this directly. So thank them for their interest in
0:34:44 Zapier. Yeah. I’d like that. Uh, direct them to the career page. Yep. That sounds great. Um,
0:34:49 mentioned that they can find current opera openings and apply directly through the career page. Yep.
0:34:55 I like that. Keep the tone welcoming and professional. Um, I like that. Okay. But you know,
0:35:03 what I really want it to do is, um, rub them the wrong way with a knob, like, uh, you know,
0:35:15 let’s see, I want them to be polite, but really brief. Cause I find that these agents like get really
0:35:19 wordy and that’s not how I write an email. Like I do really short emails where I’m like, Hey, thanks
0:35:24 for, thanks for checking us out. Did you check out the jobs page? You know, maybe I actually should
0:35:30 ask them maybe and say, thank them for their interest in Zapier and ask if they’ve already
0:35:37 applied for a job, something like that. Yeah. Um, if I was being really fancy, what I could do
0:35:43 is say, I want you to actually go look inside our applicant tracking system and go.
0:35:50 That’s crazy. If they’ve already replied. Um, so you could do something like that. Uh, say this is
0:35:56 a draft reply in Gmail. So you can, you know, review and send it manually. If the email is not job
0:36:00 related, take no action. Right. Uh, that’s really important. Like I do not, you know, I do not want
0:36:08 you writing draft emails for, I don’t know, a customer. So there you go. And I can be like, Hmm. All
0:36:14 right. So this feels pretty good here. I like this. So, you know, go test the agent and,
0:36:20 and turn it on. Uh, and so it’ll go in now and look at my own inbox and see, you know, Hey, do I have
0:36:26 anybody that is asking for a job in my inbox right now? And I actually cleaned out my inbox before
0:36:31 this. So it’s probably not going to find anything, which is why there was a problem testing this agent
0:36:36 here. How hard has it been to encourage, I guess, I mean, your company is very technical, but how hard
0:36:43 has it been to encourage your staff to really embrace this stuff? So for us, I think we have it better than
0:36:48 a marginal company because we’re an automation company. Like our employees nerd out over this
0:36:55 stuff. We have a company value that’s don’t be a robot, build the robot. So we’re literally trying
0:37:00 to teach people that automation is a core primitive. But even for us, there still is a learning curve.
0:37:06 Like, yeah, we employ a bunch of engineers, but you know, we have accountants on staff and HR folks on
0:37:14 staff and, you know, folks that, you know, probably haven’t by default been exposed to this stuff as
0:37:22 much. And so we really do make it our mission to help people help make this technology a lot more
0:37:27 accessible. So like you could see when we were building this agent, like we’re just assuming that
0:37:32 somebody is going to come in and do a bad prompt. Like we just know that because most people don’t come
0:37:37 in breaking the problem down step by step by step by step like this.
0:37:43 Do you have like a full, like you, you, you know, at 700 people, you almost need like a five person
0:37:47 team. And it’s like, all I’m going to, or, or do you just send them a bunch of YouTube channels? I
0:37:51 don’t know. Like, how do you train? Because the shit changes every three weeks.
0:38:02 We had a wake up call when ChatGPT launched because we were like, holy cow, our roadmap and how we are
0:38:09 operating the company, it needs to shift. Like it is, there’s so much more opportunity and candidly
0:38:15 threats to our business if we are not paying attention to this stuff. And so we did a handful of
0:38:24 things that has gotten our usage of AI from effectively zero to now just shy of a hundred
0:38:29 percent. The last time we, we did a stats on it, we were right around 90% of our employees using this
0:38:37 stuff daily. And so the three things were first, we called a code red and we did a hackathon where I
0:38:42 stopped the company for an entire week. And I said, I don’t care what job you’re in. You know,
0:38:48 if you’re in HR accounting or support or sales or engineering, we’re all going to press pause for
0:38:52 the whole week and we’re going to go build stuff with AI. You know, if you’re an engineer, maybe you’re
0:38:58 going to build a feature for our products. If you’re in recruiting, maybe you’re going to go see how you
0:39:06 could use ChatGPT to write job descriptions or, you know, how you could do basic research. You know,
0:39:15 this is 2023, I think. Right. So it’s pretty basic stuff back then. So that was really important for
0:39:20 people to just start to get familiar with the tooling. Then from there, at the end of the hackathon,
0:39:26 we did show and tell. So we said, Hey, everybody’s got to show off what they built. That does two
0:39:30 things. One, it promotes accountability. So people are actually going to take this stuff seriously
0:39:35 because they got to show it off to their teammates. Two, it also promotes knowledge sharing because
0:39:40 now you get to see how other people do this stuff. And I have found that that’s been the most impactful
0:39:45 for my own learning. It’s like, Oh, tell me what prompt you did there. Like, show me how you did that.
0:39:51 Because there’s just like a bunch of people out there that are like constantly experimenting and
0:39:56 nerding out on this stuff in ways that I just simply don’t have time on my hands to look like
0:40:02 try all this stuff. So I benefit a lot from just like watching how other people are using this stuff.
0:40:11 Then the second thing we did is we said, we’re going to go do these hackathons every so often. So about
0:40:16 every three to six months, we do it again. Now we don’t do it for a full week. Usually we just do a
0:40:22 day or two. But that gets people to keep coming back to the watering well to see what’s changed,
0:40:30 what’s new. And that helps again, people get like refresh their mental model of what these models are
0:40:33 capable of and what the tools are capable of. It’s so awesome, man. This is so awesome.
0:40:38 All right. So when my employees join Hampton, we have them do a whole bunch of onboarding stuff.
0:40:42 But the most important thing that they do is they go through this thing I made called Copy That.
0:40:45 Copy That is a thing that I made that teaches people how to write better. And the reason this
0:40:51 is important is because at work or even just in life, we communicate mostly via text right now,
0:40:57 whether we’re emailing, slacking, blogging, texting, whatever. Most of the ways that we’re
0:41:01 communicating is by the written word. And so I made this thing called Copy That that’s guaranteed
0:41:05 to make you write better. You can check it out, copythat.com.
0:41:09 I post every single person who leaves a review, whether it’s good or bad. I post it on the website
0:41:13 and you’re going to see a trend, which is that this is a very, very, very simple exercise,
0:41:16 something that’s so simple that they laugh at. They think, how is this going to actually impact
0:41:21 us and make us write better? But I promise you, it does. You got to try it at copythat.com.
0:41:24 I guarantee it’s going to change the way you write. Again, copythat.com.
0:41:27 Do you want to do one more or do you have one more or no?
0:41:33 I don’t, I can’t demo this one because it’s a lot more sophisticated to demo, but I want to show like
0:41:39 what great can actually look like. I think mostly what I’ve showed today is candidly like pretty
0:41:47 basic starter stuff. But this is where if you have a couple people embedded in all your functions inside
0:41:53 of a company, you can really start to use AI at a pretty impressive rate. So for example,
0:41:57 a couple of weeks back, like the internet went viral because there was this guy who
0:42:03 had been hired by a bunch of different YC companies. He was, he had like five or six jobs at once.
0:42:08 Tell that story. So basically, I think, I forget the guy’s name, but I started Mixpanel,
0:42:13 called him out, but he was like, just so you know, I just caught this one employee working for us.
0:42:18 And it turns out he’s had another job. And then like dozens of other companies were like,
0:42:25 dude, he worked for me too. Turns out he got called out. Then he did a podcast where he was like,
0:42:29 yeah, I’ve been working three to four to five jobs at any given point. I’ve been doing this for two to
0:42:36 three years. And everyone said the same thing, which was he passed the, uh, he was amazing. Like he,
0:42:42 I thought he was this amazing employee and he nailed the job interview and everyone was like,
0:42:45 how that, that, that was the most impressive part, which is how on earth did this guy
0:42:50 crush the interviews so well that he got these positions. So that’s the story.
0:42:57 Yeah. Yeah. And it turns out there’s a whole subreddit about this. There’s a subreddit called
0:43:03 like overemployed. It’s crazy. It’s crazy. It’s, it’s like, I mean, hats off to him. Like,
0:43:07 I think if these people worked that hard at like starting a business or like just even in their
0:43:12 core job, I think they would be incredibly successful. These folks obviously have some
0:43:18 unique skills. They just employ them in like, you know, nefarious ways. Yeah. Nefarious ways.
0:43:23 I’ve always thought like, I think there was, um, a book, uh, freaking Amits wrote a book where they
0:43:27 like look at drug dealers and like how much work they do. And they like, it turns out they only make
0:43:32 like $14 an hour for how much work. And like the conclusion was like, you guys are, you should do
0:43:35 normal jobs. You would make more money and you’re clearly very hardworking.
0:43:43 Totally. So what is this? This is a, this is a template that I think would have caught this guy.
0:43:50 It’s a candidate risk detector. So effectively what you do here is it hooks into things like Ashby,
0:44:00 Slack, Verifone, an IP API, and you run through applicants and then it tries to score their risk
0:44:09 on, is this applicant potentially fraudulent? And so effectively, you know, you get an applicant that
0:44:16 comes in, it takes the details of what came in from the applicant, and then it runs checks on the IP
0:44:22 address, phone numbers, and a whole bunch of other metadata. And then it compares them to other
0:44:28 applicants to try and spot mismatches or suspicious patterns or things like that.
0:44:34 10 years ago, this would have been like machine learning engineers that are like building this type
0:44:39 of stuff. They’d be like, you know, you, you really would have like, it would have really been
0:44:47 tough to go set this up. But this was built by Casey, who is on our talent team. She just,
0:44:50 just part of the talent team. Like that’s what she’s good at.
0:44:54 Is Casey like Frank Agnelli Jr. Where you remember the Catch Me If You Can movie where they like,
0:44:58 he gets, he’s like a Czech fraudster. And after 20 years, he gets caught. And the FBI is like,
0:45:03 hey, do you want a job catching other fraudster? So did Casey have like 10 jobs and you caught her?
0:45:06 No, she didn’t. But that would make a better story.
0:45:07 Yeah. If it, if we did.
0:45:09 Casey should have done more illegal stuff.
0:45:14 Yeah. And so you can see pretty much here, like how the, the, the process,
0:45:15 how the template actually works.
0:45:19 Do you, does the way your business work? So if you scroll up, it said,
0:45:24 can’t a kid, this is like an agent that someone made or do you guys call agent or templates?
0:45:28 Yeah, this is a, this is an eight, this is actually, I mean, you could call it an agent.
0:45:33 This is actually just a straight up workflow in this case, but it has AI as part of it.
0:45:38 So are you guys going to become a platform where people can sell their agents that they make?
0:45:41 I like that idea.
0:45:44 So yeah, understood.
0:45:49 Yeah. I mean, that, that’s a no brainer, you know, is a, that’s a no brainer.
0:45:50 So that would be awesome.
0:45:58 Yeah. And it would definitely like blow you guys up. I mean, very similarly to Microsoft and Shopify,
0:46:01 like the platform model, like is, is an amazing model.
0:46:02 Yeah.
0:46:06 And these are the types of templates you could sell, right? The thing, like the, you know,
0:46:10 thing I was showing before about the like email reply thing. It that’s, that’s super simple,
0:46:17 but this, this takes some effort. Like Casey, you know, she probably went, I don’t know. I’d have to
0:46:21 ask her, but I would guess this probably took her a couple days of just like trying to think through,
0:46:27 break it down into all the different steps, you know, find all the tools she needed to, to, to use.
0:46:35 But at the other end, you know, it saves our HR team, like a huge amount of headaches because now
0:46:40 we’re like not having to go spend time on these candidates that are, you know, maybe trying to
0:46:41 pull one over on us.
0:46:45 What, what do you call your industry automation, like platform automations?
0:46:51 So we think about this as like AI orchestration at the end of the day. It’s like AI orchestration,
0:46:57 workflow automation, like AI automation. This is the kind of stuff that like,
0:47:03 like the most sophisticated teams are, are doing right now is they’re building things like
0:47:08 these candidate risk detector for hiring teams. And they’re using that to like solve problems that
0:47:13 candidly they couldn’t solve before or like do work that they just couldn’t do before.
0:47:17 Who, who’s the biggest in your space? Are you the, are you guys the big guys?
0:47:24 There are, I mean, I, yeah, we are like, it’s us. It’s, um, you know, Microsoft’s got a product
0:47:27 that does stuff like this, you know, Workato that’s like,
0:47:32 you know, much, uh, has started like much, much, much more enterprise oriented though.
0:47:37 These days Zapier is like very enterprise oriented as well too. And then, uh, you know,
0:47:41 there’s a handful of like small startups that are doing stuff like this as well too.
0:47:46 Dude, this is awesome. I, um, do you remember what, so I used to have this trick and you’re
0:47:51 the first, uh, person who was a victim of this trick that I will admit that this was my trick.
0:47:58 So I had, so for years from the ages of like 24 to like 28, I would host this event called
0:48:04 hustle con where I would get people like you to come give a talk. And I would lie to everyone.
0:48:09 The speakers, I would be like, you know, you’re talking at three o’clock. You have to be there
0:48:16 at 10 AM for the, uh, mic check and all that stuff. And at conferences, there aren’t mic checks. The
0:48:21 mics, the mics work. It’s the same mic. It works fine. The reality was, is I wanted you to come
0:48:26 backstage to just hang out. I wanted to like, not necessarily hang out with me, but I wanted to see
0:48:30 Wade talk. I think it was like, I was in the room, you were in the room and then like the founder of
0:48:35 the athletic and I would just sit and listen to you talk. And, and just like, it was, it was very
0:48:43 inspiring. Um, that was, I think 16 or 17. I forget exactly when, and you were there. I didn’t even
0:48:48 have to lie to you. You were there from like eight to seven, two days in a row, just sitting on this
0:48:53 couch with me. And I don’t know if you were doing this, this, like on purpose, but I’m pretty sure
0:48:57 you were doing the same thing I was doing. And it was awesome because that, that I, that was the
0:49:01 biggest impact of probably on my business that I’ve ever had because, or my life, because I remember
0:49:07 being with you and the founder of WeWork, Miguel and Casey Neistat and all these ballers. And I was
0:49:12 like, Wade might be a little different, but most, all these guys, they’re not that much smarter
0:49:16 than me, but they’re like, I was like, they’re not a thousand times smarter than me, but there
0:49:21 are a thousand times more successful than me. Why, why does that gap exist? Uh, it’s because
0:49:26 they are fearful, but they do it anyway, or, you know, things like that. And it was very inspirational.
0:49:30 Well, I think that’s like, there’s this meme that goes around the internet of like, you can
0:49:36 just do things. Yeah. And I think that that is like, if I can sort of like go back to my former
0:49:41 self or just talk to the graduating class or whatever, it’s like, just do stuff. Like it’s
0:49:46 like, you know, I think most people are so scared that they’re going to have egg on their face. But
0:49:52 usually what happens is that when you fail, nobody even noticed, nobody even cares. Like that’s what
0:49:59 usually happens. And so if you mess up, who cares? Nobody saw it. Like try again. Um, and so there’s
0:50:05 just so much advantage to be had around just like trying stuff. Well, um, you did just do stuff.
0:50:11 You, you did the damn thing. So I appreciate you coming here and doing this. Um, uh, thank you for
0:50:15 being so gracious and making this happen. You bet. When I come back, we’ll actually have to do the MFM
0:50:21 thing and like jam on business ideas and stuff like that. Right after we get done hitting, uh, uh,
0:50:24 you know, off for this, we’ll, we’ll get you scheduled. We’ll do the second one, right?
0:50:29 I’m down. No, I’m, uh, we’re in. Um, all right. God bless. Thank you. That’s it. That’s the pod.
0:50:36 I feel like I can rule the world. I know I could be what I want to put my all in it. Like no day’s
0:50:43 all on the road. Let’s travel. Never looking back. All right, my friends, I have a new podcast for you
0:50:50 guys to check out. It’s called content is profit and it’s hosted by Luis and Fonzie Cameo. After years
0:50:54 of building content teams and frameworks for companies like Red Bull and Orange Theory Fitness,
0:51:00 Luis and Fonzie are on a mission to bridge the gap between content and revenue. In each episode,
0:51:03 you’re going to hear from top entrepreneurs and creators, and you’re going to hear them share
0:51:09 their secrets and strategies to turn their content into profit. So you can check out content is profit
0:51:11 wherever you get your podcasts.

0:00:05 Here’s a business-in-a-box side hustle that’s got the potential, the possibility to turn
0:00:07 into a full-time income stream.
0:00:13 Let’s call it reselling return items, but not like the treasure hunt of liquidation pallets
0:00:14 or something like that.
0:00:15 This is a little more systematic.
0:00:20 It’s got lower transaction volume and hopefully a higher profit per item, and it’s got the
0:00:24 ability to get inventory for free, which is pretty cool.
0:00:27 The catch is that these items are big.
0:00:30 They’re bulky, they’re furniture, they’re mattresses, they’re exercise equipment, so you’ve got
0:00:31 to have a way to transport them.
0:00:32 You’ve got to have a way to store them.
0:00:36 Today’s guests have been doing this for the last eight years, the last three of which has
0:00:41 been a full-time income, flipping anywhere between 40 and 60 items per month.
0:00:43 Matt and Hannah, welcome to the Side Hustle Show.
0:00:45 Thanks for having us.
0:00:51 This is all facilitated through a side hustle app called ShareTown, which we’ve covered before,
0:00:56 but my hope is this will be the deep dive because you guys have been in it since almost the
0:00:57 beginning.
0:01:01 Hannah, you mentioned you found out your brother had a friend who was doing it, but Matt,
0:01:05 what’s your reaction when you hear about this random side hustle?
0:01:09 You can make money reselling semi-used mattresses, mattress returns.
0:01:11 What’s your gut reaction here?
0:01:13 Just one of those things where I was like, is this a joke?
0:01:18 It just sounded kind of out there, and it sounded too good to be true.
0:01:23 And I think when I got started, before we got started, it also was like, well, how is this
0:01:24 logistically possible?
0:01:28 Because you think about a mattress, and it’s pretty big, and it’s like, how am I going to
0:01:29 be able to do this?
0:01:32 So I think I went through all of the ways it wouldn’t work.
0:01:35 And then it was like, well, let’s just give it a shot.
0:01:37 That was the decision process.
0:01:38 But I had a full-time job.
0:01:40 It was busy already.
0:01:42 We had little kids, and I had a career.
0:01:45 And so it was like, but at the same time, we also had debt.
0:01:48 And so it was like, let’s figure out ways to pay that off.
0:01:51 I was game to try it out.
0:01:51 To be creative.
0:01:54 Because we needed it, and then it just worked out.
0:01:55 It’s funny.
0:02:01 I think that I remember we were going to Southern California within a month or two.
0:02:03 And I remember being like, what if we just try it?
0:02:05 We could just pay for our Disneyland tickets.
0:02:09 If we do this, we could try to make it some incentive.
0:02:12 Anyway, but I do think I remember you laughing at me just all in place.
0:02:13 It’s funny.
0:02:17 It’s definitely one of those things where when it first came across my desk, I had the same
0:02:17 thing.
0:02:19 I was like, is this for real?
0:02:20 How does this work?
0:02:22 Because there’s a lot of moving parts to it.
0:02:26 And I’ll give you my high-level understanding, and you can fill in the gaps.
0:02:31 So these direct-to-consumer mattress brands, and furniture brands, and exercise equipment
0:02:32 brands to a certain extent.
0:02:35 ShareTown, as a company, has expanded into different product categories.
0:02:37 But my understanding started with mattresses.
0:02:41 And so all these companies have their 100-night, better sleep or it’s free guarantee.
0:02:46 And so a customer buys the mattress, and we’ve actually returned a mattress through a ShareTown
0:02:49 rep where you get it, you try it out.
0:02:50 You’re like, it’s not for me.
0:02:54 And you feel kind of bad, but it’s like, hey, that was the risk reversal that led us
0:02:57 to pull the trigger on the purchase in the first place.
0:03:00 You say, hey, Mattress Company, I didn’t love it.
0:03:02 Sorry, we need to return this.
0:03:05 The Mattress Company is like, we can’t really take it back.
0:03:08 We can’t really resell it as a new mattress because it’s not new anymore.
0:03:12 And so this is where ShareTown comes in to facilitate these returns and either get those
0:03:14 donated or get those resold.
0:03:16 Because the company probably can’t resell them.
0:03:21 But as an individual contractor, as an individual reseller, like, hey, I’ve got this like new
0:03:22 or almost new mattress.
0:03:24 It’s still in really good shape.
0:03:27 And we can put that out into the marketplace.
0:03:28 Pretty spot on.
0:03:34 The logistics for a mattress company just is not easy for them to finish that end.
0:03:39 And they started out eight years ago before this was like really a common, well-known thing.
0:03:43 I think people are kind of more familiar with it now, but they suggested donating them.
0:03:46 So if you don’t like it, donate it, give us a receipt.
0:03:50 And I think that they just found that wasn’t, customers were frustrated because they couldn’t
0:03:51 actually get them picked up.
0:03:54 You know, there weren’t very many companies or charities that could come pick them up.
0:03:59 Anyway, so now people like us come pick them up, help make sure that they’re like new.
0:04:02 And then we help to resell them so that they stay out of landfills, so that the original
0:04:03 customer gets their money back.
0:04:09 And so that lots of people in our communities are getting killer deals on a basically new mattress.
0:04:11 Yeah, so that’s the revenue flow.
0:04:16 So you pick it up, you go list it for resale on Facebook Marketplace for a decent discount
0:04:18 off of the retail price.
0:04:21 And the customer gets their money back.
0:04:25 And you take the proceeds from that sale and you give some back to ShareTown.
0:04:28 Do they share some of it back with the original company?
0:04:30 And then they take their cut and then you take a cut.
0:04:33 It’s like the revenue gets sliced up in a bunch of different ways.
0:04:35 Yeah, we don’t see their end of it.
0:04:37 So we’re not sure what the split is there.
0:04:39 But we get a cut and then ShareTown gets a cut.
0:04:44 And then we assume that they distribute some back there or something happens on that end.
0:04:46 And they have different contracts with each company.
0:04:49 Yeah, it probably looks different for each partner of theirs.
0:04:52 Is there a target profit per item that you guys aim for?
0:04:56 Well, we found over the years that about $200 is kind of a good average.
0:04:59 Some certainly can be more, which is awesome.
0:05:02 The majority, I would say, aren’t.
0:05:06 But there are some here and there that are kind of the unicorn items that you’re just like,
0:05:07 oh, that was awesome.
0:05:10 You know, and then there are plenty that are less.
0:05:13 But average is $2 to $2.50-ish.
0:05:14 Yeah, I’d say about $2.50.
0:05:15 And still around that ballpark?
0:05:17 Or has there been some downward pressure on that?
0:05:19 I do think that it’s decreased a little bit.
0:05:24 We used to kind of have a little bit of a monopoly on the markets that we’ve lived in in the Bay Area,
0:05:25 just because we were new.
0:05:27 The whole thing was new, you know?
0:05:28 So we are kind of the guinea pigs.
0:05:34 And so I do think that we had a little bit more leeway back then with pricing and stuff like that.
0:05:37 Yeah, we were one of the only people that did it in the Bay Area.
0:05:38 We went all over the place.
0:05:42 Again, kind of the guinea pigs, just like, we don’t even know how to pick these up.
0:05:43 We don’t even know how to package these.
0:05:44 We don’t know how to market them.
0:05:45 Nobody did.
0:05:47 We didn’t have shared resources.
0:05:48 We just kind of…
0:05:50 Funny, I wonder if you guys were the ones that come to our house.
0:05:52 We should go find our little paperwork.
0:05:57 It’s a Honda Pilot with a little pull-behind utility trailer type of thing.
0:05:58 Maybe not.
0:05:58 We had a…
0:06:01 Did shove a lot of big mattresses into a small CRV.
0:06:02 Okay, wow.
0:06:07 That’s another piece of the pie is like the logistics of like, well, you need a truck.
0:06:09 Or a bigger car to be able to…
0:06:12 Okay, even if you fold it in half, is it really going to fit and bag it up?
0:06:15 These people who came were clearly not their first time.
0:06:20 Real quick, get it down the stairs, fold it in half, bag it, boom, off to the next one.
0:06:20 It’s like…
0:06:24 Because that’s out of the $200 expected profit on it.
0:06:28 It’s like you got to account for the drive time and the storage and the real estate and all this stuff.
0:06:28 Yes.
0:06:31 Well, yeah, I guess we’re not taking that into account.
0:06:40 It’s hard to say exactly what we’re spending per mattress because it depends on how long it sits in our storage unit and how much space does it take up in our storage unit.
0:06:45 So I’ll say our $200 to $250 profit is what we’re making.
0:06:55 It’s not really accounting for the gas that we used or the packaging or the cleaning products just because, like I said, it can be really hard to monetize accurately the price per item.
0:06:58 All right, let’s walk through a typical transaction.
0:07:04 And so maybe either a memorable one of yours or the first pickup or maybe a typical pickup.
0:07:10 You get a ping request as it comes to your phone through the app and say, okay, it’s 20 minutes away.
0:07:11 Do you want it?
0:07:11 Do you claim it?
0:07:13 Like, what’s this process like?
0:07:14 Now we have an app.
0:07:15 When we began, we didn’t.
0:07:18 But now we have an app and it’s really awesome and great.
0:07:20 And you don’t get a pick and choose.
0:07:22 It’s just kind of assigned to you.
0:07:24 You have a radius that you’re willing to go.
0:07:27 Ours is about 60 miles.
0:07:28 And that’s pretty typical.
0:07:34 If you really want to be able to get stuff, you kind of can’t just say, I’ll just get anything that’s down the street, you know?
0:07:38 So we do have some decent, like, traveling that we do.
0:07:41 They give you a window, like you say, within the next three, four days.
0:07:43 Like, you make an appointment to get out there.
0:07:45 They expect you to contact them right away.
0:07:50 But it’s up to us and the customer to schedule it within whatever time frame works for both parties.
0:07:51 Yeah.
0:07:55 Typically, we try to have it scheduled within about seven days.
0:07:59 But again, sometimes there are circumstances that keep that from happening.
0:08:03 And as long as we’re both on the same page, then it’s usually fine.
0:08:06 But we go ahead and reach out and schedule it.
0:08:08 And we do that all through this app.
0:08:12 And then I am the one who goes and picks up the item.
0:08:16 So we usually, I just have an F-150 truck, a Ford F-150.
0:08:23 And so we always try to get about four mattresses per run.
0:08:23 Yeah.
0:08:31 If it’s local, if it’s like in our town or really close, then we’re a lot more willing to say, let’s go get one or two because it fits with their schedule or whatever.
0:08:36 But if I’m going into Seattle, I want to get four just to make the most of the day.
0:08:39 It’s just way more efficient that way.
0:08:44 So when we first started, I just had either a CRV or a Acura MDX.
0:08:45 So just one mattress at a time.
0:08:55 So after, I’d say a year, maybe a little less than a year, we upgraded to a truck because we started to realize that it made sense to scale up.
0:09:01 But anyway, so then I’ll go pick up four mattresses at a time and then bring them home and then we clean them.
0:09:04 And eventually, Hannah finds customers who want to buy them.
0:09:07 You’re able to do the pickup on your own.
0:09:08 Yeah.
0:09:18 We utilize help for a lot just because they are either too thick to fold on my own or too heavy to do that.
0:09:19 But yeah.
0:09:22 And just so that we can protect customers’ homes.
0:09:31 So generally, ShareTown really wants you to have a reliable helper that you can pay or work that out amongst yourselves, whatever.
0:09:38 But generally, they want you to have a helper so that you’re not banging up walls or knocking off picture frames or this and that.
0:09:38 Yeah, exactly.
0:09:41 And it’s not a great customer experience on the return side.
0:09:41 Yeah.
0:09:42 Yes.
0:09:44 So who’s helping you then?
0:09:47 Is it just a part-time employee or part-time contractor or helper person?
0:09:53 Yeah, I’ve utilized a lot of just family friends and people that we know through church or neighborhoods or whatever.
0:09:59 So people that I don’t love to just do it with just anybody because I’m driving around for a long time.
0:10:00 A couple hours in the car.
0:10:03 Small talk gets pretty soon if you don’t get along with the person.
0:10:12 But try to just like high school-aged or late high school or early college-aged kids that want some money and have flexible hours.
0:10:13 It works out really well.
0:10:13 Yeah.
0:10:15 You can manage most of it on your own.
0:10:18 So you really just need an extra set of hands.
0:10:24 I don’t feel like we’ve been able to get away with a lot of 18-year-olds that are wanting some side work.
0:10:29 In the beginning, eight years ago, everything was new and everything was overwhelming.
0:10:30 Okay, how are we going to do this?
0:10:32 And now a lot of it is just so second nature.
0:10:34 I’ve done it a million times.
0:10:37 I just, like Hannah said, I just need a second set of hands.
0:10:40 In the beginning, it was like, all right, let’s figure out how to package this.
0:10:42 Let’s figure out how to lift this.
0:10:45 Let’s figure out how to put it in the back of the car or whatever.
0:10:51 Now it’s just, let’s make sure we’re not knocking over the urn, you know, on the nightstand, on the manor.
0:10:52 You got it all dialed in now.
0:10:57 SideHustleNation.com slash ShareTown is my direct referral link if you want to learn more.
0:11:00 I’ll be right back with Matt and Hannah with some of their marketing best practices.
0:11:04 Hey, we got this inventory, but if we want to get paid, now we got to sell it.
0:11:06 That’s coming up right after this.
0:11:13 For such an important channel like Found, the software powering this important channel was super outdated and clunky.
0:11:20 We wanted to make it delightful and make it very easy for businesses to connect with their customers through voice and text.
0:11:24 That’s Darina Kulia, co-founder of our sponsor, OpenPhone.
0:11:31 Trusted by more than 60,000 customers, this is the number one business phone system that streamlines and scales your customer communications.
0:11:37 I like to think of it like a centralized hub to receive and respond to calls and texts in your business.
0:11:41 And I asked Darina about who’s typically signing up for this kind of service.
0:11:49 We definitely have a lot of folks who come to us and their personal cell phone has become their company phone number.
0:11:57 And they’ve hired a team or they’re starting to scale their business and they just find themselves as a business owner, as a founder, being the bottleneck.
0:11:59 So we see that all the time.
0:12:11 And then we also see folks much further along where they’re using some legacy complicated tools that are just not really made for how communication happens these days.
0:12:18 We also just recently launched Sona, which is our voice AI agent that can handle any missed calls.
0:12:30 If you have clients calling outside of business hours, instead of them going to voicemail, it can go into Sona, which is capable to handle any replies and can also take a message.
0:12:32 So you are capturing that lead information.
0:12:38 And it’s like, and it’s a robot, like it responds like on the fly with some pre-programmed responses.
0:12:40 It does such a great job.
0:12:42 This way they can handle questions 24 seven.
0:12:44 Now here’s a, here’s a scenario for you.
0:12:50 So let’s say I’ve committed to a certain business phone number and I’ve distributed flyers.
0:12:51 It’s printed on my business cards.
0:12:56 It is on my local business listings on directories throughout the internet.
0:13:01 Like what’s the process to now have that ring open phone system versus the current system?
0:13:02 Totally.
0:13:04 So we see this all the time.
0:13:06 This process is called phone number porting.
0:13:09 We port numbers from all kinds of carriers.
0:13:15 So basically no matter what provider you’re using, we can take that number and move it over to open phone.
0:13:16 It is free.
0:13:18 We handle the whole thing.
0:13:21 And if you want to try out open phone, we have a free trial.
0:13:22 You can try it out, see how you like it.
0:13:28 And if you like it, you can then decide to port your existing number over and we handle the whole process.
0:13:34 Now, open phone has automatic AI call summaries, so you don’t have to worry about taking notes while you’re on the call.
0:13:46 But another cool feature is what Darina called AI call tagging, basically allowing you to quickly filter for the calls that were sales objections or customer complaints or requests for a discount.
0:13:54 So you can review those and see what worked, what didn’t, and train team members on the most effective tactics and language in those cases.
0:13:59 And it’s all in the name of building a better, faster, and friendlier customer experience.
0:14:02 I want all open phone customers to have five stars only.
0:14:09 Right now, open phone is offering Side Hustle Show listeners 20% off your first six months at openphone.com slash side hustle.
0:14:15 That’s O-P-E-N-P-H-O-N-E dot com slash side hustle.
0:14:21 And like we talked about, if you’ve got an existing phone number with another service, open phone will port it over at no extra charge.
0:14:25 Open phone, no missed calls, no missed customers.
0:14:27 Let me know if this sounds familiar.
0:14:32 You’ve got more ideas than you’ve got hours in the day, and that to-do list is never quite done.
0:14:37 That’s why finding the right tool to stay on top of everything and simplify things is such a game changer.
0:14:43 For millions of businesses, including dozens of Side Hustle Show guests, that tool is Shopify.
0:14:48 One thing I love about our partner Shopify is you don’t have to start from scratch.
0:14:53 They’ve got hundreds of ready-to-use templates that help you build a beautiful online store to match your brand’s style.
0:15:00 Plus, Shopify makes it easy to create email and social media campaigns to capture customers wherever they’re scrolling or strolling.
0:15:02 And they’re not sleeping on AI either.
0:15:07 I’m talking tools to write product descriptions, page headlines, and even enhance your product photography.
0:15:09 If you’re ready to sell, you’re ready for Shopify.
0:15:11 Turn those dreams into…
0:15:14 And give them the best shot at success with Shopify.
0:15:20 Sign up for your $1 per month trial and start selling today at shopify.com slash side hustle.
0:15:23 Go to shopify.com slash side hustle.
0:15:25 Shopify.com slash side hustle.
0:15:31 Okay, so you get them home three or four at a time, clean them up.
0:15:34 Do you have to like do individual listing photographs?
0:15:36 Or is it just like, hey, this is the brand.
0:15:39 This is the model number that we have.
0:15:43 And we’re going to throw up a generic listing for that piece of inventory.
0:15:47 Photos, I feel like, are one of the most important pieces of the puzzle.
0:15:52 Because you can have a really nice mattress and it can be staged with terrible lighting.
0:15:59 And it’s going to sell for less or not quickly versus you could have a more used mattress.
0:16:00 But if it’s staged…
0:16:02 Or just not as nice of a model or something.
0:16:03 Yes.
0:16:04 But the photo is awesome.
0:16:08 I mean, think about any time that you’re going on Facebook Marketplace to look for an item.
0:16:11 Even the things that are around it.
0:16:12 I’m like, oh, she has a cute home.
0:16:14 She must be nice and her house is clean.
0:16:16 You know, you’re very subtle like positioning.
0:16:16 Yeah.
0:16:17 Yes.
0:16:18 But those things add up.
0:16:21 I’m like, oh, I like the pictures that she has in her background.
0:16:23 So, I don’t try to worry too much about those types of things.
0:16:26 Because that can get very work heavy.
0:16:28 But we try to stage them where we can.
0:16:29 Some of them are in our own home.
0:16:33 Some of them we’ve staged in a garage or a storage facility.
0:16:35 And then we also do share some resources.
0:16:39 The reps that are elsewhere in the country.
0:16:40 It’s gotten a little bit trickier.
0:16:46 Because there are so many reps that I really don’t want to be utilizing the same photos as anybody else that’s in my area.
0:16:48 Because there are plenty of people and I don’t want it to look spammy.
0:16:50 It can look spammy.
0:16:54 If we’re using the same photos as someone else is using the photos that we’re using.
0:16:55 Yeah.
0:16:59 So, we try to stage as many as we can and take pictures of them as we can.
0:17:02 And then we just kind of will reuse the same.
0:17:05 So, it’s not like I’m taking a new picture for every single item we get.
0:17:10 But I can pull from the previous one of the same model and list it again.
0:17:13 But often people will ask, can I see photos of the item?
0:17:15 And then we’ll just take pictures of it and send it over.
0:17:18 Because we do take pictures of everything.
0:17:26 But as far as listing goes, sometimes we do use staged photos for the item, not the exact item.
0:17:26 Make it look good.
0:17:37 I feel like this is a story from the early days of Airbnb where people were throwing up just these dark, backlit, you know, real sketchy pictures of wondering why nobody is booking this place.
0:17:42 And so, they would send in the professional photographer to take like the wide angle, you know, brightly lit pictures.
0:17:45 Oh, look at the difference that made in the bookings.
0:17:48 So, so far, no money has changed hands.
0:17:51 You didn’t have to pay the customer that you went and picked the thing up from.
0:18:02 Now you’ve got it listed, all the Facebook Marketplace best practices, like you mentioned, having really nice pictures and an accurate description of, you know, what it is, the brand, the model, all of this stuff.
0:18:04 Anything else you’re doing to make your listings stand out here?
0:18:08 Well, I would say one of the big things is that we have a ton of reviews.
0:18:13 So, Hannah does a lot of work to request reviews and then to, or ratings.
0:18:13 Yeah.
0:18:16 And then also give ratings to people that buy from us.
0:18:21 So, it, you know, kind of inspires or spurs them to say, I’ll, I’ll rate you back.
0:18:33 So, Hannah has a lot of, you know, five-star reviews on her page that makes people say, oh my gosh, like used mattress might sound a little weird, but look at all these people who have said that it was a great experience.
0:18:36 So, that is a huge differentiator for us.
0:18:41 And I can’t always pretend to understand the algorithms on Facebook because I think they change all the time.
0:18:51 So, it’s always a guessing game and I’ve learned over the years to try not to stress myself out trying to figure out what is going to get my view, my listings viewed the most, you know.
0:19:00 But definitely in my head, if I can mark something as sold and get a good review and all that, it’s going to tell Facebook that, hey, this is legit.
0:19:01 To put our stuff up.
0:19:03 Yes, keep showing my items.
0:19:11 But I think something that I would say my number one tip, and I think this applies to a lot of side hustles, is just consistency.
0:19:17 I post mattresses every single day and I’ve posted mattresses every single day for eight years.
0:19:20 They seem to reward like the recency of that listing.
0:19:27 Yeah, and then it’s just, I just think old stuff just becomes stale and stops getting views and stuff like that.
0:19:37 If I’ve got something up that’s getting lots of attention, I think that, again, the way algorithms work, it’s telling other people to keep clicking on it because, wow, look how many people have already clicked on it.
0:19:43 But if something just, like, for whatever reason didn’t get any traction, I’ll take it down.
0:19:48 I might change the photo or change the ad a little bit and just repost it.
0:19:49 And I just do it over and over.
0:20:00 And I think that is a big difference because getting the item is hard work and time-consuming, but relatively straightforward.
0:20:04 I think that people can get discouraged because they aren’t moving things.
0:20:07 And I think that all has to do with selling things.
0:20:08 Yes, they’re not selling things.
0:20:10 They’re like, man, I picked all these up.
0:20:12 Everybody says it’s great, but they’re not selling.
0:20:19 I think that the big difference maker is how much, like, energy they’re putting into that item, you know?
0:20:23 Is it all Facebook Marketplace or are there other channels that you like for reselling?
0:20:24 We use some other ones.
0:20:30 Facebook is definitely the most lucrative or the, you know, the biggest bang for our buck as far as time.
0:20:31 It yields the most sales.
0:20:33 It yields the most sales, yeah, for sure.
0:20:34 OfferUp is pretty good.
0:20:36 I’ve seen that kind of decline recently.
0:20:37 I don’t know why.
0:20:38 But that, we haven’t.
0:20:42 We used to get, there’s a time there where we were getting quite a lot of interest there.
0:20:44 We still get some every week from that.
0:20:46 But, and then we used to use Craigslist.
0:20:55 But I feel like the bigger the other ones get, the less people are utilizing something like Craigslist or whatever your local, you know, online.
0:20:58 10, 20 years ago, Craigslist was the only game in town.
0:21:00 And that was the place to go for all this furniture stuff.
0:21:01 Yeah.
0:21:03 So, I think it’s kind of slowly dwindling out.
0:21:13 I used to make a point to list there because, again, that consistency mindset, I’ve always been like, I’m going to put some effort into every single avenue so that I have no reason.
0:21:15 Then I know I did everything I could do, you know.
0:21:25 Does ShareTown give you a pricing guidance on, well, this is the product that you have, this is like suggested list price or anything like that, or based on the condition of it, like maybe it’s a sliding scale?
0:21:28 Every item has what we call a minimum ad price.
0:21:34 So, that’s all based off of numbers that they found to be successful for that item.
0:21:40 So, you’re able to list above that price if you want to, but you can’t list below that price.
0:21:47 And that kind of helps so that we’re not undercutting other people in our area or, you know, that type of things.
0:21:52 And then they have a set price per item that we’re required to pay once we sell it.
0:21:56 And so, you have some room because people are going to negotiate on Facebook Marketplace.
0:21:59 So, you kind of know your floor.
0:22:00 Yes.
0:22:05 And so, you’re able to say, well, if it hasn’t moved for a while, maybe it’s worth it to take a lower price and clear it out.
0:22:06 Totally, yeah.
0:22:08 We can take less than that.
0:22:09 We just can’t advertise it for less.
0:22:13 So, if somebody comes in and offers us less, we can take that.
0:22:13 But, yeah.
0:22:21 We used to kind of have a little bit more room, but now that we’re not the only people in our area doing this, there’s quite a few.
0:22:28 We can’t get away with listing at much above minimum ad price anymore just because they can go somewhere else and get it.
0:22:28 Yeah.
0:22:28 Yeah.
0:22:29 Okay.
0:22:29 That makes sense.
0:22:37 Talk to me about the payment logistics because you’re going to receive payment in cash, Venmo, who knows what else.
0:22:42 Or maybe, like, since you’ve done so many of these, like, do you have, like, a little square reader or something like that?
0:22:43 Yeah.
0:22:44 So, we use all of that.
0:22:52 I would say that we try to steer people toward Venmo and cash more than anything else just because we’re really comfortable with those.
0:22:53 Quick, reliable.
0:22:53 Yeah.
0:22:55 And we use Zelle.
0:22:58 We do use the square reader, but, you know, it charges a fee.
0:23:04 So, a lot of people don’t want to do that just because it makes it end up costing a little bit more for them.
0:23:12 Let’s say you take the payment, say it’s $800, and now you have to report that sale to share to, hey, we sold this one.
0:23:13 We picked it up last week.
0:23:14 We sold it.
0:23:19 And now they’re going to want their cut, their, say, $600 if we’re going to aim for that $200 profit per average.
0:23:22 And so, is that sale what triggers that?
0:23:26 Or you have to, like, manually report, you know, once a day, once a week, like, what moved?
0:23:35 Typically, you will mark it as sold upon the sale, and you can even send the customer a receipt through that app.
0:23:37 So, now ShareTown knows that you’ve sold that item.
0:23:39 You write in how much you sold it for, all of that.
0:23:45 And then every Monday, it prompts you to pay for all of the ones that you’ve sold in the previous week.
0:23:53 Do you find people coming to pick this stuff up from the storage unit and, you know, open up the door and seeing, like, a wall of mattresses and be like, these guys are, like, dealers?
0:24:00 Well, it’s funny because people will ask what I do for work, and I’m like, well, how much time do you have?
0:24:08 Because if I just say I sell used mattresses out of a garage or out of a storage unit, it sounds nefarious or weird, you know?
0:24:14 So, we do have people who are, like, unprepared, I think, for, like, what it is that we do.
0:24:17 And I’ll open up, you know, a storage unit, and they’re like, what is going on?
0:24:21 But, you know, you spend two minutes explaining what it is, and it just clicks.
0:24:22 People get it.
0:24:31 When we first started doing it, I felt like people were really, really skeptical because I think even then, buying a mattress online and having it delivered to your door was a very new concept.
0:24:33 But now, I feel like people are aware.
0:24:37 I feel like they’ve bought mattresses from these companies themselves, or they know people that do.
0:24:45 It’s just become a lot more commonplace, and I think a large majority of people are like, oh, yeah, I think I’ll get one this way, you know?
0:24:45 Yeah.
0:24:48 At least relative to what it was before.
0:24:52 And us having all of those good reviews on Facebook really helps with that.
0:25:00 But, like, literally yesterday, somebody came to look at a mattress and was like, I’m a little skeptical about buying anything used.
0:25:02 Like, can you please pitch me on why I shouldn’t be?
0:25:08 And I was able to talk through it and just gave them a good customer experience, and they walked away with a mattress.
0:25:12 I mean, they’ve been able to see my profile where I have dozens of mattresses listed.
0:25:15 We’ve got over 700 reviews, you know?
0:25:19 Like, so it’s not terribly surprising usually once they come show up.
0:25:24 Yeah, we had a guy years ago whose specialty, his flipping specialty, was appliances.
0:25:25 So, same thing.
0:25:29 Open up the door to the garage, and it’s, you know, wall-to-wall washers and dryers.
0:25:34 And so people would be like, you know, they pause for a second, and then it’s like, well, I still want the thing, you know?
0:25:36 Even though you’re clearly in the business.
0:25:41 But this is, what does the storage unit cost on a monthly basis?
0:25:43 I’m trying to break down some of the other.
0:25:43 Too much.
0:25:47 And we have some pretty big units, and we have multiple.
0:25:53 So, but off the top of my head, I’d say about $300 a storage unit.
0:25:55 Definitely depends on where you live.
0:26:00 We’ve got a few of them, and they’re on average about $300 a piece.
0:26:02 Right now, we’ve got four storage units.
0:26:04 We’ve had as many as seven.
0:26:08 It just kind of depends on our inventory and the size of the units.
0:26:10 Right now, it’s good because we have four big ones.
0:26:12 Is it at the same facility?
0:26:17 Yeah, so we’ve got a really good relationship with our facility, which is great.
0:26:19 We just add and drop them when we need to.
0:26:25 Yeah, because our inventory size situates with how many we sell versus how many we’re picking up.
0:26:32 We have friends and contacts that do the same thing we do out of state, and they have a warehouse, which sounds great.
0:26:41 And I think it’d be great to have a warehouse, but you’ve got to set price for a longer contract, and often you don’t need that much space.
0:26:44 And so anyway, storage units works for us.
0:26:49 I will say, though, we do this on a larger scale than other people.
0:26:51 We’ve been doing it, so it’s grown.
0:26:59 A new rep these days would start probably in their garage, and then would maybe move to a unit, maybe eventually two.
0:27:00 That was our experience.
0:27:06 We started in our garage in our townhouse, and it was one of those things where we just were running out of space.
0:27:08 And so it was like Jenga in our garage.
0:27:13 And so then we moved to a house with a three-car garage, and then we got a couple storage units.
0:27:16 And every time we scaled up, it was great.
0:27:23 You know, it meant life was easier as far as storage, but it also, you know, with more space, it meant more inventory, which meant more sales.
0:27:29 Do you do any of the other inventory items, or have you focused just on mattresses?
0:27:34 We’ll take almost anything that we can get, but the majority really is just mattresses.
0:27:38 They do, ShareTown has other partners that allow us to get some furniture items.
0:27:42 We’ll get couches and chairs and dressers and love sacks, occasionally.
0:27:43 That’s a while.
0:27:46 You know, some exercise equipment, too.
0:27:50 But I’d say the vast majority of what we have is mattresses.
0:27:53 Is there a rule of thumb of how fast an item should turn?
0:27:57 We’re like, we want to have, you know, we want to flip it every two weeks, like four weeks.
0:27:58 Like, what’s typical, like, to sit on something?
0:28:04 The goal is to move something maybe within about six weeks, but it just really depends.
0:28:08 Sometimes we get three of the same item in one week, and so then it’s going to take a little
0:28:14 bit longer for those items to move, or particular models might be more of a niche, you know, it’s
0:28:20 an organic latex mattress, which is really perfect for an organic buyer, but not necessarily a crowd
0:28:21 pleaser.
0:28:29 So nearly everything we get, we’re pretty thrilled to sell, but it really can just depend on how
0:28:31 much you have, the time of year, all that.
0:28:37 But I would say that Sharetown’s goal is to help us to support people through selling
0:28:38 it within about six weeks or so.
0:28:43 What happens if you come across something that no amount of cleaning is going to salvage, and
0:28:50 you’re like, no, no way, I can’t in good conscience sell this as a, even a semi-used mattress?
0:28:51 That definitely happens.
0:28:57 I mean, if that does, then we just, we request through Sharetown to say, hey, this is not sellable.
0:29:02 And so then we just, we mark it as a dump item, and then we just go dump it, take it
0:29:02 to the dump.
0:29:06 That could be because it’s dirty or damaged, you know, sometimes.
0:29:06 Defective.
0:29:07 Yeah, defective.
0:29:08 Not supportive.
0:29:13 So sometimes mattresses, they sink, you know, because it wasn’t manufactured the way it should
0:29:15 have been, things like that.
0:29:20 So anything under those umbrellas of, it’s just not sellable, then we just request to
0:29:22 get it dumped, and then we dump it.
0:29:26 But I will say, we try hard not to, just because we do want to keep things out of landfills, but
0:29:28 some things, you just can’t sell them.
0:29:29 So.
0:29:34 Do you ever have a situation where something just sat in inventory for 12 months, 24 months,
0:29:36 and you’re like, dude, this thing is a dog?
0:29:37 Yes.
0:29:38 Yeah.
0:29:39 Yes.
0:29:45 Probably something that was an organic, a California King, kind of unique size, unique
0:29:46 mattress.
0:29:52 Doesn’t happen very often, but there are some things that you’re like, shoot, I am, there’s
0:29:55 things that come in, and I’m like, I know it’s going to sell right away, and so I give
0:29:58 it lots of time and attention, and then there’s other things that I’m like, I don’t know if
0:30:01 I want to list this tonight, because nobody’s going to message me about it, you know?
0:30:05 Unfortunately, that’s not the norm, but there are things once in a while that you’re just
0:30:07 like, this is a weird one.
0:30:07 Okay.
0:30:09 Do they, is there any support there?
0:30:13 Is it just like, just keep deleting and relisting, like somebody, eventually somebody’s going
0:30:14 to come along.
0:30:18 Yeah, they kind of have some practices in place now where it didn’t quite used to be this way,
0:30:22 and it was a little bit more hands-off, and we just like, put our heads down and worked,
0:30:27 and we could ask for help when we needed it, but now they have a lot of assistance, and
0:30:32 so they’ll kind of watch your ads and make sure that you’re posting them, and then at
0:30:37 that point, they can see, okay, you have given this a fair shake, we’ll knock it down.
0:30:41 You can list it a little bit lower, we’ll take a small chunk out so that you can afford
0:30:42 to sell it for less.
0:30:45 So there’s help there to help you, because they want you to turn over items, right?
0:30:48 If we keep sitting on items, they want you to be successful.
0:30:50 If we’re sitting on items, then…
0:30:51 No one’s winning.
0:30:52 Then nobody’s winning.
0:30:55 Yeah, they’re not making money, we’re not making money, we’re probably not going to be inclined
0:30:57 to go pick up more items, you know, so…
0:31:04 Yeah, so if that happens, then we can request an adjustment of, like, minimum ad price and
0:31:05 what we owe.
0:31:05 Okay.
0:31:09 So it’s helpful to hear some items, obviously, are going to be more popular than others,
0:31:13 but don’t expect it to be, you know, pick it up today, sold tomorrow, boom, instant $200
0:31:13 in my pocket.
0:31:14 Yeah, not typically.
0:31:15 Sometimes.
0:31:15 Yeah.
0:31:20 Sometimes there are some, you know, and the more your reputation builds, the more I’m like,
0:31:23 I have somebody waiting for this one, and we’re getting it on Thursday, you know?
0:31:28 I will go in and list things that I know we’re getting in a couple days just to kind
0:31:35 of try to catch a little bit of a head start, but typically it’s not that quick, so you do
0:31:39 have to have some patience and consistency, but then, you know, then you’re starting to sell
0:31:42 the things that you picked up a week or two ago or whatever.
0:31:46 Yeah, and then the cash flow starts to be more and more consistent as the inventory grows.
0:31:47 I think that makes sense.
0:31:54 Another rep I talked to mentioned keeping kind of like their buyers list or, you know, everybody
0:31:58 who messaged you about the thing but didn’t end up, you know, maybe they weren’t fast
0:32:02 enough or they, you know, didn’t end up getting it, kind of keeping a Rolodex of those people
0:32:07 for the next time that item comes back in, and so you can almost have it pre-sold or have
0:32:09 it at least have a warm marketing list to reach out to.
0:32:11 I used to do that some.
0:32:14 I’d have a list of, oh, this person’s waiting for this, this person’s waiting for this.
0:32:19 Now I feel like not very many when I come back to them are still looking because there
0:32:23 are other reps in the area or there’s a lot more mattresses on the market than there
0:32:27 used to be, and so if they don’t get it with me, they can probably go find it somewhere
0:32:32 else unless they bought from me before and feel that loyalty and just want the experience
0:32:33 with us, which certainly happens.
0:32:38 We have a lot of people that are repeat buyers or come because their friends had a great experience.
0:32:42 Again, sidehustlenation.com slash share town is my direct referral link.
0:32:46 If this sounds like a fit for you, you want to learn more, that’s an easy way to support
0:32:47 the show.
0:32:51 I’ve got more with Hannah and Matt coming up, including their take on the competitive landscape
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0:35:09 What’s your take on the competitive landscape?
0:35:12 Because obviously, ShareTan wants to have coverage.
0:35:18 If a customer requests a pickup, they need to be able to have somebody go pick it up right
0:35:18 away.
0:35:21 But at the same time, you start eating each other’s lunch.
0:35:25 And it’s kind of like when I worked at Ford, it was like, well, how many Ford dealers do we
0:35:25 really need?
0:35:30 Is somebody willing to drive 45 minutes to save $5,000 on a new truck?
0:35:33 Probably, do we need this dealer right here?
0:35:35 What’s your take on that landscape?
0:35:38 Does there become a point where it’s not a great side hustle anymore?
0:35:38 It’s just too saturated?
0:35:41 I think it will always be a good side hustle.
0:35:47 The adjustment for us is just that recognition that there are others doing what we’re doing.
0:35:52 And so we used to have people who would drive all the way from Seattle from us, and we still
0:35:53 have that.
0:35:55 But now there are other reps in between.
0:36:00 And so like Hannah was saying, sometimes we get repeat buyers or referrals that will
0:36:04 bypass all those people to come to us, but we are being impacted by that.
0:36:08 We switched from side hustle to full-time three years ago.
0:36:14 So as far as it being a full-time gig, it’s less reliable than it was because of the saturation
0:36:18 of the other reps, but it still makes sense for us to do it.
0:36:23 I will have a very hard time walking away from doing this because it’s pretty great for what
0:36:23 it is.
0:36:24 Yeah.
0:36:26 Your Ford example is spot on.
0:36:28 It’s just, it has become saturated.
0:36:30 They need all those reps though.
0:36:35 So they need all those reps in order to keep these contracts and to be able to get new contracts.
0:36:38 So they’re bringing people in, but it definitely has affected our sales.
0:36:39 That’s for sure.
0:36:44 But we’re still really grateful for what it is and we’re just adjusting accordingly.
0:36:45 Yeah.
0:36:47 There’s always going to be pickups to do.
0:36:49 So it’s like, it’s not the pickups.
0:36:52 There’s no lack in pickups, but it does affect the sales.
0:36:55 It’s similar to, you can’t sell on Amazon anymore.
0:36:56 It’s too saturated.
0:37:01 But at the same time, Amazon’s market share as a percentage of total commerce continues
0:37:01 to grow too.
0:37:06 And so ShareTown continues to expand its partnerships, its brand partnerships.
0:37:12 And so there’s more and more pickups coming on and trying to balance the volume of reps as
0:37:14 well to go out and fulfill those pickups.
0:37:20 Every area is going to be a little bit different, but we had the luxury of being kind of in on
0:37:23 the ground floor where we were kind of the only ones in our area.
0:37:25 So we’ve watched the growth happen.
0:37:30 Aside from the storage unit and obviously gas and wear and tear on the car, anything other
0:37:33 expenses that new reps need to know about?
0:37:36 I mean, like I said, eventually we did scale up and get a truck.
0:37:38 If you’re going to do this seriously, I think it makes sense to do that.
0:37:40 That’s a huge expense, right?
0:37:41 Big business write-off, I suppose.
0:37:42 Right.
0:37:43 Yeah, true.
0:37:48 The other things that I think make a big difference for me is the materials that I use.
0:37:53 When we first got started, I used big rolls of plastic sheeting, like painters, plastic
0:38:01 sheeting, and eventually decided that it was worth the added cost to get mattress bags for
0:38:01 every pickup.
0:38:08 Also, like the right tape, like things that I never knew I’d care about is like the quality
0:38:12 of the tape gun, the quality of the tape, the quality of the plastic, the quality of the hand
0:38:13 truck.
0:38:19 Those are all things that impact the pickup side and the resale side because I’m using
0:38:20 a mattress bag.
0:38:25 It’s so much easier to pop that sucker open and show it and people lay on plastic rather
0:38:27 than an exposed mattress.
0:38:33 So those are kind of the intricacies of that side that I deal with that I think have a
0:38:38 little bit of an added cost to some cheaper alternatives, but I think make a big difference.
0:38:46 On relative to other gigs, your price per item material-wise is and can be pretty low.
0:38:50 So you kind of listed the expensive ones, the storage unit, the gas, the truck.
0:38:53 But per mattress, those materials-
0:38:55 Yeah, five or ten bucks for a mattress bag, maybe?
0:38:59 Yeah, a few bucks a pop, or can be as low as a few bucks a pop.
0:39:01 We use some cleaning supplies.
0:39:02 We use a product called Sterifab.
0:39:08 And then we have like an upholstery, I mean, like a Bissell, like not some industrial size
0:39:09 anything, but-
0:39:10 An upholstery cleaner.
0:39:11 An upholstery cleaner, yeah.
0:39:12 Sorry, that we can-
0:39:15 Lint rollers, you know, getting good high quality lint rollers.
0:39:19 See, these are the things that some of your listeners are going to be like, interesting,
0:39:21 and everyone else is going to be like, what is this guy talking about?
0:39:25 No, this is like, I love the details surrounding this because it’s like, why is somebody going
0:39:26 to buy from you from somebody else?
0:39:31 Because we use the right mattress bags, because we have this, you know, cleaning process that
0:39:32 we’ve done dozens of times.
0:39:34 Like, you know, it all makes sense.
0:39:37 I did have a comment on a YouTube video about insurance.
0:39:42 Like, do you need commercial insurance to start selling this, to start driving for these pickups
0:39:44 while you’re, you know, clocked in on the app or anything like that?
0:39:48 You’re required to have a certain level of extended insurance.
0:39:51 And off the top of my head, I can’t remember what all those details are.
0:39:56 So we do pay a little bit more in insurance than we would if we did do this for the truck,
0:39:59 but we don’t have an individual insurance, if that makes sense.
0:40:03 So we just have higher coverage with the vehicle that we use already.
0:40:04 Yeah.
0:40:07 Versus, you know, product liability is like, well, it’s not really my product.
0:40:08 You know, maybe it’s still-
0:40:09 Right.
0:40:12 We want to work for ShareTown as long as it makes sense to do so.
0:40:18 But one of the reasons that we went full-time three years ago is because my career, my background
0:40:19 is in human resources.
0:40:22 I worked for a big manufacturing company for years.
0:40:28 And one of the big driving factors of me quitting and doing mattresses full-time is so that I could
0:40:34 also go back to school and so that I could also, like, create an HR consulting company.
0:40:41 And so, like, the principles that we’ve learned through doing this has helped inform me on,
0:40:45 like, the decisions that I make, I’ve made in creating another side hustle that I hope
0:40:46 to turn full-time.
0:40:51 Are there any surprises that come to mind or something you might do differently related to
0:40:51 ShareTown?
0:40:55 I don’t know if I quite understood the potential.
0:40:59 You know, this kind of started as something that was going to help us pay off some-
0:41:01 We had a baby and we’d had some medical debt.
0:41:07 And we had just a little bit of student loans and we lived in an expensive area and we wanted
0:41:11 to save for a house and all those things seemed really out of reach.
0:41:14 And so, I feel like maybe the biggest surprise was, and I think that that can be true for
0:41:19 a lot of side hustles, is just that you don’t ever know what it could evolve to, you know?
0:41:23 We thought that it was a side hustle and it was something that, I mean, Matt worked nine to
0:41:25 five and even traveled for work.
0:41:30 And then in the evenings drove into San Francisco and I just feel like we were willing to do
0:41:32 something different because we had some goals.
0:41:36 And it’s not that I’m, like, crazy passionate about selling mattresses.
0:41:38 I have learned, like-
0:41:41 Ever since you were a little girl, you wanted to sell mattresses.
0:41:44 No, it’s not that I’m crazy passionate about selling mattresses.
0:41:49 I have learned to really enjoy the interactions and those sales and get a lot of satisfaction
0:41:50 out of helping people that way.
0:41:55 And it makes it hard to ever consider working for somebody again because we work together
0:41:56 and we have flexibility.
0:42:01 And I think that that can be the beauty of a side hustle, is it helps you to achieve your
0:42:08 goals and it gives you the flexibility to kind of live life on your own terms, you know, the
0:42:10 way an extra source of income does.
0:42:11 Yeah, it’s really powerful.
0:42:16 That line of, we were willing to do something different to get out of this situation.
0:42:20 People that are willing to do something different and work at it, even when it’s hard or even
0:42:21 when it’s not yielding results.
0:42:26 Fortunately, ShareTown, I feel like, is a pretty results-driven gig.
0:42:30 It’s hard to fail at, I feel like, but I feel like it’s that willing to work hard.
0:42:34 And willing to fail, you know, willing to try, willing for things to not work out,
0:42:38 and then willing to pick yourself back up and keep trying until it does.
0:42:43 And that’s what we found with your, you know, business too, is just trial, a lot of trial
0:42:44 and error and not giving up.
0:42:46 Matt, can we plug the HR company?
0:42:47 Do you have a site for it?
0:42:48 Oh, sure.
0:42:49 I mean, it’s called Circle Consulting.
0:42:52 So, it’s like fractional HR support.
0:42:54 Circle, like the shape?
0:42:54 Yeah.
0:42:58 So, it’s spelled normally, you know, Circle Consulting.
0:43:05 So, I kind of specialize in culture and providing fractional HR to like small to mid-sized companies.
0:43:11 And then also like project-based stuff too, going and doing culture checks for offices.
0:43:13 Helping make sure people are in the right positions.
0:43:14 Yep.
0:43:17 Organizational effectiveness, kind of.
0:43:17 Very cool.
0:43:20 Well, Circle Consulting, we’ll link that up in the show notes.
0:43:23 This is like something else that you got going on.
0:43:24 Lots of side hustles here.
0:43:27 Anything else that you’re excited about coming up through the rest of this year?
0:43:32 We have some financial goals and that’s what drives our side hustles is the desire to accomplish
0:43:35 these goals and to grow and to evolve.
0:43:38 And to do that on our own terms where we can spend a lot of time with our family.
0:43:46 We have four young kids and having the flexibility to kind of tag team both work and play and parenting
0:43:49 and all the things is really exciting.
0:43:57 One of the things that’s cool about it is you can bring in this money and it’s not like you’re locked into a cubicle nine to five.
0:44:02 Like there’s a lot of flexibility in when you schedule these pickups and when you go meet with buyers and stuff for them.
0:44:05 So, do you have an example of the next financial goal?
0:44:06 Is it a net worth milestone?
0:44:07 Is it an income target?
0:44:10 Is it we’re going to save up for that trip to Disneyland with the family?
0:44:13 We’ve got just like some house projects that we really want to get done.
0:44:15 We bought a new house a couple years ago.
0:44:21 We’re in an open loft and so we’d love to close this off or turn it into an office.
0:44:26 You know, we have some space above our garage that could be turned into like a mother-in-law suite.
0:44:28 We’d love to do that down the road.
0:44:30 So, like…
0:44:31 Doesn’t sound very exciting.
0:44:32 Yeah, I know, but…
0:44:37 I love the idea of having like a specific target and then using a side hustle.
0:44:40 Using some extra income to like erase that.
0:44:47 That’s what got us started with it was, hey, we had this amount of, you know, debt that we wanted to pay off and we achieved it.
0:44:50 And we were like, holy crap, like that happened, you know?
0:44:58 And so, it’s something that’s continued to drive us is, okay, look at what we can unlock by working hard.
0:45:07 I loved the safety of a 95 job, but you can’t always say, I’m just going to work this X amount harder to get to where I want to go.
0:45:11 Financially, it was a nine-to-five job because you’re locked into that salary.
0:45:16 And so, there’s a lot of benefits that come with that type of salary, but we love the…
0:45:23 A side hustle allowed us to say, hey, if I want to work harder for this season of life, it’s going to pay off.
0:45:23 Yeah.
0:45:26 You know, nobody’s going to keep me from that.
0:45:33 Yeah, you front load that earning power, let’s that, you know, get the compound interest working in your favor instead of against you and paying off that debt.
0:45:34 Really powerful move.
0:45:35 And I’m excited.
0:45:36 I’m rooting for you guys.
0:45:40 We’ll get this, check off the next goals here and get those house projects taken care of.
0:45:40 Yeah.
0:45:46 SideHustleNation.com slash ShareTown is my referral link for ShareTown if you want to learn more and submit your application there.
0:45:51 Let’s wrap this thing up with your number one tips for SideHustleNation.
0:45:53 Hannah, ladies first.
0:46:04 Consistency and the willingness to work hard and being willing to try things and have them fail and pivot and just keep going until you find something that sticks.
0:46:10 You know, I feel like that’s kind of what’s going to lead anybody to a successful SideHustle is just the willingness.
0:46:23 I mean, I would love to sit and play from five to nine every night, but some nights we are doing things other people aren’t doing because we, you know, are trying to accomplish these goals that we have.
0:46:31 So the opening tagline on the show for, I don’t know, eight, 10 years was, you know, your nine to five makes you a living, but your five to nine makes you alive.
0:46:33 And it was from five, you know, to the next nine coming around.
0:46:36 But it’s the same thing, you know, evening or the rest one.
0:46:37 So, Matt, what about you?
0:46:40 I just want to echo what Hannah said, which is consistency.
0:46:47 So, like, Hannah, I used to tease her when we were on vacation because she would be on a beach in Hawaii posting mattresses.
0:46:49 That sounds depressing.
0:46:50 I also enjoyed the demo.
0:46:51 I know.
0:46:56 But, like, but that’s what I mean is, like, I used to tease her for it and I just don’t anymore because, like, that’s what.
0:46:57 That’s what keeps things driving.
0:47:00 And when I say tease, like, it really is, like, really lighthearted.
0:47:02 I’m not, you know, some short husband.
0:47:05 But, like, I would just be like, hey, that can wait.
0:47:06 Like, it’s okay.
0:47:09 And she’s like, trust me, it makes a difference.
0:47:15 And I think that’s applicable to, you know, to everything else is, like, no, we have to be willing to say yes to things.
0:47:15 Yeah.
0:47:16 Say yes to sales.
0:47:22 Say yes to the, you know, hard work of doing it so that we can, so that that opens up those doors.
0:47:23 Give some momentum.
0:47:24 Yeah.
0:47:27 It just keeps that momentum going rather than, you know, ebbing and flowing.
0:47:34 But, yeah, I would just say consistency with, like, with the work, you know, with the work and the willingness to do the hard things.
0:47:35 I’m with you.
0:47:37 It’s building that hustle habit almost.
0:47:39 And it’s like, this is just something that I do.
0:47:41 It’s hard to imagine not doing it.
0:47:43 It doesn’t matter if I’m on vacation.
0:47:44 It only takes a few minutes.
0:47:46 Well, and oftentimes they’re small things.
0:47:48 You know, it’s five minutes here.
0:47:48 It’s ten minutes there.
0:47:51 It’s not always, you know, big.
0:47:51 Yeah.
0:47:52 Super cool.
0:47:53 Well, I love this low-risk side hustle.
0:47:56 I like the we were willing to do something different.
0:48:00 I love the idea of having a goal to shoot for versus something more nebulous.
0:48:01 Ah, I want to side hustle to make extra money.
0:48:04 No, I’ve got to make 20 grand to pay off this loan or whatever.
0:48:07 I’ve got to have something, have a target, have a finish line, have something to shoot for.
0:48:14 Again, sidehustlenation.com slash ShareTown is our referral link if you would like to learn more about becoming a ShareTown rep yourself.
0:48:17 Big thanks to Hannah and Matt for sharing their insight.
0:48:20 Big thanks to our sponsors for helping make this content free for everyone.
0:48:27 As always, sidehustlenation.com slash deals is where to go to find all the latest offers from our sponsors in one place.
0:48:30 Thank you for supporting the advertisers that support the show.
0:48:31 That is it for me.
0:48:32 Thank you so much for tuning in.
0:48:35 Until next time, let’s go out there and make something happen.
0:48:38 And I’ll catch you in the next edition of the Side Hustle Show.

0:00:05 Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life.
0:00:15 I’m Andrew Huberman, and I’m a professor of neurobiology and ophthalmology at Stanford School of Medicine.
0:00:17 My guest today is Dr. Nirao Shah.
0:00:24 Dr. Nirao Shah is a professor of psychiatry and behavioral sciences and neurobiology at Stanford University School of Medicine.
0:00:34 Dr. Shah is both an MD and a PhD, and his laboratory focuses on understanding the neural and hormonal mechanisms underlying sex differences in the brain.
0:00:39 During today’s episode, we discuss what is known about male and female differences in brain structure and function,
0:00:47 and how those differences arise across development, both in utero and postnatally, that is, during puberty and into adulthood.
0:00:56 A lot of our discussion centers around testosterone and estrogen, and how both of those hormones play a profound impact on the development of both the male and female brain,
0:01:00 but leads to different outcomes in male versus female brains.
0:01:08 We also discuss the neural circuits that control sex behavior and aggressive behavior in both males and females, and how those are activated by different hormones.
0:01:14 As you all know, there is immense interest and a lot of controversy around sex differences and how that relates to gender.
0:01:29 Today’s discussion centers around the biology of sex differences in the brain and body, and it will provide a very useful template for everybody in thinking about male versus female differences in behavior, in emotions, and how that intersects with gender and culture.
0:01:36 As you’ll soon see, Dr. Shah is a true expert in understanding sex differences in the brain and body, and how those arise.
0:01:46 He’s also unafraid of addressing what is known and unknown about those differences and their origins, and he embraces that sex differences are one of the most impactful aspects of human biology and health.
0:01:52 So by the end of today’s episode, you will indeed have the most up-to-date information on this important topic.
0:01:57 Before we begin, I’d like to emphasize that this podcast is separate from my teaching and research roles at Stanford.
0:02:04 It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public.
0:02:07 In keeping with that theme, today’s episode does include sponsors.
0:02:11 And now for my discussion with Dr. Nirao Shah.
0:02:13 Dr. Nirao Shah, welcome.
0:02:14 Thank you, Andrew.
0:02:15 Pleasure to be here.
0:02:25 You work on one of the most interesting topics in the entire world, which is sex differences in the brain and the impact of hormones on the brain, on behavior.
0:02:28 Let’s start with a very straightforward question.
0:02:33 Are there male-female differences in terms of brain structure and function?
0:02:34 Yes.
0:02:36 Let me qualify that.
0:02:45 So we work on the mouse, on the mouse brain, and we and others have identified lots of differences in structure and connections and numbers of neurons, numbers of cells in the brain.
0:02:51 And also, my own lab is focused on identifying differences in gene expression between females and males.
0:02:52 And there are huge differences.
0:02:57 For the topics we’re going to discuss today, I know that we’re going to lean heavily on mouse data.
0:03:10 But I think it’s fair to say that because so much of those data rely on the structure and function of the hypothalamus, which you’ll educate us on, how conserved is the hypothalamus between mouse and human?
0:03:17 I would say anatomically, from an atlas, if you’re just looking at atlases of humans and mice, they’re very conserved.
0:03:26 You can point to regions in the mouse brain, the ventromedal hypothalamus, for example, the VMH, which we might talk about, controls aggression and other behaviors, female sexual behavior.
0:03:28 You can say, this is the VMH in the mouse.
0:03:31 And you can basically pinpoint the same region of the human brain.
0:03:34 And it’s turning out to be clinically relevant as well in humans.
0:03:40 You can do the same thing for the preoptic area, which controls maternal behaviors, preoptic, you know, male sexual behavior.
0:03:43 And we can identify the same region in the human brain as well.
0:03:49 So anatomically, there are very similar analogs in the human hypothalamus as there are in the mouse.
0:03:54 And this region is conserved because it controls, as you pointed out, very fundamental functions.
0:03:58 Reproduction, aggression, taking care of young, thirst, temperature.
0:04:05 So these tend to be conserved because you don’t want to muck with the circuit that’s already functioning and that’s essential for survival.
0:04:13 So you can find analogs of these structures all the way from birds across vertebrates, from birds, lizards, rodents, non-human primates, and humans.
0:04:19 I think many people lean toward the idea that humans are so different than mice.
0:04:37 And they like that idea because it somehow, I don’t believe this, but I think it somehow gives them the impression that they have more degrees of freedom over their feelings and behavior than perhaps they would if we were a slave to our hypothalamus or something of that sort.
0:04:53 But studies on the human, as you and I know, where different hypothalamic circuitries have been stimulated reveal that you can elicit rage, you can elicit sexual desire, behavior, and on and on in a human just as you can in a mouse.
0:05:07 I mean, I think we are different in the sense that we have a huge cortical sort of normal volume, we have a huge cortex, and that, you know, gives us many more degrees of freedom in deciding when and what to do and where to do it.
0:05:15 So there is flexibility granted by that enormous expansion of the cortex, but the basal structure for those behaviors, the hypothalamus and the amygdala, are very conserved.
0:05:23 So the behaviors exist, of course, and could in the brain, but we can control them or inhibit them, if you will, and in appropriate moments.
0:05:34 So we’ve all heard of nature versus nurture, and I think that’s a very kind of relevant theme as we wade into this topic of sex differences in the brain and sex hormones and behavior.
0:05:43 Could you explain for us how it is that hormones act on genetics in order to set up a bias for behavior?
0:05:49 And for those that are familiar with the idea that nature and nurture are both involved, which should be everybody,
0:05:55 what I’m getting at here is this notion of organizing effects of hormones versus activating effects.
0:05:57 You’ll educate us on what those are.
0:06:01 So we work on hormones like testosterone, estrogen, progesterone, which are steroid hormones.
0:06:07 And as, you know, as you pointed out, Andrew, they act at least two different stages of life.
0:06:21 And early on in development, at embryonic stages in some species, like in humans, in utero, when the woman’s pregnant, or in mice just at birth, perinatally, just after birth,
0:06:30 these hormones generate what is thought to be an irreversible differentiation of the brain along a female or a male pathway.
0:06:41 So they sort of set the circuits, if you will, so that these behaviors can then be displayed in adult life after puberty when the hormones kick back in again.
0:06:48 So after this early critical period, and I know you’ve talked about critical periods before in your podcast,
0:06:54 there’s a critical window that is species-specific when hormones sort of organize the brain, sort of irreversibly set down circuits.
0:07:01 And then, you know, the gonads, testes, and ovaries go quiescent until puberty hits.
0:07:08 And then at puberty, the hormones come back on again, and then they activate, if you will, these circuits, so that adult behaviors can be displayed.
0:07:12 But the circuits were sort of initially laid down at some point in development.
0:07:23 Correct me if I’m wrong, but my understanding is that the presence of a Y chromosome is really the key differentiating factor for setting up circuitries to be more male-like or female-like in the brain,
0:07:24 so these organizing effects.
0:07:27 Could you explain what’s on the Y chromosome?
0:07:33 Actually, you should probably remind everybody how chromosomes and genes work very briefly, right?
0:07:36 23 sets of chromosomes, and then we have the sex chromosomes.
0:07:43 If you don’t mind educating us just on chromosomes and then how the presence of a Y chromosome is really the key deterministic factor.
0:07:53 Not just if you get a male or a female as it’s, you know, on a birth certificate, but the whole kit and caboodle in terms of brain structure and function as well as genitalia.
0:07:53 Sure.
0:08:04 So, as you pointed out, you know, there are 23 sets of chromosomes, and there’s a set of chromosomes called autosomes, which are identical between males and females, and they’re completely conserved.
0:08:04 They’re the same.
0:08:10 And then females have a set of chromosomes, the sex chromosomes, referred to as X chromosome and Y chromosome.
0:08:14 And females have two, I’m sorry, two X chromosomes, X and X.
0:08:16 And males have an X chromosome and a Y chromosome.
0:08:17 Those are the sex chromosomes.
0:08:18 Those are the sex chromosomes.
0:08:20 So males have X, Y, females have XX.
0:08:21 Okay.
0:08:31 And the Y chromosome is very special in the sense that it has, on the chromosome sits a gene called SRY, sex-determining region on the Y, SRY gene.
0:08:36 And this gene essentially dictates whether or not the embryo will have testes or not.
0:08:43 And then if, yes, if the embryo has testes, then they’ll make testosterone and masculinize both the genitalia and the brain and the rest of the body.
0:08:44 In utero?
0:08:45 In utero.
0:08:53 Okay, so just to step back for people that aren’t so familiar with how chromosomes and genes work upstream of hormones.
0:08:56 So what you’re telling us is 22 sets of autosomes.
0:08:57 Then we have the sex chromosomes.
0:08:59 In females, it’s XX.
0:09:00 In males, it’s XY.
0:09:02 On the Y chromosome, there’s this SRY gene.
0:09:03 There’s a single gene, SRY.
0:09:10 And the presence of that gene means that there will be RNA and then protein made.
0:09:10 That’s correct.
0:09:16 And some of those proteins will cause the development of the testes.
0:09:26 And then the testes will secrete testosterone in utero and shape the brain for its potential to be male when puberty happens later on, right?
0:09:26 Yes.
0:09:28 Let me qualify that.
0:09:28 Okay.
0:09:34 So SRY is a transcription factor, which means it is a gene that encodes a protein from RNA.
0:09:37 You know, it gets transcribed into RNA and then RNA gets made into protein.
0:09:40 And the protein is a transcription factor, the SRY protein.
0:09:44 And what that means is it sort of can regulate expression of other genes.
0:09:50 So it can sort of switch on or silence suites of genes that take the bipotential gonad.
0:09:54 So the gonad, before it becomes testes or ovaries, is a bipotential gonad.
0:09:55 It can go either way.
0:09:59 At what stage of embryonic development in human is the gonad bipotential?
0:10:01 It could become male or female.
0:10:05 It’s thought that it’s early, late first or early second trimester.
0:10:12 So as late as the second trimester, the gonads are equal potential.
0:10:13 They could become male or female.
0:10:19 And which direction they go depends entirely on the presence of this SRY transcription factor.
0:10:19 That’s right.
0:10:21 And the same is true in the mouse as well.
0:10:24 So in the mouse, the gonads are bipotential until day 12 of gestation.
0:10:26 The mouse gestation is about 20 days.
0:10:30 So does this mean that prior to the beginning of the second trimester,
0:10:35 because the SRY transcription factor isn’t active yet,
0:10:39 that the brain of the fetus is essentially identical between males and females?
0:10:40 That’s the thinking, yes.
0:10:41 Yeah.
0:10:42 And that same is true in the mouse.
0:10:46 In fact, in the mouse, which is our model organism in the laboratory,
0:10:50 the brain is thought to be bipotential right almost until birth.
0:10:51 Really?
0:10:51 Yes.
0:10:53 And I’m sure we’ll get into this,
0:10:57 but the organizing effect of testosterone, as we sort of talked about,
0:11:02 can, in fact, be detected even as late as after birth in the mouse.
0:11:06 So you can take a female mouse at birth and give it testosterone,
0:11:09 and you can masternize her behaviors down the road.
0:11:10 But she doesn’t have testes.
0:11:11 That’s right.
0:11:13 So the simple act of giving testosterone will do that.
0:11:16 So that’s the organizing action of testosterone,
0:11:21 irreversible differentiation of a bipotential brain along a male pathway with testosterone.
0:11:24 Okay, but in humans, as early as the second trimester beginning,
0:11:28 the SRY transcription factor kicks on.
0:11:28 Yes.
0:11:31 My understanding, based on my training from some years ago,
0:11:34 hopefully this is still true, you’ll correct me if it’s not,
0:11:40 is that some of the genes downstream of SRY start to suppress the Mullerian ducts,
0:11:41 the fallopian tubes,
0:11:46 and instead you get testes and the vasodeferins and, you know,
0:11:53 basically all the structure for delivering sperm out of the penis for copulation later in life.
0:11:53 That’s right.
0:11:58 So SRY sort of takes the gonad, makes it into a testes.
0:12:00 The testes secretes at least two hormones that we know about
0:12:02 that are very important for sexual differentiation.
0:12:05 One is testosterone, which, you know, people have heard about,
0:12:07 and the other is an anti-malarian hormone.
0:12:11 And this hormone from the testes sort of suppresses differentiation of the uterus
0:12:17 and the vaginal tract, okay, and the fallopian tubes and the ovaries, right?
0:12:20 So you get a testes that, you know, suppresses female gonadal development,
0:12:21 genitalia development,
0:12:25 and you have testosterone that takes the bipodential genitalia
0:12:28 and then masculinizes them and you get a penis and a scrotal sac.
0:12:32 And what about the role of dihydrotestosterone?
0:12:35 My understanding is that the development of the male brain
0:12:41 and the development of male genitalia was strongly dictated also by dihydrotestosterone.
0:12:45 So the action of dihydrotestosterone, which is a derivative of testosterone
0:12:48 from a single enzyme, you know, 5-alpha reductase,
0:12:51 converts testosterone and makes it into dihydrotestosterone or DHT.
0:12:55 The action of DHT is best understood on the external genitalia.
0:12:59 So DHT acts on the same receptor as testosterone does, the androgen receptor,
0:13:02 except it binds at much higher affinity.
0:13:04 So it’s a much more potent activator of the receptor.
0:13:09 And this activation of the receptor in the external genitalia tissue
0:13:12 really is what gives you masculinization of the penis and the scrotal sac.
0:13:19 So what I’m taking from this is that the hormones themselves shape circuitries in the brain.
0:13:20 We’ll talk about how that happens.
0:13:22 They shape the external genitalia.
0:13:25 But unless you have the SRY transcription factor,
0:13:29 you won’t get the suppression of the ovaries and the Müllerian ducts and all of that stuff.
0:13:34 So it’s not as if the presence of androgens, testosterone and DHT,
0:13:42 to a female XX chromosomal fetus will make that female fetus male.
0:13:46 It’s really the presence of that SRY gene.
0:13:51 You need suppression of femaleness, plus you need amplification of maleness, so to speak.
0:13:52 That’s exactly right, yeah.
0:13:59 Okay, so the reason I’m asking all of this and the reason we’re painting this tapestry of hormones and genes, etc.,
0:14:11 is because, as you know, these days it’s very controversial out there as to when sex versus gender is established.
0:14:21 And some of that, I think, is born of political leanings, but it’s also born of this understanding that there’s perhaps a continuum between masculinity and femininity.
0:14:36 That you can find males that you can find males that are at the extreme stereotype of femaleness in terms of behavior and external morphology, right?
0:14:37 Presence of breasts, etc.
0:14:41 But that there seems to be a continuum of phenotypes.
0:14:50 But when it comes down to the genetic biology, it really is about the presence of this SRY gene.
0:14:52 That seems to be the deterministic factor.
0:14:53 That’s right.
0:14:59 So you can even have SRY sort of hop chromosomes from a Y chromosome onto an autosome.
0:15:00 That’s happened?
0:15:01 That’s happened.
0:15:02 In humans?
0:15:03 In humans and in mice.
0:15:08 And if that happens, you can have a full complement of XX chromosomes.
0:15:11 It can be female, but SRY is sitting on an autosome.
0:15:12 And then that animal becomes a male.
0:15:15 So you can have XX males as well.
0:15:18 So it’s not the Y chromosome per se.
0:15:19 It’s a gene, SRY.
0:15:23 So one gene, SRY, determines maleness or femaleness.
0:15:24 That’s right.
0:15:36 And if you take away SRY, if you mutate it, for example, genetically with experiments in the mouse or naturally occurring mutations in humans, SRY, you know, loss of function of SRY, you will have XY females.
0:15:36 Wow.
0:15:39 It’s really all about SRY.
0:15:40 Yeah.
0:15:53 Like the entire political debate, you know, not sociological debate, but the entire political debate as to whether or not someone is male or female, if you wanted to boil it down to a biological factor, it’s one factor.
0:15:54 It’s SRY.
0:15:55 Yes.
0:15:56 To make a female or a male, yes.
0:15:59 A chromosomal genetic female or male would be SRY.
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0:19:13 A couple of examples that I learned about years ago, tell me if these are still considered true,
0:19:25 that for instance, there are XY people, so they have the SRY gene, they make testosterone and dihydrotestosterone,
0:19:27 but they have a mutant copy of the androgen receptor.
0:19:28 That’s right.
0:19:37 Those people do not have ovaries, so they’re infertile as a female.
0:19:43 They also, however, don’t have testes or the testes don’t descend.
0:19:47 They make testosterone, but the body can’t respond to the testosterone.
0:19:53 So they look female, maybe a little bit smaller breast development, et cetera,
0:19:58 but they look female, but they are infertile as women.
0:20:06 And if you were to rely on the presence of SRY gene as a definition of maleness or being male, they qualify.
0:20:12 If you rely on the presence of testosterone, they qualify, but there have been no action of testosterone.
0:20:17 And so they go through life, at least until puberty, thinking that they’re female.
0:20:18 Is that right?
0:20:18 That’s correct.
0:20:20 The parents think they’re females.
0:20:21 They think they’re females.
0:20:22 They’re piercing their females.
0:20:24 They look completely feminized.
0:20:26 How common is that?
0:20:27 It’s not that common.
0:20:31 I think it’s, I’m going to get the numbers exactly, you know, I’m not going to get the exact numbers right,
0:20:34 but I think it’s one in 10,000 maybe, or one in 20,000.
0:20:39 I mean, these numbers are changing all the time as diagnostic tests get better, but it’s not that common.
0:20:44 But there’s still, that’s still a significant number of human beings you’re talking about.
0:20:55 And then my understanding is there’s also a mutation where people lack the enzyme that converts testosterone to dihydrotestosterone.
0:20:57 So they’re born appearing female.
0:21:01 They have SRY, that gene, this deterministic gene.
0:21:02 They make testosterone.
0:21:04 It doesn’t convert to dihydrotestosterone.
0:21:13 Then puberty rolls around, and they go from having what the parents and they thought was a vagina and a clitoris, and they sprout a penis.
0:21:13 That’s right.
0:21:15 How common is that?
0:21:16 It’s not that common.
0:21:19 I think it’s more common in places where there’s consanguinous marriages.
0:21:23 So, you know, in some villages in some countries, it’s fairly common.
0:21:25 And they even have sort of local dialect names for this condition.
0:21:28 I forget what it’s called in those languages.
0:21:33 But there’s definitely, so it’s called a penis at 12 syndrome in sort of medical textbooks.
0:21:40 Because as you said, there’s part of penis at 12, because the orally penile development and the squirrel sac development depends on DHT,
0:21:43 which is a much more potent activator of the androgen receptors.
0:21:48 If you can’t have DHT, then testosterone alone cannot masculinize the external genitalia.
0:21:50 It’s feminized early on.
0:22:01 But after puberty, when the testosterone levels go up again, that level of testosterone is now sufficient to differentiate the external genitalia into a penis.
0:22:07 So in the strictest sense, the presence of the SRY gene is deterministic for maleness.
0:22:08 Yes.
0:22:10 It’s not even just the Y chromosome.
0:22:14 It’s really SRY gene on the Y chromosome.
0:22:18 Because as you point out, if the SRY gene is on a different chromosome because it got translocated there,
0:22:20 then you still get a male fetus.
0:22:28 Is it also fair to say that the absence of the SRY gene is what determines femaleness?
0:22:33 Or are there a separate set of deterministic genes that designate femaleness?
0:22:38 Some people might be confused by this question only because what I’m not being clear about is
0:22:43 you could imagine that it’s the presence, yes, of SRY that creates maleness.
0:22:45 And in its absence, you just get a female by default.
0:22:52 Or it could be that there’s a deterministic female gene that makes the brain and body of females female.
0:22:53 Right.
0:22:54 So that’s not known in mammals, at least.
0:23:01 There’s no single gene that’s been identified in mammals, in mouse or humans, that determines femaleness.
0:23:08 So no gene that if placed onto a Y chromosome would drive the differentiation of that fetus to female.
0:23:09 That’s right.
0:23:09 Okay.
0:23:12 What does that tell us about human evolution?
0:23:14 I don’t know what it says about evolution.
0:23:23 It says that there’s a genetically programmed pathway that in the fetus in the absence of SRY will give you a female body and a brain.
0:23:27 So that pathway, the genetic program exists.
0:23:31 And that SRY sort of temps it down and boosts maleness.
0:23:32 Okay.
0:23:35 I want to get back to sex differentiation and behavior in a moment.
0:23:43 But I want you to tell me if the news report from a few years ago, the California condors can reproduce from two females.
0:23:44 Is that true?
0:23:46 I’ve not seen that report.
0:23:47 I don’t know.
0:23:47 Okay.
0:23:57 Years ago, when I was at Berkeley, there was a graduate student in our program who was studying a species of moles that live in Tilden Park.
0:24:11 And these moles apparently can transdifferentiate their ovaries into testes depending on the population numbers of males versus females is why I asked about evolution.
0:24:19 You know, you could imagine that if such a capacity existed, that could be very beneficial for the propagation of a species.
0:24:26 Like if you run out of males, a female can turn her ovaries into testes and reproduce with another female.
0:24:31 Or if you run out of females, the males could transdifferentiate their testes into ovaries.
0:24:47 This sort of alludes to the idea that this business of X chromosomes and Y chromosomes and genes on Y chromosomes, in theory, if we were to zoom out from human existence, you know, we’re at one point in human existence.
0:24:54 You could imagine that there was a kind of a larger control over this so that our numbers never run out.
0:24:56 What are your thoughts on that?
0:25:02 I’m not talking about, you know, where the origin of control would be, but how plastic, how variable is this?
0:25:12 Or is it like the SRY gene is on the Y chromosome 99.999% of the time, and therefore, like, these instances of translocation on X chromosomes is kind of rare?
0:25:13 It is rare.
0:25:21 So let me point out that SRY is not even determining sex across all vertebrates.
0:25:24 Okay, so it’s not as if birds have an SRY.
0:25:30 You know, most genes, as you know, Andrew, many genes, most genes are conserved between, say, birds and humans.
0:25:38 You know, the way you get the axis of the animal developing from front to back, hawks genes, controlled by hawks genes, is very conserved from birds to humans.
0:25:41 And there’s a similar set of genes even in flies.
0:25:43 Even the placement of the eyes.
0:25:43 That’s right.
0:25:44 One gene, Pax6.
0:25:45 Pax6.
0:25:46 Places eyes on the front of the head.
0:25:49 So, but SRY is sort of special.
0:25:51 So, birds don’t have an SRY.
0:25:53 Flies don’t have an SRY.
0:25:57 And in fact, SRY has been evolving very quickly.
0:26:04 So, many genes you can take from the human genome and put in the mouse and can get, you know, mouse mutations rescued.
0:26:07 But you can’t do that with SRY.
0:26:16 So, it’s been mutating so fast because it’s sort of important for speciation and protecting the sort of species advantages that led to the development of that species.
0:26:19 So, you can’t take SRY and sort of move it between species.
0:26:28 Not only that, but as you sort of were alluding to, there are many species in which, in vertebrates in which SRY is not even relevant for sexual differentiation and determination.
0:26:32 What happens is, as you pointed out, population densities can regulate that.
0:26:33 Temperature can regulate that.
0:26:34 Sex differentiation.
0:26:38 I think it’s true in alligators and crocodiles, maybe.
0:26:42 And certainly, adult fish can trans-differentiate from female to male as well.
0:26:42 Wow.
0:26:43 I didn’t realize it was that common.
0:26:44 Yeah.
0:26:55 But it makes sense if, for these ectotherms that regulate their temperature based on the environment, look, every species’ main goal is to make more of itself and protect its young.
0:27:01 Protect the advantages it has as a species in the sort of ecological environment it finds itself in.
0:27:02 Right?
0:27:07 So, you sort of close, you don’t exchange gene pools between species, for example.
0:27:07 Right?
0:27:11 Yeah, there’s a whole other discussion years ago.
0:27:22 I think you and I attended a talk where it became, you know, somebody working on Drosophila, you know, a species of fly, said, you know, that Drosophila prefer to mate with Drosophila as opposed to other species.
0:27:35 And this gets a little bit kind of gross slash edgy when you start thinking about, yeah, like, why is it that species maintain reproduction basically within species, one hopes, as well as sex behavior within species?
0:27:38 And as you point out, every species is vying for itself.
0:27:40 In fact, we had a plant biologist on here recently.
0:27:46 The plants are making things to kill off their predators, you know, limit their fecundity.
0:27:53 Let’s talk about how hormones downstream of SRY or the absence of those hormones shape the brain.
0:27:59 Because I think people listening to this certainly know people of both sexes.
0:28:00 Right?
0:28:17 I don’t think it’s that politically edgy to say that most people probably believe that men and women, boys and girls even, respond very differently to the same stimuli.
0:28:18 That’s right.
0:28:23 You know, and the stereotype here is, you know, she started playing with dolls from the beginning.
0:28:33 You know, he picked up a stick and pretended it was a weapon from the moment that he picked up a stick prior to puberty, prior to the testes secreting testosterone.
0:28:41 So what is known about hormone-based differentiation of the brain in terms of maleness and femaleness?
0:28:47 And let’s just, for the moment, suspend all politics, all stereotypes.
0:28:49 Just ask, like, what does the biology say?
0:28:59 So there are a couple of classic experiments in the field done in the 1950s that really speak to this, the sort of organizational differentiation effect of hormones.
0:29:02 And then we’ve done some additional work in the mouse that also relates to this.
0:29:05 And then there are human conditions that can inform this discussion as well.
0:29:10 So the first experiment I would like to talk about is by Charles Phoenix in 1959, I think.
0:29:20 And he did this experiment on guinea pigs, and guinea pigs become female, masculinized or feminized in utero, prenatally, just like humans do.
0:29:34 And if he gave testosterone to the pregnant female, then females that were born to that mother had seen testosterone, their brains had seen testosterone in development in utero.
0:29:42 And when they were born and became adults, very high probability of mating like a male, like sexual mating, you know, having sexual behaviors like a male.
0:29:43 So thrusting behavior.
0:29:44 Thrusting behavior.
0:29:49 And they had very little receptivity, sort of female-type receptive behaviors.
0:29:52 Which in rodents is typically lordosis.
0:29:53 Right.
0:29:54 The arching of the back.
0:29:56 People who have cats know about this, right, for example.
0:29:58 Cats in heat will lordose.
0:30:16 So that, and even if he gave the females, adult females, who had seen testosterone early on, if he gave these adult females boosts with estrogen and progesterone to sort of increase female sexual behavior in these females, they had very little displays of female sexuality.
0:30:18 They’re still mounted like males.
0:30:19 Okay.
0:30:28 So the exposure of females to testosterone in utero sets up a program whereby their sexual behavior appears more male-like.
0:30:28 That’s right.
0:30:30 Thrusting behavior and lack of lordosis.
0:30:35 So there’s a, there’s a, the presence of something and the absence of something.
0:30:35 Correct.
0:30:36 What about aggression?
0:30:38 Were they more aggressive?
0:30:40 That paper didn’t look at aggression.
0:30:41 We’ve done that in the mouse.
0:30:43 And you basically see the same thing.
0:30:48 Now in mouse, sexual differentiation, as we talked about earlier, happens right at birth or just around birth.
0:30:51 So we could take day one pups.
0:30:58 And if you give them testosterone, these females became territorial like males as adults.
0:30:59 Interesting.
0:31:03 So territorialism is a, is a male specific trait?
0:31:03 In mice.
0:31:05 Mice, male mice are territorial.
0:31:10 Female mice, at least in the laboratory, don’t fight as much, except when they’re mothers and nursing a letter.
0:31:12 Maternal aggression is very real.
0:31:13 That’s right.
0:31:14 Is it testosterone mediated?
0:31:16 We don’t, we don’t know.
0:31:17 Interesting.
0:31:19 Okay.
0:31:26 So exposure to testosterone in utero sets up male-like behaviors in female offspring is what I’m hearing.
0:31:39 I’m aware of at least one condition in humans where this might occur, which is when there’s either a tumor or stress-induced stimulation of the, or overstimulation of the adrenal glands.
0:31:49 And of course the adrenals make adrenaline and cortisol, but also they have a layer of cells that produce androstenedione, which is a, an androgen.
0:32:00 What is the outward appearance of female babies born to women who had an overactive adrenal during pregnancy?
0:32:07 Yeah, so I think you’re referring to congenital adrenal hyperplasia, which is, you know, a mutation in an enzyme that typically makes cortisol.
0:32:09 And this happens in the baby itself.
0:32:11 So the baby’s a mutant for this enzyme.
0:32:15 Oh, so the baby’s adrenals are the ones that are disrupted in this condition.
0:32:23 And because they can’t make cortisol, these sort of precursors to cortisol get shunted into making, as you pointed out, androgens.
0:32:26 Because there’s excess precursor, it just gets shunted off into a different pathway.
0:32:32 So these babies, these females, are born with sort of masculinized external genitalia.
0:32:35 Based not on the presence of testes or testosterone.
0:32:36 Or SRY.
0:32:39 But presence of testosterone, of androgens, right?
0:32:42 Because the adrenals are now pumping out androgens rather than cortisol.
0:32:51 Are the androgens that come from the adrenals the same in terms of they bind the androgen receptor just like testosterone would?
0:32:52 So they look like testosterone.
0:32:56 Actually, some years ago, androstenedione was the topic of a lot of news.
0:33:02 Because of Mark McGuire, the baseball player, was accused of taking Androstenedione.
0:33:08 I mean, it’s not hard to see the differences in his physical size from one season to the next.
0:33:11 Whether or not he did that or not, I don’t know if it was ever confirmed.
0:33:12 I think it was.
0:33:13 I see.
0:33:14 We can ask him.
0:33:18 I don’t want to put anything on him that wasn’t true.
0:33:19 But that’s what the news claimed.
0:33:22 And you could buy androstenedione in the GNC.
0:33:28 But the adrenals make testosterone-like substances.
0:33:28 Androgens.
0:33:33 In this person that doesn’t have the capacity to make enough cortisol.
0:33:36 So what does the female offspring look like?
0:33:39 She has sort of masternized external genitalia.
0:33:43 And that can be surgically corrected because now doctors are aware of this condition.
0:33:45 So they can surgically sort of correct that.
0:33:50 And you can give the baby, when she’s born, cortisol because that’s absolutely essential for survival.
0:33:54 So she’s XX, genetically female.
0:33:56 She has no SRY gene.
0:33:59 She made too much testosterone in utero.
0:34:03 So the clitoris resembles a penis, more or less.
0:34:04 Yes.
0:34:08 And the reason I say more or less is not to be facetious.
0:34:11 It’s that there’s a continuum there, right?
0:34:15 And it depends on exactly when the androgens kicked in from the adrenals, yeah.
0:34:20 So it could be an enlarged clitoris, or it could be a small penis, or it could be a normal-sized penis.
0:34:21 It just depends on how much androgen.
0:34:23 She’s virilized, as we say, right?
0:34:24 Virilized.
0:34:24 Okay.
0:34:25 Does she have facial hair?
0:34:26 As a baby, no.
0:34:27 Okay.
0:34:28 Later?
0:34:29 No.
0:34:31 I mean, there’s surgically corrected for, right, as I pointed out.
0:34:33 You give cortisol to the females.
0:34:38 But she’s fertile as a female because she still makes ovaries because she doesn’t have the SRY gene, correct?
0:34:39 Yeah.
0:34:39 Wow.
0:34:40 All right.
0:34:45 What about stress-induced androgen release in the pregnant mother?
0:34:47 Does that arrive to the fetus?
0:34:49 So let’s assume there’s a female fetus.
0:34:52 Everything’s progressing normally.
0:34:55 She has normal adrenal function.
0:35:02 But mom, who also has normal adrenals, no CH mutation, goes through a period of extreme stress.
0:35:05 She’s making a lot of cortisol, but also a lot of androstenedione.
0:35:11 Or maybe she has a challenge stress that requires she produce more androgens, which happens.
0:35:13 Does the baby see those androgens?
0:35:18 And does it partially masculinize or virilize, as you said, the fetus?
0:35:21 There’s no reason why the baby won’t see the testosterone or the androgens.
0:35:24 Because it’s lipid, it should cross over into cells.
0:35:28 Whether or not it affects her behavior, I don’t know, actually, the human data on that.
0:35:30 Or whether or not it virilizes, I don’t know the data on that.
0:35:33 But we know stress during pregnancy is not good.
0:35:34 It’s not good, yeah.
0:35:38 It’s associated with higher incidence of schizophrenia and things like that.
0:35:41 But we don’t know that it’s because of stress-induced release of androgens.
0:35:42 Is that right?
0:35:42 Yeah, okay.
0:35:43 It is adamal, right.
0:35:50 I think it’s just an important thing to distinguish because people will hear, oh, goodness, I had a stressful second trimester or something of that sort.
0:35:57 To step back for a moment before going into more of these kind of naturally occurring experiments.
0:36:00 I don’t know if that’s the proper way to think about it.
0:36:02 But they are, they’re naturally occurring outcomes.
0:36:10 How much variation is there in terms of masculine to feminine phenotypes at birth?
0:36:12 Has anyone ever looked at that?
0:36:15 You know, I mean, we sort of present, like, you know, it’s a baby girl.
0:36:16 It’s a girl.
0:36:17 It’s a boy, right?
0:36:19 You know, the gender reveal thing or whatever.
0:36:22 You know, on the ultrasound, it’s a boy.
0:36:24 Okay, there’s no penis.
0:36:24 It’s a girl.
0:36:32 You know, and there’s other markers too, you know, that people have gotten quite good at recognizing male versus female fetus on the basis of a number of different things.
0:36:42 But most notably, the absence of a penis is generally driving the conclusion that it’s a female until chromosomal typing.
0:36:43 That’s right.
0:36:49 But what is the range in terms of phenotypes, right?
0:36:50 Has anyone ever actually explored that?
0:36:55 I think Johns Hopkins had a program to do that back in the, you know, about 50 years ago.
0:37:03 And I think back then, at least, it was just the size of the penis that said, this is a boy or not, or the external genitalia.
0:37:05 I don’t know what the current criteria are.
0:37:06 I’m not a practicing MD.
0:37:08 You are an MD, though.
0:37:08 I am an MD.
0:37:09 I don’t practice that, yes.
0:37:12 So I don’t know what the current criteria are.
0:37:14 But with karyotyping, you can easily tell.
0:37:16 You look whether or not it’s XX or XY.
0:37:16 That’s right.
0:37:17 Okay.
0:37:18 Well, thank you for saying that.
0:37:31 Because the reason I asked that question is that some years ago, there were these reports of people who had grown up being treated as a male, having received testosterone injections or something like that.
0:37:35 And then later discovered that they have XX chromosomes.
0:37:47 Other people reported having XX chromosomes, never been treated with anything, but they thought they were, you know, appeared male because they had one of these conditions that increased testosterone.
0:38:01 And my understanding at the time was that the level of okayness, I don’t even know what the word is, the level of okayness of the person with how they were raised, oriented very strongly with whether or not they were XX or XY.
0:38:04 Not which hormones they had seen during development.
0:38:22 In other words, if somebody had XX chromosomes, no SRY gene, but was exposed to a lot of androgens, maybe from their adrenals or elsewhere, a drug that the mom was treated with during pregnancy, perhaps, that they would hit puberty and they didn’t feel, quote unquote, right.
0:38:24 And in fact, genetically, they were female.
0:38:28 And then the reverse cases were also true.
0:38:32 And oftentimes these people would seek corrective hormone therapy or surgeries.
0:38:38 So what I’m talking about here is actually the opposite of what we hear so much controversy about today, where people want to switch.
0:38:44 These are people who were forced by their parents and their doctors to be raised a certain way that did not match their chromosomes.
0:38:48 And it generally did not feel good to them.
0:38:48 That’s right.
0:38:55 What does that tell us about the role of genes in establishing maleness or femaleness of the brain?
0:39:05 So we can go back to the condition we talked about earlier, you know, where at puberty you sprout a penis because you had a deficiency in alpha reductase, so you’re not picking DHT, right?
0:39:11 So these kids were raised as girls because the external genitalia looked like they’re feminized.
0:39:17 But as soon as, you know, they hit puberty and they start getting virilized, they get this part of penis, as you put it.
0:39:21 Many of them switch over to being boys and becoming men.
0:39:22 Happily?
0:39:24 I guess so.
0:39:24 I mean, they switch, right?
0:39:25 It’s not forced on them.
0:39:31 Okay, so they voluntarily go in the direction of their XY chromosomes.
0:39:31 Right.
0:39:35 Because in theory, they could, well, it’s tricky because they’re now making testosterone.
0:39:37 So they’re sort of in a…
0:39:38 Well, they’ve always been making testosterone.
0:39:40 It’s just they have not been making DHT.
0:39:42 Sorry to interrupt, but…
0:39:43 No, no, no, please.
0:39:45 You’re being accurate.
0:39:48 So testosterone can still act on the brain, remember, during development.
0:39:52 So what you’re basically saying is that the growth of the penis is largely determined by DHT.
0:39:52 Right.
0:39:53 Early on, yes.
0:39:54 Pre-pubertal.
0:39:57 And then after puberty, it’s controlled by testosterone.
0:39:59 But testosterone is sufficient to drive penile development.
0:39:59 Got it.
0:40:00 Okay.
0:40:02 Goodness, what does this tell us?
0:40:16 Does this tell us again that XX versus XY is really the driver of one’s own sex preference?
0:40:19 And I don’t mean sexual preference for partner.
0:40:22 I mean sex preference, like of their own sexual identity.
0:40:22 Yeah.
0:40:25 At least that’s what these natural variations tell us, right?
0:40:27 These, as you put it, natural experiments tell us.
0:40:35 The same is true for complete androgen insensitivity syndrome in which humans have this mutation in the androgen receptor.
0:40:37 So they can’t see testosterone.
0:40:41 And, you know, as we discussed, they are completely feminized externally.
0:40:45 But they have testes because they’re XY.
0:40:46 Wow.
0:40:46 Right.
0:40:49 So they have testes, but they’re feminized and they think of themselves as females.
0:40:51 They’re racist females.
0:40:51 They look like females.
0:40:55 It’s just that puberty, you know, they don’t start menstruating.
0:41:01 So they go to the clinic, they’re diagnosed as XY with an SRY, but not responsive to testosterone.
0:41:07 So the inability to respond to testosterone sort of masculinized, feminized them.
0:41:12 This is a tricky topic because we haven’t injected kind of how people are socialized.
0:41:18 We haven’t talked about, you know, pink versus blue clothing, which is socialization.
0:41:19 It’s a choice, obviously.
0:41:28 But a strong choice that’s very, you know, statistically, you just see that almost across the board unless people deliberately go against that.
0:41:35 It all seems so clear and straightforward based on the presence or absence of this SRY gene.
0:41:43 Until I start looking at the genetics and I, which I did in anticipation of this episode,
0:41:50 and I discovered that one in 12 people, which is a very high number, is heterozygous for congenital adrenal hyperplasia,
0:41:53 meaning they have one mutant copy, one healthy copy.
0:41:56 They’re fertile, which is probably why it’s so prevalent.
0:42:05 And yet those people make less cortisol and more androgen in response to a stressor.
0:42:12 So then you say, well, okay, maybe as a fetus, they were making a bit more androgen.
0:42:20 So is that going to drive a kind of hyper-maleness or is it going to be in an XY baby and it’s maybe going to drive a little bit more maleness,
0:42:23 a little bit less femaleness in an XX baby?
0:42:25 I mean, it starts getting really tricky.
0:42:26 It is very tricky.
0:42:34 What is known is that boys who have congenital adrenal hyperplasia seem to be completely like boys.
0:42:35 They’re fertile.
0:42:36 Fertile.
0:42:39 And the behavior seems to be unchanged as well.
0:42:40 So it’s not as if they’re hyper.
0:42:42 They’re not hyper-masculinized.
0:42:43 They’re not hyper-masculinized.
0:42:44 At least that’s what the data suggests, yes.
0:42:47 But of course, we don’t know what the measures are.
0:42:48 We don’t know what the measures are.
0:42:51 And we don’t know what social, cultural exposures they had as well in the environment.
0:42:56 Having grown up in a very conventional home with respect to these things,
0:43:01 I mean, it’s like looking back and comparing to what I see now, it’s so vastly different.
0:43:03 And I was born in 1975.
0:43:07 So it kind of blows my mind how different things are even in the last, you know, 20, 30 years
0:43:09 in terms of how boys and girls are socialized.
0:43:15 I mean, things were, I remember the first television show coming out in the, I forget when it came
0:43:19 out exactly, but all in the family where like the mother is going to work.
0:43:23 You know, this was like a revolutionary thing at the time, right?
0:43:25 But it wasn’t terribly long ago.
0:43:31 Okay, so let’s talk about hormones shaping brain structure and function.
0:43:36 What are some of the anatomical and or functional differences in brains?
0:43:40 Let’s stay with the most typical scenario.
0:43:51 XY chromosomes makes testosterone, makes DHT, all the receptors are functional versus XX, no SRY
0:44:00 gene, all the stuff, testosterone and estrogen are functional, receptors are functional, the
0:44:00 typical pattern.
0:44:01 Yes.
0:44:06 How are the brains of those babies and later adults different?
0:44:07 What do we know about that?
0:44:08 Yeah.
0:44:13 So there are a lot of cells in the brain that express receptors for testosterone, androgen receptor,
0:44:15 and estrogen and progesterone.
0:44:20 So people have looked over the last 40, 50 years to see how these cells are responding to
0:44:21 these hormones.
0:44:28 And it seems that at least one major theme that emerges is that early on, at least in
0:44:32 the mouse, right, this is, you can still see that the brain is by potential at the first
0:44:32 day of life.
0:44:35 It looks sort of somewhat neutral.
0:44:40 And then if you have testosterone, then in some brain regions, more neurons will survive.
0:44:44 And in those regions in the female, those neurons would die.
0:44:51 So then as adults, you end up with a male brain that has more neurons in one region compared
0:44:51 to a female.
0:44:55 And conversely, in the female brain, there are structures that, you know, survive.
0:44:57 And the males, you lose cells.
0:45:02 So in those structures in the adult, females will have more neurons than males or cells in
0:45:02 males.
0:45:08 So you have cell death that can be sex-specific, you know, female-specific or male-specific.
0:45:10 Actually, I should step back.
0:45:11 It’s not specific.
0:45:12 It’s more statistical.
0:45:15 There are more cell death in one than the other.
0:45:18 So you end up with different numbers of neurons in the adult animal.
0:45:21 And you’re not getting those neurons back.
0:45:22 You’re not getting those neurons back.
0:45:25 And the same is true for connectivity.
0:45:36 So it’s fair to say that as a consequence of genes and hormones in utero, males have certain
0:45:39 neurons and circuits that females don’t have.
0:45:42 And females have certain neurons and circuits that males don’t have.
0:45:50 And it doesn’t matter how much testosterone or estrogen you put into the adult of those people.
0:45:52 They’re not getting those circuits back.
0:45:53 Right.
0:45:55 In utero, they’re the same.
0:46:00 Where once they’ve been exposed to testosterone or estrogen and progesterone, you get cell loss
0:46:01 in one or the other sex.
0:46:05 And once you get that cell loss, you’re not going to recover that as an adult.
0:46:12 Is there any evidence in humans or in mouse that the loss of these cells or the maintenance
0:46:15 of these cells, we can look at it through either lens, is along a continuum?
0:46:19 Or is it a pretty strict divide?
0:46:23 Like if we were to plot the number of cells in one of these brain areas, would it be a binary
0:46:31 distribution where you get a big pile of neurons on one side of the graph?
0:46:35 And many fewer in the female with a big trough between?
0:46:37 Or are we talking about a more single hump?
0:46:39 In some regions, it looks pretty binary.
0:46:45 And these are regions that control innate behaviors, like mating or aggression, for example.
0:46:47 But in others, there’s going to be overlap.
0:46:52 And the animals we work in, in the mouse, they’re sort of specifically bred to be genetically identical
0:46:53 to each other.
0:46:57 So we can sort of really parse out what the differences look like.
0:47:00 And if you will, there are more extreme examples, these animals.
0:47:04 And there, in some regions, we can really see that, you know, there’s always about two
0:47:08 to threefold more cells in one sex compared to the other.
0:47:11 And that’s pretty much true for all animals for that region.
0:47:14 But other regions, there might be more overlap.
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0:50:31 To remove some of the sociological, political, and other sorts of biases that understandably
0:50:33 kind of get into people’s minds when you start talking about this.
0:50:43 If you just look back in history, were there examples of intersex people just born of, you
0:50:47 know, without any knowledge of chromosomes, without any knowledge of hormones?
0:50:54 People intuitively understood hormones, but based on damage to the testes or things like
0:50:54 that, right?
0:50:55 What would happen?
0:50:57 But I think you get the idea.
0:51:05 But were there examples that were cultures where it was kind of understood that this was
0:51:05 along a continuum?
0:51:09 Because everything you’re describing makes it sound pretty darn binary.
0:51:15 And, you know, again, this isn’t a political discussion.
0:51:16 It’s a biological discussion.
0:51:18 SRY, yes or no?
0:51:18 Yes.
0:51:20 That seems to be pretty much what it’s about.
0:51:21 Yeah.
0:51:22 So, but there are cultures.
0:51:25 I mean, we mentioned about these consanguineous marriages where people, you know, would have
0:51:30 kids, where they would look feminized early on because they have a deficiency in the 5-alpha
0:51:32 reductase, no DHT production.
0:51:36 And then at 12, they would become, you know, masculinized.
0:51:36 They would sprout a penis.
0:51:38 But never in the other direction.
0:51:39 No.
0:51:41 Males converting to females.
0:51:41 Right.
0:51:42 Yeah.
0:51:43 Physically, no.
0:51:43 Right.
0:51:47 So at least in these cultures, it’s a known thing that there will be…
0:51:51 a subset of kids who are born with this, if you will, intersex condition.
0:51:52 Right.
0:51:55 And there are descriptions of, you know, what people used to call, it’s no longer politically
0:51:57 correct to call them hermaphrodites.
0:52:00 But there are examples of, you know, intersex individuals across history.
0:52:02 Hermaphrodite is not a politically correct…
0:52:03 That’s what I’ve been told.
0:52:05 Intersex is the medically sort of accepted term.
0:52:05 Got it.
0:52:10 And people have also known that testosterone or hormones, sex hormones, play a huge role
0:52:12 in regulating behavior, right?
0:52:18 So eunuchs and castrates, castratis, have been used in palaces and courts sort of to guard
0:52:20 harems, for example.
0:52:21 That was the motivation?
0:52:22 Yep.
0:52:30 Wouldn’t you favor a more aggressive, testicularly intact male if you think the goal is protection?
0:52:34 I think the idea was that if you had, you know, a castrate guarding a harem of females, then
0:52:37 they can’t sort of, you know, have sexual behavior with them.
0:52:38 They can’t have sex with them.
0:52:39 Oh, they weren’t going to do what the cuttlefish do.
0:52:40 Right.
0:52:45 Cuttlefish males will pretend they’re females, befriend females, and then they’ll mate with
0:52:45 them.
0:52:49 And also in opera singing, right, you would have castratis who would have a high-pitched voice.
0:52:54 And they were castrated early in life to maintain the high-pitched voice.
0:52:54 Yes.
0:52:58 Anyway, I’m just going to refrain from any…
0:53:02 I mean, the poor kids that presumably they didn’t get a choice.
0:53:03 Presumably, yeah.
0:53:04 Yikes.
0:53:06 Okay.
0:53:14 So here’s where I’m stuck, right?
0:53:21 I can hear all this biology, and it’s very clear that the genes and hormones are affecting
0:53:23 peripheral, what we call phenotypes.
0:53:25 Presence or absence of penis.
0:53:27 Presence or absence of descended testes.
0:53:29 Presence or absence of menstruation.
0:53:34 But in the brain, it just seems that there are different circuits that kind of pile up more
0:53:37 neurons or maintain more neurons in males versus females.
0:53:40 In females, what are the circuits that get favored?
0:53:44 Are they circuits for lactation, for child rearing?
0:53:45 I mean…
0:53:46 For sexual behavior, for example.
0:53:48 Ovulation.
0:53:53 So cells that control ovulation, for example, would be very dimorphic.
0:53:55 But not in terms of behavior, right?
0:53:58 Like, it seems like it’s the presence or absence of rough and tumble play.
0:54:01 Presence or absence of thrusting behavior.
0:54:06 I mean, maybe this is for historical reasons, or maybe it’s for biological reasons.
0:54:13 But I guess what I’m getting at here is, what are the things that babies that are XX, that
0:54:16 are females, how are their brains specialized?
0:54:20 I mean, or is it just the absence of copulatory thrusting and aggressive behavior?
0:54:23 It seems to me that there would be circuits that were female-specific.
0:54:24 That’s right.
0:54:27 So there are circuits that are specific of female sexual behavior.
0:54:29 So you can take an adult male, for example.
0:54:33 And you can remove testosterone, you can castrate him.
0:54:36 And you can give him female hormones, estrogen and progesterone.
0:54:38 And ask, this is in mice now.
0:54:44 You can ask, will he now be sexually receptive, will he lardose, like a female mouse would?
0:54:45 Arched back, sexual…
0:54:46 Arched back, that’s right.
0:54:47 Sexual deceptivity posture.
0:54:49 And in most cases, he won’t.
0:54:50 He won’t?
0:54:51 No, he won’t, because the circuit’s missing.
0:54:53 Right, the neurons just aren’t there.
0:54:53 That’s right.
0:54:55 Or at least they’re not responsive to the hormones.
0:54:59 We don’t know if the circuit’s there, but it’s not responding to hormones, or we don’t
0:55:00 know if the circuit’s not there.
0:55:05 We now know that there are connections in the female brain that are simply missing in
0:55:05 the male brain.
0:55:09 And these connections are from neurons that regulate sexual behavior.
0:55:13 So we know that some circuits are missing in the male brain for female sexual behavior.
0:55:22 So lordosis behavior in females seems to be a very XX chromosomal-driven outcome.
0:55:25 But it’s not as black and white like that.
0:55:30 There are circuits that seem to be conserved in both sexes for the behavior of the
0:55:31 opposite sex.
0:55:33 And I’ll give you two examples of that.
0:55:39 If you take an adult female mouse, and this is an experiment done in the 70s by David Edwards
0:55:40 and Catherine Berge.
0:55:42 It’s a really beautiful experiment.
0:55:45 And it came around because he was doing a control experiment.
0:55:50 He was simply giving testosterone to adult females, adult female mice.
0:55:59 And the idea was to sort of see if he got the same results as, you know, Charles Phoenix did
0:55:59 with guinea pigs.
0:56:04 So he gave testosterone to young females at birth, as well as to adult females.
0:56:05 And the adult females were controlled.
0:56:09 The idea was, will these females mount like males if they’ve seen testosterone early on?
0:56:15 The surprising result that he got was that adult females given testosterone mounted like males.
0:56:20 So they have the circuit for male sexual behavior, but it’s not activated because there’s no
0:56:20 testosterone.
0:56:26 Similarly, if you take, and this is work by Catherine DeLocke at Harvard, if you take mice
0:56:32 and you sort of remove pheromone sensing from them, you know, pheromones are these chemical
0:56:38 cues that animals use to sort of recognize sex and social status of other individuals of
0:56:44 their species, if you sort of disable pheromone sensing in mice, females will now show male-type
0:56:45 sexual behavior.
0:56:50 It’s as if that pheromonal input is inhibiting male sexual behavior.
0:56:54 But if you take away the pheromone sensing capacity, then the females will start mounting
0:56:55 like males.
0:57:02 So you have at least two sort of control mechanisms, if you will, to inhibit adult male sexual behavior
0:57:03 in adult female mice.
0:57:08 One is the essence of testosterone, or very low levels of testosterone, and the other is
0:57:13 the sort of pheromonal input, this chemosensory, olfactory input that is inhibiting male sexual
0:57:13 behavior.
0:57:17 You take either one of those, I mean, you give testosterone or you take away the inhibition
0:57:19 from those pheromones, you get male sexual behavior.
0:57:24 So it seems that parts of the circuit for male sexual behavior to display the behavior are
0:57:24 there.
0:57:27 In the female, in the adult female brain.
0:57:32 So in some cases, the circuit seems to be missing, like the female sexual behavior circuit,
0:57:37 because you can give an adult male estrogen and progesterone to mimic estrus or heat, and
0:57:37 he doesn’t learn those.
0:57:43 But you can take an adult female and give her testosterone, and she will have, you know,
0:57:44 she’ll show sexual behavior like a male.
0:57:49 And because it’s probably in the back of people’s minds, and because I’m very familiar with this
0:57:58 literature, I should just point out that all data point to the fact that you don’t see
0:58:07 market differences in androgens or estrogen if you were to look between women who define
0:58:15 themselves as heterosexual versus homosexual, so heterosexual women versus lesbians, or heterosexual
0:58:16 men versus homosexual men.
0:58:23 If anything, the data point to homosexual men having higher levels of testosterone.
0:58:29 It’s been difficult to tease apart from some lifestyle and behavioral things, but when teased
0:58:35 apart, and it’s been done, you’re not going to find anything that screams hormone levels
0:58:36 define sexual orientation.
0:58:38 You just don’t find that.
0:58:39 You don’t see that, no.
0:58:45 You see a lot of data that points to changes in utero that may be hormone-driven, but nothing
0:58:47 As adults.
0:58:47 Nothing as adults.
0:58:52 And in fact, if you can take, you know, what we call wild-type male mice, if you will, right,
0:58:58 meaning they’re sort of completely typical or normal male mice, and you can measure their
0:59:04 testosterone levels, and you get a huge range of circulating testosterone in otherwise normal
0:59:07 mice of, you know, about five to tenfold difference in testosterone.
0:59:08 Or humans, for that matter.
0:59:09 Or humans, for that matter.
0:59:12 And they’re still, you know, these mice will still behave like males.
0:59:18 I won’t out this person, but I’m not talking about sexual orientation.
0:59:25 The CEO of one of the most successful media companies in the world came up to me at a gathering
0:59:30 like two years ago, and he said, listen, I have this, I have a problem.
0:59:35 So usually when a guy says that to me, it’s going to be something about testosterone or sexual
0:59:36 dysfunction or something.
0:59:42 And he said, his testosterone is down in the 300s, kind of lower end of reference range.
0:59:43 He said, but I feel great.
0:59:46 He’s like, he’s saying, my libido is great.
0:59:47 My work drive is great.
0:59:48 I feel great.
0:59:52 And I said, well, your free testosterone is probably normal and high.
0:59:54 And he goes, no, that’s also low, but I feel great.
0:59:55 Should I take testosterone?
1:00:00 And I said, listen, I’m not an endocrinologist, but my advice would be no.
1:00:05 So, and I point this out, I think he’s probably in his late 50s, early 60s.
1:00:12 And what he was revealing was, you know, unique among the questions I typically get around
1:00:12 testosterone.
1:00:17 But I think it points to the fact that who knows, maybe he has a higher than normal receptor
1:00:21 density that can make use of those levels of testosterone.
1:00:24 I mean, there’s so many ways in which hormone levels can play out in one direction or another
1:00:25 or something in between.
1:00:26 That’s right.
1:00:28 I think it’s worth people knowing that.
1:00:28 That’s right.
1:00:33 I have so many questions, but this feels like thorny territory.
1:00:39 And I’ve learned when doing this podcast, whenever something feels like thorny territory, that
1:00:40 to go right into it.
1:00:51 These days, we hear a lot, endlessly, it seems, about the debate as to whether or not sex differentiation
1:00:59 and gender are biologically determined or are more mutable than that.
1:01:02 We’re certainly not going to resolve that question here.
1:01:03 Certainly not for everybody.
1:01:05 I’m sure you have your stance and I have mine.
1:01:13 But how is it that we bring together our understanding of sex differentiation versus this gender word,
1:01:14 right?
1:01:17 It seems to me that in a lot of talks you’ve given, you use the word gender.
1:01:20 I know because I’ve listened to those talks and I’ll reveal it now.
1:01:21 We’ve been friends for a long time.
1:01:22 That’s right.
1:01:24 And you’ll sometimes say sex and you’ll sometimes say gender.
1:01:29 And I understand that sex is a confusing word because the moment they hear it, they think of the verb sex.
1:01:30 Right.
1:01:39 How do we think about sex versus gender when it comes to understanding brain and, yeah, just brain?
1:01:41 Let’s just stay with that, not even body.
1:01:45 Because clearly the data in mice and humans point to the fact that the administration of hormones
1:01:46 can change the body.
1:01:49 It can shift things in one direction or the other.
1:01:50 Given at the right time.
1:01:51 Given at the right time.
1:01:52 And we can talk about that.
1:01:55 But what about the brain piece?
1:01:58 How mutable is this?
1:02:01 And what are your thoughts on the controversy?
1:02:03 And how should we be thinking about this?
1:02:04 Forgive me for stumbling.
1:02:07 But it’s not that I’m trying to avoid upsetting anyone.
1:02:11 It’s like we don’t have a good language to differentiate these things.
1:02:16 And I think part of the issue, part of the problem for not having a good language and good understanding
1:02:17 is we don’t have an animal model for it.
1:02:20 Gender is such a human-specific construct.
1:02:26 You know, it’s the sort of constellation of behaviors and expectations generated from within
1:02:30 and by our society and culture about what gender is.
1:02:35 And gender sort of includes not only sort of identification of yourself as a male or a female
1:02:41 or something in between, having sort of attraction for one sex or the other, or not having any attraction for anybody,
1:02:47 or sort of having this sort of comportment of behaviors, like dressing in a particular way,
1:02:51 sort of speaking in a particular way, or having meeting societal expectations.
1:02:53 All of those sort of comprise gender.
1:02:55 And it’s hard to do that in the mouse.
1:02:56 We don’t know enough about mice.
1:03:00 We don’t even know about mice enough to say they have a gender.
1:03:05 We know that they have sexes, females and males, based on SRY, testosterone, estrogen, and progesterone.
1:03:10 So it’s hard to have an animal model for something like this, which is so complex.
1:03:12 And so it seems human-specific.
1:03:21 Well, you said one thing that, at least my understanding, checks off one box,
1:03:30 which is that sexual orientation and how people self-identify in terms of maleness or femaleness is separable.
1:03:33 We know that because there are people who are homosexual.
1:03:39 And we know that because there are people who switch gender by way of hormones,
1:03:42 obviously not from birth, but later in life.
1:03:47 And in many cases, they don’t change sexual orientation.
1:03:48 That’s right.
1:03:49 Sometimes they do.
1:03:52 But my read of the data is that usually they don’t.
1:03:58 In other words, if somebody preferred females before, they might administer hormones, change their body,
1:04:02 but they’ll continue to like females or vice versa, right?
1:04:04 That’s my understanding of the data.
1:04:07 And I went into the data looking prior to this conversation.
1:04:08 And there are a lot of data now.
1:04:11 The problem is it’s difficult to find unbiased data.
1:04:12 I’ll be very honest.
1:04:14 I feel like the data are biased on both sides.
1:04:17 People seem to be arguing for something going in.
1:04:23 Okay, so sexual orientation and how people self-identify, we know is separable.
1:04:27 That’s not a controversial thing.
1:04:28 We just know because that’s what happens.
1:04:34 But when it comes to when people are administered hormones, how that changes the brain in human,
1:04:35 what do we know?
1:04:40 You said it depends on whether or not they’re administered hormones early versus later in life.
1:04:44 Well, I think the early data, and, you know, we talked about congenital adrenal hyperplasia.
1:04:46 We talked about antigen insensitivity syndrome.
1:04:50 Those data really say that hormones at a point in development, maybe in utero,
1:04:57 have a profound effect on masculinization or feminization external as well as of the brain.
1:04:58 Right.
1:05:04 These kids that don’t make DHT, that are raised as girls but later sprout a penis,
1:05:10 are, at least as you described it for all the world, raised as girls and happy being raised.
1:05:17 as girls, identify as girls until testosterone kicks in and then – but it’s interesting, right?
1:05:22 Because their body changes, so it’s unclear to what extent the bodily changes are driving,
1:05:23 the psychological changes.
1:05:29 But presumably if the brain is organized male because they’re XY and they have the SRY gene.
1:05:29 And they have testosterone.
1:05:30 And they have testosterone.
1:05:33 There’s a substrate for it.
1:05:36 Like it’s waiting for that testosterone.
1:05:38 There’s something for it to act on.
1:05:43 And similarly, if you’re insensitive to testosterone, if you have androgen insensitivity syndrome,
1:05:47 then you’ve not seen testosterone sort of biologically.
1:05:50 It’s present in the circulation, but your brain, for example, can’t respond to it.
1:05:52 So you’re feminized externally.
1:05:57 And you’re also behaving as a female all the way through adult life.
1:06:00 So that’s the early action of testosterone, right?
1:06:07 So I think what you’re referring to is people deciding to sort of take hormones at a later
1:06:10 point in life, after birth, much later after birth, to switch genders.
1:06:11 Right.
1:06:18 And maybe the starting place to really understand this is when people take hormones but don’t
1:06:19 want to switch genders.
1:06:26 So these days it’s very common for – more common now for men typically, but women also.
1:06:29 But let’s just say men taking testosterone or augmenting testosterone.
1:06:36 For women to augment estrogen, this is now because of the increasing attention on menopause and
1:06:42 perimenopause and the women’s health initiative and trials that looked at this, it’s very
1:06:48 clear that there are some advantages to estrogen therapy in women who identify as women.
1:06:51 I’m just making this – like I’m trying to simplify this as much as possible.
1:06:58 Our colleague, Robert Sapolsky, who knows a lot about testosterone, has written books about
1:07:04 it, said when somebody increases their testosterone pharmacologically, it just makes them more the
1:07:05 way they are.
1:07:07 If they’re an aggressive jerk, it makes them more an aggressive jerk.
1:07:10 If they’re altruistic, it makes them more altruistic.
1:07:11 But it’s really about hierarchy.
1:07:19 It’s really about a willingness to lean into effort, to suppress amygdala activation, and
1:07:22 to lean into effort within the domains where they feel a lot of agency.
1:07:25 It’s kind of what he describes as the main effect of testosterone.
1:07:33 It’s a little unclear what the main effect of estrogen is when given to a woman in adulthood
1:07:40 besides the ones that have been described like preservation of cognitive function, skin texture,
1:07:47 what, you know, vaginal lubrication, like a bunch of things that are kind of youthful restoration
1:07:48 type phenotypes.
1:07:52 I don’t think there are a lot of data about the psychological changes, but they seem to be
1:07:56 in the direction of feeling better because there are a lot of women now who are seeking estrogen
1:07:57 replacement therapy.
1:08:02 With menopause, there’s a sharp increase in the incidence of Alzheimer’s disease in women,
1:08:02 right?
1:08:07 So as you pointed out, you know, taking estrogen after menopause, if it’s medically sort of,
1:08:12 you know, fined once you’ve consulted your doctor, then that will at least prevent the
1:08:16 decline in cognition because you now have estrogen on board.
1:08:20 So that’s the thinking behind, you know, sort of hormone replacement therapies for cognition
1:08:20 at least.
1:08:28 Coming back to the testosterone thing that you mentioned from Robert Spolsky, we did a
1:08:33 similar experiment in the mouse where we just mutated the antigen receptor only in the
1:08:33 brain.
1:08:37 And this is going to get complicated, I think.
1:08:38 No, it’s a cool experiment.
1:08:43 So penis can respond to testosterone, muscle can respond to testosterone, connective tissue
1:08:45 can respond to testosterone, brain can’t respond.
1:08:48 And you did that from birth in these fields?
1:08:51 It’s going to get interesting because we’re going to have to talk about aromatization now.
1:08:55 So these males are still masculinized.
1:09:00 They just mate and fight less than normal males would.
1:09:02 Okay.
1:09:06 So their brains are a little, it’s, again, there’s a dearth of language here.
1:09:15 But these mice that don’t have testosterone acting on their brain are a little less stereotypically
1:09:15 male.
1:09:16 That’s right.
1:09:16 That’s right.
1:09:19 They fight, but they don’t like to fight as much.
1:09:21 They mark territory, but not so much.
1:09:22 Interesting.
1:09:23 Right.
1:09:25 Someone’s in the comments already saying beta male.
1:09:26 Right.
1:09:28 That’s the kind of YouTube speak.
1:09:33 YouTube, by the way, because it’s male dominated in terms of its audience, is if you look at the
1:09:39 comments on YouTube, not just for this podcast, but other podcasts, it’s a rich data set for
1:09:45 how males compete when anonymous and when physical strength is not involved.
1:09:47 Very interesting.
1:09:59 A lot of hierarchies in comment sections that are removed from the stereotypical kind of notions
1:10:01 of how hierarchies were played out.
1:10:04 Because aggression is, it’s all words.
1:10:05 Right.
1:10:07 And memes.
1:10:12 Well, you mentioned aromatization, so we should tell people what aromatization is.
1:10:14 This always throws people for a loop.
1:10:19 When you tell men that they’re very male-like because of estrogen, freaks them out.
1:10:19 Right.
1:10:20 Well, go ahead, freak them out.
1:10:26 So this all started with classic work by Frank Naftalin in the 70s when he was sort of working
1:10:34 on human embryonic tissue, brain tissue, and he realized that the embryonic human brain contained
1:10:37 an enzyme that converted androgen into estrogen.
1:10:39 And the enzyme is called aromatase.
1:10:44 And this is, in fact, the primary way that the ovaries make estrogen.
1:10:50 They first make testosterone, then gets aromatized by this enzyme aromatase and gets made into
1:10:50 estrogen.
1:10:52 Okay.
1:10:56 So it turns out that Naftalin’s sort of discovery is exactly right.
1:11:01 Even in the mouse brain, in the mouse male brain, we and others have shown that there is aromatase,
1:11:04 the enzyme expressed in very specific circuits in the brain.
1:11:05 Can I just stop?
1:11:07 You mentioned this early experiment by this gentleman.
1:11:08 Yeah.
1:11:09 It was done on human brain tissue.
1:11:10 Yes.
1:11:11 And rats and, you know, others.
1:11:13 It’s a very important point.
1:11:15 I think she will appreciate hearing this.
1:11:21 But a long while ago, I mentioned this thing about aromatization of testosterone to estrogen
1:11:24 is really what masculinizes the male brain.
1:11:29 And a very prominent author in the testosterone space, a female author, wrote to me and said,
1:11:29 It’s just mice.
1:11:36 So, but she’s very scholarly and I think she’ll appreciate hearing that the original data come
1:11:37 from human.
1:11:37 Great.
1:11:38 Thank you.
1:11:40 So it’s not just mice.
1:11:42 Yet another way that we’re conserved.
1:11:48 To be fair, though, I think the idea with what she might have been referring to is that aromatization
1:11:55 in the human brain may not be playing as dominant a role in masculinizing the brain as it does
1:11:57 in rodents and other animals.
1:11:57 Okay.
1:12:01 So that, you know, we can’t really speak to that because you can’t do those experiments in humans.
1:12:08 But if you have a male mouse lacking aromatase, so he can’t make estrogen, then, you know,
1:12:10 his behaviors won’t be masculinized.
1:12:11 He appears more female.
1:12:17 Not appears, behaves more like, doesn’t behave like a male because he’s not converting testosterone
1:12:18 into estrogen.
1:12:21 And this happens very early at birth in mice.
1:12:25 So testosterone gets made by the testes, gets in the brain, gets converted into estrogen.
1:12:30 And then, you know, as we talked about earlier, there are some cells that die or survive depending
1:12:30 on the sex.
1:12:36 And this conversion of testosterone into estrogen enables specific sets of cells in the male
1:12:37 brain to survive.
1:12:43 This is probably a good place for us to inform people that these steroid hormones, testosterone
1:12:48 and estrogen, are very interesting because they can have immediate effects and they can also
1:12:49 change gene expression.
1:12:52 This is a good opportunity for you to teach us some cell biology.
1:12:58 So is it by virtue of the fact that they are lipid soluble, they can go all the way into
1:13:00 the nucleus of a cell?
1:13:03 I mean, you know, this is very different than like dopamine, right?
1:13:04 Dopamine can impact cells.
1:13:05 You know, don’t do this, folks.
1:13:09 But, you know, if you were to take methamphetamine or something, your brain would go very dopaminergic
1:13:10 very fast.
1:13:13 But it’s not going to change gene expression in the short term.
1:13:15 Maybe in the long term, but not in the short term.
1:13:22 But testosterone administration or estrogen administration is literally changing the genes that are expressed
1:13:24 in the cells they interact with.
1:13:26 How does that work?
1:13:27 I mean, what’s going on?
1:13:29 What are they actually controlling?
1:13:35 So the receptors for these hormones, testosterone, estrogen, progesterone, they sit in the satoplasma
1:13:36 of cells, not in the nucleus.
1:13:39 And as you pointed out, these are, you know, steroid hormones are lipids.
1:13:41 They can cross cell boundaries, cell membranes.
1:13:47 And once they bind to the receptor, the receptor bound to the hormone is translocated into the
1:13:52 nucleus, where it finds stretches of DNA that it recognizes.
1:13:57 It sort of sits on them, binds them, and then changes or regulates gene expression of what we
1:13:58 call target genes.
1:14:02 And that’s how, you know, you get gene expression changes by these hormones.
1:14:07 So this is why whenever I hear, like, the Sapolsky argument, which I totally agree with, that,
1:14:11 you know, you give someone testosterone and they become a lot more like themselves.
1:14:14 They don’t – if they’re a nice person, they become that much nicer.
1:14:16 If they’re aggressive, they become that much more aggressive.
1:14:18 But those are short-term studies.
1:14:23 So we don’t really know how the administration of hormones, testosterone or estrogen,
1:14:29 to a self-declared male or female, or X, Y, X, X, doesn’t matter.
1:14:35 The point is that we don’t know how the long-term administration of these hormones literally
1:14:39 changed the genes and therefore the thought patterns and behaviors and feelings of these
1:14:39 people.
1:14:45 You’re basically changing the molecular fingerprints of specific sets of cells in the brain with
1:14:46 hormonal action.
1:14:54 A big debate these days is whether or not people, if they seek to change their gender identity,
1:14:58 whether or not they’re in a position to make that decision because they’re a minor, right?
1:15:05 Myers are not legally allowed to make all sorts of decisions like vote, drive a car, all sorts
1:15:05 of things.
1:15:06 Marry, yes.
1:15:08 Work in this country anyway, work a job.
1:15:10 I think you have to be – used to be 14.
1:15:11 I don’t know what it is now.
1:15:18 But it’s an interesting biological question when you just say, okay, at forgetting all of
1:15:26 that and just asking, okay, what is the condition of a – like a 10-year-old brain versus a 14-year-old
1:15:31 brain that’s entering puberty versus a 16-year-old brain that’s still transitioning through puberty
1:15:37 maybe in late phases of puberty versus 25, which is when we know brain development is more or
1:15:40 less coming to a close, although brain development continues forever.
1:15:47 I mean, how is anyone going to eventually come to an agreement one way or the other on
1:15:47 this?
1:15:53 Is there real biology that we can look at in mice or in humans and say like, okay, here’s
1:15:54 the dynamic tension.
1:16:00 The dynamic tension out there is there are people saying they’re kids that are too young
1:16:03 to know what they are, let alone choose what they want to be.
1:16:07 And then on the other side, you’ve got people battling saying, no, it’s essential to get
1:16:13 in early because then the trajectory is more malleable and then you don’t want somebody
1:16:16 to end up in a place where change isn’t possible.
1:16:21 And then you have people saying, well, wait, they changed gender and then now they want to
1:16:25 reverse later because – and they’re angry that they were allowed to make the decision.
1:16:26 So it’s a mess.
1:16:32 It’s a genuine mess in terms of defining what the key parameters are.
1:16:34 Do you think it will ever be resolved?
1:16:38 Let me step back and say we don’t even know much about this in the mouse yet, right?
1:16:41 So we don’t know what happens to the mouse brain at puberty.
1:16:42 Really?
1:16:47 There are experiments being done, but certainly not the same detail as in the adult mouse brain.
1:16:52 So how circuits are made plastic or how they’re malleable at puberty is still sort of being
1:16:53 worked out in the mouse.
1:16:56 So that’s the first answer.
1:17:02 The second one, the reason I think it’s contentious is A, it’s both deeply personal, what the kids
1:17:07 are feeling, but also there’s these huge sort of societal political forces that come into
1:17:07 play.
1:17:13 So I think the tension there has to be resolved, I think, politically and sort of socially rather
1:17:15 than, you know, just resorting to science.
1:17:19 I think science will give you data, but you will still have to make a decision as to whether
1:17:21 or not, you know, that’ll be allowed.
1:17:23 So I think that’s the reason it is so contentious.
1:17:28 The data is not there in terms of, at least in the mouse or other animal models, or it’s
1:17:30 coming out, it’s coming out slowly.
1:17:34 And socially and politically, it’s very volatile.
1:17:40 Because it’s not clear how you sort of, you know, have kids’ rights, parental rights, societal
1:17:44 expectations intersect and give a result that is satisfactory to everybody.
1:17:47 So that’s where we are.
1:17:49 I’m not saying I’m pro one or against the other.
1:17:52 I’m just saying that’s why it’s so contentious in my mind.
1:17:58 Today is a biological discussion because that’s what we can say things about for sure, right?
1:18:00 We can talk about biology for sure.
1:18:06 The other pieces are, they’re even prone to tripwires related to language.
1:18:10 And that for biologists is no fun.
1:18:17 And the whole reason to become a biologist as opposed to a psychologist is because while
1:18:21 I have tremendous respect for the field, biologists have nomenclature committees.
1:18:25 We agree, this is, because you could make this argument about anything.
1:18:30 Again, by way of example, I mean, you could say, oh, the SRY gene is the SRY gene.
1:18:33 But what if it’s just two amino acids different and it’s still functional?
1:18:34 Is it still the SRY gene?
1:18:37 Well, there are nomenclature committees where people decide yes or no.
1:18:42 You have a community agreement in order to go forward.
1:18:47 And you don’t have that in terms of the discussion around gender, but you have it around the discussion
1:18:49 of sex, right?
1:18:50 And circuits.
1:18:51 And circuits.
1:18:54 So let’s talk about circuits for sex.
1:18:55 Start there.
1:19:02 Let’s start with a recent discovery your laboratory made, which is about sexual behavior in males
1:19:05 and the frequency of sexual behavior.
1:19:19 I think most everyone who has gone through sex education in one form or another understands that males have a refractory period after ejaculation in which they don’t mate again.
1:19:22 And in some cases can’t mate again.
1:19:29 What did you discover about the neural circuits responsible for mating and the refractory period?
1:19:30 Yeah.
1:19:35 So this is in the mouse and we were working in male mice and we sort of hit upon these neurons.
1:19:45 We identified these neurons using genetics that express the specific set of genes in the hypothalamus that if we activate them, male mice no longer have a refractory period.
1:19:51 And the strain of mouse you’re working on has a post-ejaculation refractory period of about four to five days.
1:19:52 Typically.
1:19:52 Typically.
1:19:55 So he won’t mate for up to four days with a female after ejaculation.
1:20:04 So if he is presented a female and they mate, he ejaculates, you remove that female, you give him a new female, he won’t mate with her for four or five days.
1:20:04 Correct.
1:20:08 He’s content or he’s not able or whatever.
1:20:09 Okay.
1:20:12 So we sort of switch these cells on with optogenetics.
1:20:17 You know, we sort of electrically activate these cells with light and they lose their refractory period.
1:20:19 They start mating within a second.
1:20:23 As soon as the light comes on, the cells start firing, they start mating again and they can ejaculate again.
1:20:27 So you reduce the refractory period from four to five days to one second.
1:20:27 That’s right.
1:20:30 How long can they keep this up?
1:20:31 No pun intended.
1:20:32 As long as the light is on, they’ll keep mating.
1:20:35 And you’re not talking about light presented to the eyes.
1:20:39 You’re talking about basically a light-driven way to stimulate the neurons.
1:20:39 That’s right.
1:20:40 What are these neurons?
1:20:41 What are they called?
1:20:43 They’re in the hypothalamus.
1:20:49 They’re in the preoptic area, which is one of the most sexually differentiated areas in the brain across vertebrates.
1:20:53 And they express the gene tachykinin receptor 1, TACR1.
1:20:56 I thought tachykinin is associated with aggression.
1:20:59 Social behaviors, depending on the circuit.
1:21:00 Right?
1:21:02 So flies, it’s been shown.
1:21:05 David Anderson has shown, for example, the tachykinin gene regulates aggression.
1:21:10 In this circuit, in the male mouse, it regulates sexual behavior.
1:21:11 How many neurons?
1:21:14 Maybe about 1,200, 1,500 on each side.
1:21:16 So about 2,000, 2,500 cells total.
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1:23:09 If we were to scale the size of the pre-optic area from the mouse to the human,
1:23:13 back of the envelope calculation, how many neurons is this in humans?
1:23:17 Roughly the same range because the human hypothalamus hasn’t expanded that much.
1:23:19 It’s the human cortex that’s expanded.
1:23:19 Yeah.
1:23:22 We should remind people of this or let them know.
1:23:26 The hypothalamus in your brain is what?
1:23:31 The size of a couple of marbles sitting above the roof of your mouth, controlling all of this stuff.
1:23:31 That’s right.
1:23:42 So in the mouse, these cells account for, about 3,000 cells account for, I don’t know, one ten-thousandth of the mouse brain.
1:23:46 So take the same number to the human brain, which has, you know, 80 billion neurons.
1:23:50 So it’s really a tiny, tiny subset of cells.
1:23:54 So a few thousand, maybe 100,000 on the human, 10,000 on the human.
1:24:01 So if stimulation of these cells reduces the refractory period to essentially zero, one second.
1:24:06 It’s not zero seconds, but, and that’s with the same female, or you can replace females.
1:24:07 He’ll just keep mating.
1:24:11 Without the light, without the activation, he wouldn’t have ejaculated again for four or five days.
1:24:16 So this tells us that these neurons control the entire circuit down to ejaculation.
1:24:22 So, because the words refractory period encompass a bunch of things, right?
1:24:28 The difficulty in achieving erection as easily as one did prior to the first mating.
1:24:36 Presumably this bypasses all the dopamine aspect of it.
1:24:38 What about prolactin controlling the refractory period?
1:24:40 Yeah, I don’t think the data on that is super strong.
1:24:46 I think Susanna Lima has done some work and she doesn’t find any sort of relation with prolactin and refractory period.
1:25:00 Although in humans, there’s a practice of people taking, I forget what the, I’m not pretending to forget what the drug is.
1:25:09 It’s cabergoline, which is a dopaminergic agonist which is used to treat hyperprolactinemia, to reduce prolactin.
1:25:14 And it seems to be very pro-libido in males and females.
1:25:17 People, and I do not recommend this, people take it recreationally.
1:25:28 There’s actually a slippery slope of this where people will take it in an effort to have more sex, but they can’t achieve orgasm.
1:25:32 And so it drives them crazy and they’re institutionalized.
1:25:33 I’m just kidding.
1:25:35 They’re not institutionalized, but it drives them crazy.
1:25:36 And they decide it’s not a good choice.
1:25:39 So, yeah, I mean, I think that’s a great point.
1:25:43 Let me circle back to the same circuit and also sort of take you on a tangent.
1:25:51 I think people with Parkinson’s taking L-DOPA, also augmenting dopamine levels because they are giving the precursor to dopamine, right?
1:25:56 And there are reports in the literature saying that there is an increase in hypersexual type behavior.
1:26:07 You see this in the case that I heard years ago on the radio was of a woman who was taking L-DOPA to treat her Parkinson’s and she became a gambling addict.
1:26:08 That’s right.
1:26:17 So part of the spectrum of sort of taking L-DOPA and Parkinson’s is you become sort of, you get these compulsive behaviors coming out or hypersexual behaviors coming out.
1:26:29 And coming back to our circuit, the TAC-R1, the tachycanine receptor circuit, we also show, we also found that activating these cells leads to dopamine release in the nucleus accumbens.
1:26:30 Oh, interesting.
1:26:37 Which, it will make sense, but these neurons themselves are not responsive to dopamine, are they?
1:26:39 No, they don’t express receptors for dopamine.
1:26:48 They project to the ventral tegmental area, which is dopaminergic, which has a lot of dopamine neurons, and they activate these cells, which then release dopamine in the nucleus accumbens.
1:26:50 So these cells are like switches.
1:26:56 Yes, and they’re also, we think, encoding the rewarding aspects of sexual behavior.
1:26:58 Tell me more about that.
1:27:02 So, you know, people would describe sexual behavior as pleasurable.
1:27:03 It is pleasurable.
1:27:30 About 70 years ago, James Olds and Peter Milner and classic studies showed that there were areas in the brain that if you put an electrode in that region and you gave a rat an option to press a lever to deliver electric current into that brain region, many areas were identified by Olds and Milner where the rats would keep pressing the lever to get a hit of the current, if you will.
1:27:38 And he identified such a rewarding center or reinforcing center in the hypothalamus of the rat.
1:27:40 And he said, this must be the pleasure center for sex.
1:27:44 He had a piece in the Scientific American on this.
1:27:47 But the identity of these cells wasn’t known.
1:27:50 As we talked about, hypothalamus is super complex.
1:27:57 It regulates not only mating and aggression and maternal behaviors, it regulates body temperature, thirst, feeding.
1:27:59 It regulates many different behaviors.
1:28:04 So which cells are sort of encoding, rewarding properties of sexual behavior?
1:28:13 So these TACR1 cells, if you give mice the opportunity to activate these cells with optogenetics.
1:28:17 So instead of pressing a lever, they just poke up their nose in a hole.
1:28:23 And if they poke their nose in a hole that has the correct hole, they get light stimulation into these neurons.
1:28:33 So these mice, once they learn, once they figure out that this port or hole delivers light and therefore electrical activation of these cells, the TACR1 cells, they’ll keep doing that repeatedly.
1:28:34 Got it.
1:28:35 So it says…
1:28:36 They like it.
1:28:36 They love it.
1:28:37 Right.
1:28:39 And in fact, they could be sexually naive.
1:28:40 They could be virgins.
1:28:42 And they still love it.
1:28:49 So this rewarding property of these neurons doesn’t depend on past sexual experience.
1:28:53 These neurons are naturally encoding some form of reward or reinforcing behavior.
1:28:55 Does it require sexual behavior itself?
1:28:57 No, that’s what I said.
1:28:58 So virgin males will do it too.
1:28:59 Oh, you mean while they’re still virgins.
1:29:02 I thought you meant having never had sexual experience before.
1:29:12 This is important because, as you and I know, Dayu Lin’s work from NYU showed that these neurons in the ventromedial hypothalamus,
1:29:14 when stimulated, mice will attack another mouse.
1:29:18 They’ll even attack a glove.
1:29:21 We can put a link to these videos.
1:29:23 They’re very dramatic to see this.
1:29:29 You know, the stimulation of these neurons goes on and they just will attack the glove, attack the other mouse, stop the stimulation, they stop.
1:29:31 It’s like a rage switch.
1:29:36 But if there’s no glove or mouse to attack, they don’t attack anything at all.
1:29:37 They just cruise around their cage.
1:29:39 These neurons are different.
1:29:44 These neurons seem to make the, what you’re calling virgin males.
1:29:47 They’ll work to stimulate these cells.
1:29:51 But are they, I can’t get around this, are they masturbating?
1:29:52 What are they doing?
1:29:55 Well, the brain’s getting activated.
1:29:56 So the center for mating is getting activated.
1:29:58 But what are they doing with that activation?
1:29:59 They’re not doing anything else.
1:30:02 They’re just going into the port again and again and again.
1:30:06 Okay, so in a lot of ways, it’s like these ventromedial hypothalamus neurons.
1:30:07 They need something to mate with.
1:30:10 It’s not like they start mating with the hole in the wall.
1:30:10 No.
1:30:13 It’s not like they start mating with inanimate objects.
1:30:19 They like the feeling of these neurons being stimulated.
1:30:21 But the neurons themselves don’t trigger mating.
1:30:22 Let me step back.
1:30:25 I think we are confusing two things, right?
1:30:25 So not confusing.
1:30:27 We are conflating two things.
1:30:31 One is, do the mice like activation of the neurons?
1:30:32 And the answer is yes.
1:30:35 They love it because they keep doing it, even if they’ve never made it before.
1:30:40 Okay, so the analogous experiment for the Dayu Lin stuff would be, will animals work for stimulation
1:30:41 of the VMH?
1:30:42 And we know the answer is yes.
1:30:45 Male animals will work to fight.
1:30:47 They like to fight.
1:30:51 But if you activate these neurons, just like, you know, if you activate the VMH, you get aggression
1:30:51 towards a glove.
1:30:56 If you activate these neurons and you give them an object, they will try and mount with it,
1:30:57 as long as it looks like a mouse.
1:31:02 So if you give it a toy mouse, the males will try and mount the toy mouse.
1:31:06 But if you give them, say, a, I don’t know, a marble?
1:31:07 No.
1:31:08 A beaker?
1:31:08 No.
1:31:09 A block of, a wooden block?
1:31:10 No.
1:31:12 But if you take a test tube, they won’t mount it.
1:31:18 But if you give, if you take a toy mouse tail and glue it to the test tube, so it now has a,
1:31:21 you know, has some mouse-like elements, they will try and mount it.
1:31:26 Very low threshold for activating the behavior.
1:31:30 Yeah, I think what it says, just like the aggression sort of experiment says, is that there
1:31:35 are these innate circuits, these hardwired circuits, that if you activate them and you
1:31:40 have the right stimulus, the animals will attempt to do the behavior that these circuits are wired
1:31:41 for.
1:31:45 Or even the wrong stimulus, but one that resembles it just barely.
1:31:46 By stimulus, I mean…
1:31:47 I mean, a tail on a test tube?
1:31:48 Come on.
1:31:48 By stimulus, I mean, optogenetic activation.
1:31:52 I mean, I’ve seen some people with some pretty low standards for who they’ll mate with.
1:31:52 No, no.
1:31:55 And what they’ll mate with, but that’s pretty, that’s pretty low.
1:31:58 By red stimulus, I mean by activating these cells with optogenetics.
1:32:04 So if you activate these cells and you give them an inanimate object, if it roughly resembles
1:32:09 something that they’re familiar with, that looks like a mouse in this case, they’ll try and
1:32:09 mount it.
1:32:14 But if you give a mouse with no stimulation of these neurons a test tube with a tail?
1:32:15 Nothing happens.
1:32:18 They’ll sniff it, they’ll sort of, you know, maybe play with it, and then they’ll walk away.
1:32:23 That’s a significant result to reduce the refractory period from four days to, or five
1:32:24 days to one second.
1:32:29 What is the theory as to why there’s a refractory period at all?
1:32:31 Is this female-driven?
1:32:36 Is it based on the female sexual behavior preferences or non-preferences?
1:32:42 Or is it something related to controlling population numbers, like you would end up with, I don’t
1:32:44 know, too many pregnancies from one male?
1:32:45 What’s the idea there?
1:32:49 Actually, every species has a different refractory period.
1:32:53 And in the mouse, you know, because of genetic inbreeding, there are lots of strains of mice.
1:32:56 You know, people have been raising and breeding mice as pets and whatnot.
1:33:01 And different strains of mice will also have different refractory periods.
1:33:08 So there’s definitely sort of a genetic basis for a refractory period that may be species-specific
1:33:09 and also strain-specific in the mouse.
1:33:16 As to why you’ve genetically sort of selected for a specific refractory period in a species,
1:33:17 I think it’s generally unknown.
1:33:25 It could depend on the kinds of mating strategies different species use.
1:33:35 Well, in humans who mate not just to reproduce but also for pleasure, you know, what is known
1:33:41 about the relationship between age and the refractory period duration?
1:33:50 Some years ago, I was reading this book as I did again this weekend about hormones and behavior.
1:33:51 And it’s really interesting.
1:33:57 When you look at the distribution of testosterone levels in males from age, say, 20 up to 90, there’s
1:33:59 a big range at any given age.
1:34:04 And it’s not clear that absolute testosterone numbers are that informative anyway.
1:34:06 But they point in a certain direction.
1:34:13 But you also look at sort of copulatory frequency, sex frequency as a function of age.
1:34:15 And it’s also highly variable.
1:34:22 I mean, there are these famous slash infamous cases of like Frank Lloyd Wright, who was purportedly,
1:34:27 you know, having sex up to, you know, four, five, six, seven times a day and did that well
1:34:31 into his 80s, you know, to the point where his wife at one point was really concerned, like,
1:34:32 is this OK for his health?
1:34:37 And he was also an incredibly productive person in other domains of life.
1:34:42 Also, by the way, an incredible procrastinator, apparently did all his sketches on the like
1:34:44 cab ride over to the deadline.
1:34:51 Like he would, he sort of functioned in this like kind of thoughtful slash impulsive manner,
1:34:52 so people say.
1:34:55 But he certainly never contested these rumors.
1:34:59 And then some people probably just have lower libido, right?
1:35:03 But as a function of age, it is the idea that it’s all testosterone driven.
1:35:08 If testosterone levels drop, then a frequency of mating, assuming someone is, you know, has
1:35:11 a partner that they mate with, drops off.
1:35:12 Like what’s known about this?
1:35:15 As you pointed out, you know, testosterone levels vary all over the place, right?
1:35:20 And it’s not just, you could have normal levels of testosterone, quote unquote normal levels,
1:35:25 and there’s already a huge range of normal titers circulating levels of testosterone.
1:35:28 But also, you could have different deceptor densities.
1:35:29 In different regions.
1:35:36 So it’s hard to just take one parameter, testosterone levels, and say that that correlates with libido
1:35:40 or with the desire to mate in humans.
1:35:46 Why sexual behavior changes or defractive behavior changes, I don’t think it’s generally known.
1:35:51 It could be biological, it could be social, it could be many things.
1:35:58 I neglected to ask the obvious question, which is, do these neurons also exist in the female brain?
1:35:59 Yes, they do.
1:36:02 And what are they controlling in the female brain?
1:36:04 We don’t know yet.
1:36:10 But, each our way, a postdoctoral fellow in my lab, when he was a graduate student,
1:36:17 activated a larger subset of these cells in the preoptic hypothalamus, in the females.
1:36:22 And they all expressed estrogen receptor, estrogen receptor alpha ESR1.
1:36:25 And these females also mated like males.
1:36:27 So this sort of harks back to something we talked about earlier,
1:36:32 that the circuit for male sexual behavior is present in the female brain.
1:36:37 And he sort of identified a node in the female brain that lets them mate like males.
1:36:39 If he activates this optogenetically.
1:36:45 Whether the TACR1 cells that we identified do the same, we don’t know yet.
1:36:46 We’re working on that.
1:36:50 Okay, without getting too down in the nitty-gritty of circuit biology,
1:36:53 but also getting down into the nitty-gritty of circuit biology, I have to know.
1:36:55 So where do these cells connect to?
1:36:57 You mentioned that they’re in communication with the dopamine system
1:37:03 to activate this kind of sense of reward, pleasure, and reinforcement to drive more of the behavior.
1:37:05 Where else are these cells projecting?
1:37:13 I mean, it’s a long way from a couple, you know, from 1,200 neurons to the penis.
1:37:16 What’s in between?
1:37:20 Yeah, so one big area they project to, a really dense projection from these cells,
1:37:22 is to the periaqueductal gray.
1:37:24 An area involved in pain regulation.
1:37:27 And many other sort of innate behavioral displays.
1:37:28 Okay.
1:37:30 So fight or flight, freezing behavior.
1:37:32 And also sort of lordosis behavior.
1:37:35 And for folks that aren’t familiar with neuroanatomy,
1:37:40 the periaqueductal gray sits kind of in the back of the brain, back-ish of the brain.
1:37:43 And I always imagine it kind of like a pizza.
1:37:44 It’s got these like segments.
1:37:45 It has these sectors, yeah.
1:37:49 Like you activate one brain area, it’s involved in suppressing the pain response.
1:37:51 You activate another area, it’s involved in femoral lordosis.
1:37:55 You activate another area, it’s involved in kind of fleeing.
1:37:57 You activate another area, it’s an approach.
1:38:07 So either it hasn’t been parsed finely enough, or it’s – in fact, it’s kind of like a – it’s almost like a mirror of the hypothalamus further back in the brain.
1:38:07 That’s right.
1:38:12 So they project to the PAG, and then from there –
1:38:20 And the PAG goes to the brainstem, it’s already in the back of the brain, as you pointed out, and then goes further down through multiple connections to the spinal cord.
1:38:23 And then it innervates with the bulbal cavernosis or whatever controls –
1:38:26 Penal muscles and the thoracic muscles involved in thrusting and –
1:38:32 It’s a program that’s an innate program.
1:38:43 I mean, most animals have to learn the socialization of mating, dating, consent, all other things, but they don’t have to learn the motor programs.
1:38:45 The motor programs are activated during puberty.
1:38:46 Is that right?
1:38:46 Yeah.
1:38:56 Some years ago, I recall a paper showing that mounting behavior could be both aggressive or reproductive.
1:38:59 What’s the story there?
1:39:01 Because females do it too.
1:39:01 Right.
1:39:04 So you’re saying by aggressive, you mean like a form of dominance display?
1:39:05 Yeah, like jiu-jitsu.
1:39:05 Right.
1:39:11 So it certainly – that’s what people have certainly said, that it could be a dominance display because males will sometimes mount males.
1:39:17 Although once males start fighting and once they’ve had sexual experience, they tend less often to mount other males.
1:39:19 They just go straight for the kill, if you will.
1:39:29 And in other species, you know, many non-human primates, sort of animals will just mount each other as sort of a play behavior or also for giving pleasure.
1:39:30 Right.
1:39:31 So that’s a known thing.
1:39:33 So mount, you know, female-female, male-male mounts.
1:39:35 They will do it as play behavior in non-human primates.
1:39:40 So there are many – presumably many reasons to engage in that sort of behavior.
1:39:43 So it’s not always sexual, is the idea.
1:39:44 Not necessarily, right.
1:39:59 So what other collections of neurons live in this part of our brain that, when activated, give critters, us or otherwise, these kind of supernatural – let’s just say extreme – functions?
1:40:02 Thirst neurons, feeding neurons, right?
1:40:06 So you can activate specific sets of cells that express AGRP, for example, or other sets of cells.
1:40:08 Animals start drinking water or start eating.
1:40:10 Thank you.
1:40:13 I mean within the context of mating and sexual behavior.
1:40:19 Are there, for instance, like neurons that when you stimulate them, mice start building nests?
1:40:22 You don’t have those sets of neurons yet.
1:40:27 But there are certainly sets of neurons in the same vicinity that regulate parenting behaviors, right?
1:40:29 So they’ll start taking care of pups, for example.
1:40:32 So you can take virgin mice who don’t normally take care of pups.
1:40:37 They can activate these circuits and can prevent these mice from hurting the pups.
1:40:42 So normally mice will hurt other mice’ pups.
1:40:43 Yes, not their own, right.
1:40:44 That sucks.
1:40:45 Yeah.
1:40:46 Doesn’t say much for mice.
1:40:46 Right.
1:40:48 Well, a lot of animal species do that.
1:40:49 Yeah.
1:40:49 Right.
1:40:57 They sort of exhibit infanticidal behavior, where there are other species, like voles, that show fostering behavior.
1:40:58 They take care of pups, not their own.
1:41:00 So it depends on the species you’re talking about.
1:41:00 Yeah.
1:41:05 Years ago, I worked with ferrets, and they’re perfectly happy to raise other ferrets.
1:41:11 They kind of don’t even seem to notice if it’s theirs or some other ferrets, pups, kits.
1:41:12 Interesting.
1:41:22 Do you think when people get dogs, bulldogs in particular, I’m just joking, dogs, Nirao has one of the world’s cutest French bulldogs,
1:41:33 that some of the caretaking of dogs activate some of the same circuitries in the brain that are responsible for rearing our own species?
1:41:35 I don’t know, to be honest.
1:41:37 I’m disappointed to hear you say that.
1:41:40 I must say, I’m disappointed.
1:41:48 When I got Costello as a puppy, I’ll never forget that for the first, I don’t know, three weeks that I had him, I had very little appetite.
1:41:57 My work drive was certainly still there, but I just felt like 99% of my cognition was on his well-being.
1:42:00 But that’s certainly true.
1:42:05 And I could have sworn it was a surge in oxytocin or prolactin or something.
1:42:06 No, I didn’t.
1:42:11 I would have had I had the means to do it, but there aren’t very good tests to do that that are sold over the counter.
1:42:12 I should have.
1:42:13 But if I get another puppy, I’ll do it.
1:42:16 Although now I think I’ll go about it a little bit more differently.
1:42:22 But it was my first dog and I was just, it was like all about him.
1:42:25 Nothing else really mattered except the basics of maintaining life.
1:42:27 That’s how parents describe having a newborn.
1:42:29 So that’s certainly true.
1:42:30 Cooper’s our first dog as well.
1:42:36 And, you know, if he needs something, it basically, you know, takes precedence over everything else.
1:42:43 Like feed, if he needs food or if he needs to go out for a walk, then, you know, I have to, I do drop things and I just take care of him.
1:42:44 Yeah.
1:42:44 So that part is certainly true.
1:42:45 So if you…
1:42:47 Yeah, it inhibits selfishness.
1:42:50 Or inhibits your doing other things.
1:42:51 Yes.
1:42:51 Yeah.
1:42:53 Makes you more altruistic, yeah.
1:42:56 This was really just my ploy to bring up oxytocin.
1:42:57 Okay.
1:43:09 We hear that oxytocin is the chemical responsible for bonding between romantic partners, bonding between mother and infant, maybe even bonding between friends, et cetera.
1:43:11 What’s the real deal on oxytocin?
1:43:20 Because I think like so many things in neuroscience that were first discussed in roughly the 90s, early 2000s, we’re getting a lot more data now.
1:43:22 So what’s the real deal on oxytocin?
1:43:26 I’m not trying to burst any oxytocin bubbles, but what’s the deal with oxytocin?
1:43:33 So the paradigm that people have mostly used to study the role of oxytocin in pair bonding in animal models has been the prairie vole.
1:43:38 So these are like mouse-sized rodents with very short tails.
1:43:46 And unlike mice or rats, for that matter, voles, after having sex with one another, they will pair bond for life.
1:43:49 They form these long-term enduring relationships.
1:43:50 Completely monogamous.
1:43:54 Well, they actually just, like humans, they will have extra pair matings as well.
1:43:55 So they will cheat, if you will.
1:43:56 At a Coldplay concert.
1:43:57 Exactly.
1:43:58 Right.
1:44:01 Or, but for the most part, they’re monogamous, right?
1:44:06 So if you give them a potential mate of an opposite text, they will reject it aggressively.
1:44:07 Right?
1:44:17 So they have this monogamous behaviors and classic work from many labs had shown that oxytocin was maybe a really huge driver of the set of monogamous bonding behavior.
1:44:23 So over the last 10, it took us about 10, 15 years to develop the technology to make knockout voles.
1:44:24 And we’ve done that.
1:44:27 And this is a work of really heroic postdocs in my laboratory.
1:44:36 And knocking out the oxytocin receptor in prairie voles, we saw that these voles continued to form pair bonds.
1:44:40 They were just as monogamous as their wild-type siblings were.
1:44:54 So in fairness to oxytocin and to experimental biology generally, when you see an experiment like that, you go, darn, everything we thought about oxytocin is wrong.
1:45:02 Or you say pair bonding is so important that there’s redundancy in the system that other things can compensate.
1:45:04 Which one do you think it is?
1:45:17 So the most likely other candidate is going to be vasopressin because the same folks who had sort of identified oxytocin as being sort of really important for pair bonding had also suggested vasopressin might play sort of, you know, a similar role.
1:45:20 And vasopressin, like oxytocin, is a neuropeptide hormone.
1:45:21 So it’s about nine amino acids.
1:45:23 So it’s a short peptide.
1:45:30 And it binds a different receptor, vasopressin receptor 1A, that regulates pair bonding behavior.
1:45:35 So that’s the next experiment for us is that vasopressin receptor and vasopressin that’s required for pair bonding behavior.
1:45:38 Okay, so we shouldn’t give up on oxytocin just yet.
1:45:39 Let me also step back.
1:45:48 Let me push back against this idea of, I’m going to get some heat for this, for saying that if it’s so important, you want to sort of have redundancies built in the system.
1:45:49 We just talked a while ago about SRY.
1:45:52 You just have one copy.
1:45:53 You just have one SRY.
1:45:55 In fact, it’s only on one chromosome.
1:45:56 So you only have one copy.
1:45:59 If you don’t have it, you’re not going to become a male.
1:46:05 So there’s no redundancy for perhaps the most important decision the embryo is going to make, male or female.
1:46:07 Then there’s no redundancy built in there.
1:46:12 So I think it depends on what process we’re talking about, if there are going to be redundancies or not.
1:46:20 For something extremely critical, if you don’t have a redundancy, then I think it could be that other processes also don’t have as many redundancies as we thought.
1:46:27 Did you think you were going to get some heat because somebody would say, well, that implies the SRY gene is not important and therefore males aren’t important?
1:46:36 No, I think as you and I both were taught during developmental biology classes that we took as grad students, redundancies and sort of multiple pathways regulating a process is a thing.
1:46:41 And it’s definitely true for many things as we’ve learned during development and developmental biology.
1:46:46 But also there may be processes where you don’t have redundancies that are equally important for life.
1:46:50 Where if you don’t have the gene, you’re done.
1:46:53 Because evolution is agnostic, right?
1:46:56 If you’re not successful, it doesn’t care.
1:46:56 It just moves on.
1:46:57 So you won’t reproduce.
1:46:59 Evolution doesn’t care.
1:47:01 If you’re not fit, you’re not fit.
1:47:02 Yeah.
1:47:04 The bad ideas died, literally.
1:47:06 Or the bad experiments died, right.
1:47:07 Okay.
1:47:16 So speaking of hormones and behavior and language and where language can be a little bit complicated, let’s talk about libido.
1:47:18 Most people know what that word means.
1:47:24 It’s a drive to have sex for reproduction or pleasure or both.
1:47:29 And you discover these neurons that effectively eliminate the refractory period.
1:47:34 I don’t know how an animal could mate any faster than once a second.
1:47:35 I guess there’s…
1:47:36 No, it’s after one second.
1:47:37 After one second.
1:47:38 I guess, yeah.
1:47:38 Okay.
1:47:42 So, I mean, there needs to be some time in between.
1:47:46 One second is about as short a refractory period as possible.
1:47:51 But we don’t really know what’s going on in the mind of the mouse.
1:48:00 But when a discovery like this is made, and because of the conservation between the mouse hypothalamus and the human hypothalamus,
1:48:03 I think many people are probably thinking, oh, you know, is this a druggable target?
1:48:10 Is this the sort of thing that could be used to enhance libido or reduce the refractory period in males?
1:48:18 And that opens up a larger discussion, I think, about biology, druggable targets, and sex behavior in humans.
1:48:26 So there is an FDA-approved drug that targets the melanocortin pathway, I believe.
1:48:26 That’s right.
1:48:30 That’s used to enhance libido in females.
1:48:31 That’s right.
1:48:35 Although I hear – I would say if I had, but I’ve never tried it.
1:48:41 But I hear that men take it also, and it has a similar effect, although not as pronounced as in women.
1:48:48 Tell us about melanocortin and why a drug that stimulates melanocortin would increase libido.
1:48:56 And then we’ll talk about whether or not the tachykinin neurons that you discovered represent a good druggable target for increasing male libido.
1:48:56 Right.
1:49:07 So actually, removing melanocortin signaling in the mouse brain in male or female mice does impact sexual behavior in both sexes.
1:49:07 It does, yes?
1:49:08 It does.
1:49:08 Okay.
1:49:12 So it seems to be playing a role in sexual behavior in both sexes.
1:49:18 The effect, though, of melanocortin, of the drug, seems to be, you know, pretty small.
1:49:21 It affects – it helps a subset of women, not all women, I think.
1:49:25 And there are significant side effects as well of – what’s it called?
1:49:25 Vilesi?
1:49:26 Vilesi?
1:49:28 I think the drug is called Vilesi.
1:49:36 And my understanding is melanocortin comes from the medial pituitary and is involved in pigmentation of the skin as well.
1:49:39 So it tends to darken people’s skin.
1:49:42 It can cause hyperpigmentation in some women taking it.
1:49:43 It’s injectable, I think.
1:49:47 So it definitely seems to help a subset of women.
1:49:53 So I think that’s one of the few libido-enhancing drugs out there.
1:49:57 And it’s very different than Viagra, which works in men, as you know, right?
1:50:03 Because Viagra acts on a more peripheral vascular thing.
1:50:04 It doesn’t act on libido.
1:50:06 It acts on the ability to have interaction.
1:50:07 Right.
1:50:08 It’s pro-erectile.
1:50:16 And I think women will take some of these vasodilators as well for enhanced sexual function.
1:50:16 That’s right.
1:50:20 But libido is pretty separable from erectile function.
1:50:25 As you pointed out, libido is more the desire to engage in sexual behavior.
1:50:29 Whereas, you know, erectile function is the ability to enact on that desire.
1:50:32 So those are pretty separable.
1:50:36 And I don’t think there are very many good libido-enhancing drugs for men or for women, right?
1:50:42 We talked about this drug, Viagra, that is helpful and seems to have a positive effect.
1:50:50 But there’s certainly a big dearth out there of drugs that would enhance libido or inhibit libido for that matter.
1:50:50 Right.
1:51:01 I think when people think about drugs that inhibit libido, it’s naturally occurring experiments like opioid use does that, excessive alcohol intake.
1:51:09 Anything that diminishes dopaminergic function will do that.
1:51:18 So after you made this discovery, did people approach you about developing a drug to enhance libido in men and or women?
1:51:22 Yeah, a mutual friend of ours, Mike Eisenberg at Stanford.
1:51:22 Oh, yeah.
1:51:25 He was a guest on this podcast, our head of male sexual health and urology.
1:51:25 Exactly.
1:51:29 He approached me and he says, can we do something about this target?
1:51:31 And I said, there’s no agonist.
1:51:37 There’s no drug that would activate the TAC-R1 receptor that we know about that’s clinically proven to be safe.
1:51:41 There is an antagonist for it that’s clinically, you know, that’s FDA approved.
1:51:42 That’s used for other purposes.
1:51:44 But that would diminish libido.
1:51:45 That would diminish libido.
1:51:50 But did Mike approach you because he has a lot of patients that have diminished libido who want to enhance libido?
1:51:50 That’s right.
1:51:51 That’s exactly right.
1:51:55 Why do you think there’s such a dearth of drugs to enhance libido?
1:52:09 I think for a long time, pharmaceutical companies have stayed away from drugs that act on the CNS because, you know, back in the 90s, there were a lot of studies developing drugs to sort of enhance different functions of the brain.
1:52:10 And there are always some off-target effects.
1:52:13 So companies have typically stayed away from those.
1:52:14 Not SSRIs.
1:52:19 I mean, SSRIs were a boom industry until recently when everybody kind of turned on them.
1:52:20 That’s right.
1:52:24 And I say this every time SSRIs come up.
1:52:26 Yes, they can have pronounced side effects.
1:52:28 No, I don’t think they are always the solution.
1:52:29 Including decreasing libido.
1:52:30 Including decreasing libido.
1:52:37 For certain populations of people like who have a clinically diagnosed OCD, SSRIs have been very helpful.
1:52:40 So we don’t want to completely, you know.
1:52:47 I’m just saying that’s why there’s a general dearth of many, many drugs being developed for different conditions that affect different, you know, different functions.
1:52:50 So drug companies don’t want to make drugs that act on the brain?
1:52:55 I think now there’s a change, right, with GLIP-R1, with the GLIP agonists coming out.
1:52:57 People are suddenly, there’s a huge interest suddenly.
1:52:58 Which drug?
1:53:00 Vigovie and the Zempec.
1:53:02 Oh, for people to lose body fat.
1:53:02 That’s right.
1:53:04 But those act on the brain as well, right?
1:53:12 So there’s now a sudden surge in interest again in developing agonists, if you will, or antagonists, to modulate different pathways in the brain.
1:53:13 Because this is a huge success story.
1:53:15 So now people are energized again, I think.
1:53:25 Well, and if nothing else, those drugs prove that one of the main reasons, perhaps the main reason why so many people are overweight or obese is that they eat more than they burn.
1:53:28 You know, people debated that until very recently.
1:53:30 Now hardly anyone debates that.
1:53:39 People will say, oh, well, it’s the, you need to think about blood sugar regulation and, you know, and, but when it comes down to it, you need to ingest roughly less than you, you burn.
1:53:56 There’s some noise there, but it’s clear that that set of experiments, the healer monster that doesn’t eat very much, which makes a peptide, which then is turned into a drug, makes people not eat as much, boom, you have a trillion dollar industry.
1:54:05 So here you have a discovery where you discover an animal that when these neurons are stimulated can, has kind of an insatiable libido.
1:54:15 So it seems that the appropriate dose of a drug that targets the tachykinin-1 neurons might, might make a reasonable, druggable target.
1:54:16 I would think so, yeah.
1:54:18 Well, someone listening to this will, will take interest.
1:54:27 That’s a, what’s involved, what does it take to, to go from like a desire to make a drug like that to a drug that can go into humans?
1:54:29 I mean, how, first you go preclinical testing, obviously.
1:54:36 Right, first you actually make sure that the circuit exists, that those same neurons in the human brain express the same receptors.
1:54:37 Well, that’s easy to do nowadays, right?
1:54:37 That’s easy to do.
1:54:45 There’s some brain banks, you cut, you take some brain sections from some deceased people who’ve said it’s okay with them and you, and you do the mRNA and C2.
1:54:46 Yeah, okay.
1:54:48 All right, so the neurons are there.
1:54:51 And then you do, what, dose response curves in mice?
1:54:52 That’s right.
1:55:01 And then you do, right, and you go into preclinical trials and ask, are there agonists you can develop that are safe, that have the desired effects with minimal off-target effects?
1:55:12 I promise you that just by virtue of this discussion, somebody, someplace, and I’m not recommending this, is going to develop or acquire a tachykinin peptide and inject that peptide.
1:55:29 The reason I say that is that these GLP agonists that many people are now using were used for many years in the fitness industry by people who would read a couple papers based on animal models and be willing to acquire or develop the peptide and inject the peptide.
1:55:35 Not something I recommend, but you can be absolutely sure that someone will try this.
1:55:41 The reason I say that is that there’s a peptide in the hypothalamus called kispeptin, I think, which regulates puberty.
1:55:42 That’s right.
1:55:47 And there is a subculture of people that take kispeptin as a peptide as a libido enhancer.
1:55:47 That’s right.
1:55:54 I can’t avoid asking because we’re on the topic, but do we know what switches on puberty?
1:55:56 Kispeptin is certainly important, right?
1:56:01 So the mutations and the receptor for kispeptin seem to block puberty in humans and in mice as well.
1:56:03 So there are people that never undergo puberty?
1:56:03 That’s right.
1:56:04 Really?
1:56:06 And it’s a mutation in kispeptin?
1:56:06 Receptor.
1:56:15 Do they grow in size despite not being, like, sexually able to create kids?
1:56:16 What happens?
1:56:21 I think if you don’t undergo puberty, then you are not going to make the hormones, the sex hormones that you’d normally make.
1:56:24 So you don’t get the boost in testosterone or estrogen or progesterone.
1:56:27 So this is where gene therapy is going to be a huge boon to medicine.
1:56:35 I’m curious about the regulation of brain function, changes in brain circuitry, as female hormones change.
1:56:38 During, say, the menstrual cycle.
1:56:40 What is known about that?
1:56:44 How different is the brain at one stage of the cycle versus another?
1:56:45 Okay.
1:56:54 Stepping back, in the rodents, where a lot of this work has been done, we know that the estrous cycle, it’s not, you know, rats or mice to own menstruate, but they still have the ovulatory cycle.
1:57:04 They ovulate once every four to five days, and their hormones, estrogen and progesterone, do change correspondingly, just like they would in non-human primates or in women.
1:57:08 So you have the same hormonal cycle, roughly, and you have the periodic ovulation.
1:57:10 So it’s just compressed into five days?
1:57:10 Into five days.
1:57:10 Okay.
1:57:19 And rats has been known for a while, for about 20, 30 years now, that there are very specific sets of neurons that are responsive to estrogen.
1:57:23 That change the number of dendritic spines.
1:57:30 So these are sort of processes on neurons that receive information from other neurons.
1:57:38 As we know, neurons act in circuits, so neurons are listening to neurons upstream of them, and then transmitting information to other neurons downstream of them.
1:57:47 So some of these connections, the presynaptic connections that are receiving information from other neurons, those spines seem to increase, wax and wane across the estrous cycle.
1:58:01 And we showed in a different finding more recently that neurons that transmit, you know, when they are transmitting information downstream to other neurons, those pathways also change pretty dramatically.
1:58:07 We saw about a threefold increase or decrease every five days in the adult female brain of the circuit.
1:58:08 Wow.
1:58:09 That’s huge.
1:58:09 That’s huge.
1:58:10 Yeah.
1:58:19 And this seemed to be functionally relevant because if you, when the circuit was fully on or was fully mature, when she was ovulating, if we inhibited this pathway, she stopped mating.
1:58:27 And coming back to, sort of going back to an earlier part of the discussion, the circuit seems to be very dimorphic.
1:58:29 This pathway essentially doesn’t exist in the male brain.
1:58:30 Which makes sense.
1:58:31 Which makes sense.
1:58:32 They don’t ovulate.
1:58:38 Are there hormonal fluctuations in males across the day or the week?
1:58:43 I mean, we assume that, you know, testosterone is highest in the morning.
1:58:43 That’s right.
1:58:51 My read of the literature is that there’s a subset of men for which testosterone is actually higher in the afternoon, but in most men it’s going to be highest in the morning.
1:58:55 But we don’t think of hormones as fluctuating in men very much.
1:58:57 Cortisol, yes, but testosterone, not so much.
1:59:04 Is there any evidence of hormonal fluctuations in males that are meaningful or is it just pretty much a, you know, flat line?
1:59:06 In the experiment that we’ve done in mice, it doesn’t seem to be the case.
1:59:10 So you can just give testosterone to, you know, a male mouse.
1:59:16 If you’ve castrated him, you can basically inject it at any given time of day and it’ll have the same effect.
1:59:25 But in females, if you give estrogen and progesterone, it has to be at a very specific time point for you to see the effects of that hormone.
1:59:31 So during the menstrual cycle, it sounds like there’s profound changes in neural circuitry in the female brain.
1:59:31 That’s right.
1:59:32 It’s very dynamic.
1:59:34 Circuits are growing, circuits are disappearing.
1:59:35 Circuits are growing.
1:59:45 And people have seen in women also, women on the pill, for example, or not on the pill across the menstrual cycle, you do see changes in MRI imaging in women as well.
1:59:50 So what’s known about that in terms of blocking ovulation with oral contraception?
1:59:56 No, so I think what I’m just saying is that the brain seems to be all too dynamic, as visualized by imaging in women.
1:59:59 So it’s not just a rodent sort of phenomenon.
2:00:04 It seems to be there’s dynamic processes going on in humans as well across the menstrual cycle.
2:00:07 So what about during pregnancy?
2:00:09 We don’t know.
2:00:10 We don’t know?
2:00:16 There are a couple of reports that say there are circuits that are changing in the mouse brain when she’s pregnant, when mice are pregnant.
2:00:17 Hippocampus grows.
2:00:19 I don’t know that.
2:00:19 Maybe you do.
2:00:25 I recall there was a guy who did a sabbatical in our colleague Lee Chin-Lowe’s lab.
2:00:26 I forget now.
2:00:28 He was from Larry Katz’s lab.
2:00:29 Olfactory guy.
2:00:30 Adi Mizrahi.
2:00:31 Adi Mizrahi.
2:00:32 That’s right.
2:00:37 He showed that the auditory cortex, the circuit and auditory cortex changes, I think.
2:00:41 Mothers, so they’re more attuned to pup vocalizations.
2:00:41 That’s right.
2:00:45 Their auditory cortex changed so they could hear their pups better.
2:00:46 That’s as a mother, so yeah.
2:00:47 That wasn’t during pregnancy.
2:00:49 That was in…
2:00:54 The study might have started in pregnancy, but I’m pretty sure the experiments, the assays were done when she was nursing.
2:01:01 I definitely need more science on how the brain changes during pregnancy, how the mother’s brain changes during pregnancy.
2:01:03 What about menopause?
2:01:17 These days there is appropriately, I think, increasing attention on perimenopause and menopause as very important stages of human development that have not been entirely ignored, but that were largely ignored for a long time.
2:01:24 Now there’s a lot of attention about it, what’s known in terms of brain circuitry changing during menopause?
2:01:29 Because my understanding is one of the most marked changes hormonally is a reduction in estrogen.
2:01:37 So again, these studies are just being done in mice, just starting to be done in a very careful molecular way in the mouse.
2:01:44 And I think the jury’s still out, but it’s clear that cognitive changes happen with menopause.
2:01:48 So the estrogen going down is definitely affecting cognitive performance.
2:01:57 And this is sort of, you know, reported by women too as their mood changing, their appetite changing, and also the steep increase in Alzheimer’s incidence in women.
2:02:12 In mice, I think there’s going to be a lot of focus on the hippocampus, which is involved in learning and memory, and the frontal cortex, where in the non-aged mouse, female mouse, people have seen these dendritic spines waxing and waning across the ester cycle.
2:02:19 So what happens there and what happens to those circuits and, you know, the downstream behavior is something that’s still being investigated.
2:02:31 Yeah, I think we often hear about estrogen and we think only in terms of ovarian function and ovulation, and, you know, that, you know, tucks right in with menopause.
2:02:38 But when we hear about the effect of estrogen in preserving brain function, my understanding is it’s also true for men.
2:02:44 And that one of the ways that it helps preserve brain function is that it helps keep the blood vessels and capillaries very pliable.
2:02:47 It’s very good for the cardiovascular system.
2:02:57 Do we know if any of the reductions in estrogen that occur during menopause are acting directly on neurons, or is this all, like, downstream of reduced blood flow, for instance?
2:02:59 Yeah, I don’t know the answer to that, to be honest.
2:03:01 I suspect there’s going to be both.
2:03:05 There’s certainly going to be direct effects on neurons because neurons express the receptor for estrogen.
2:03:07 Many neurons, not all, express receptors for estrogen.
2:03:10 So estrogen going down is certainly going to affect their function.
2:03:23 Every MD that I’ve had on this podcast who has a specialization in endocrine stuff will say the goal is to keep your estrogen as high as possible without running into side effects.
2:03:38 So when people quash estrogen or when you get males that have, for instance, very high DHT levels and T levels and their estrogen is very low, it’s not a good picture cognitively.
2:03:41 Certainly not in terms of cognitive longevity.
2:03:50 So estrogen is pretty interesting, I think, from the standpoint of its effects on the body, but also as a neuroprotective agent in men and women.
2:03:53 I have all sorts of questions about why that might be.
2:03:57 I solicited for some questions from the internet.
2:03:57 Okay.
2:04:00 Always a dangerous thing to do, but a lot of fun.
2:04:04 And so I’ll ask you some of the more frequent questions.
2:04:10 Feel free to pass on any of these if you don’t feel like you have an answer or want to answer.
2:04:18 One was whether or not men’s hormones cycled throughout the day and talked about an early morning peak in testosterone,
2:04:22 which, by the way, is very correlated with the amount of REM sleep that people get.
2:04:27 It seems like that, if you don’t get enough REM sleep, that might blunt some of that testosterone increase.
2:04:28 Okay.
2:04:30 Here’s a speculative question.
2:04:38 If male and female brains are wired so differently, does that mean they experience reality in fundamentally different ways?
2:04:43 Like maybe we’re not at all having the same experience of life.
2:04:46 Let me answer that from our studies in the mouse.
2:04:56 A fundamental feature of social interactions is the ability to recognize potential mates from potential competitors,
2:05:00 recognize sex of other individuals, female, male.
2:05:02 We do that subconsciously.
2:05:04 You walk into a bar.
2:05:07 You’re subconsciously processing female, male, female, male.
2:05:08 We all do that automatically.
2:05:10 Mice also seem to do that.
2:05:17 And we identified a region of the brain, a set of neurons of the brain, that if we record from these cells,
2:05:24 you and I, if you’re just looking at the activity of these cells, we can say, he’s thinking that’s a female or a male.
2:05:28 So there’s sex recognition going on in the male-mouse brain.
2:05:35 If we record from the same cells in the female brain, those cells seem to be quiescent.
2:05:43 So it seems that male mice and female mice are using different circuits for recognizing females and males within their species.
2:05:52 So they’re wired differently, and they’re recognizing females and males using different pathways.
2:06:02 So that’s, in one sense, having a very different intake of reality, if that makes sense.
2:06:03 If that makes sense.
2:06:26 I’m remembering an early discussion that you and I had, meaning many years ago, where, for whatever reason, you said exactly what you said here, minus the difference between males and females, where you said, you know, as you walk down the street, there’s a process happening beneath your conscious awareness, where you’re going male, female, male, female, male, female.
2:06:33 You’re batching people into these two compartments based on maleness or femaleness.
2:06:37 And in the mind, it’s just happening.
2:06:45 And you said it’s because you need to know whether or not someone’s a potential mate or a potential foe or a potential collaborator.
2:06:52 Based on what you just told us, that females aren’t necessarily making the same calculation the same way.
2:06:54 I have to speculate a bit.
2:06:57 One, they have to know male versus female, right?
2:06:59 Because males could be a threat.
2:07:04 Females could be a threat too, but males are more often a threat to females than other females.
2:07:08 Females can be a collaborator, a friend, or a threat.
2:07:13 Maybe a physical threat, but could be a sociological threat.
2:07:16 I’ve observed this, okay?
2:07:28 And so it makes sense that one of the most fundamental calculations we make as we move through life is batching people into these different compartments.
2:07:31 How plastic do you think that process is?
2:07:36 Like, this sounds like a pretty hardwired thing that is difficult to get people’s minds around.
2:07:38 I mean, now it would never air.
2:07:41 But in the old Saturday Night Live, they had this character, Pat, right?
2:07:49 Which was – you were – was supposed to be neither male nor female or you weren’t supposed to be clear on what Pat was.
2:07:51 And that was the whole basis of the skit.
2:07:55 That was the whole basis of the character that was a repeated character on Saturday Night Live.
2:07:58 I don’t think they’re going to reintroduce Pat.
2:08:10 But that character was an interesting experiment at the time because it introduced this kind of circuit confusion where people didn’t quite know where to place Pat.
2:08:13 The whole basis of the script for it was exactly that.
2:08:15 So how do you think about these things?
2:08:18 I mean, most circuits in the brain are push-pull.
2:08:18 They’re binary.
2:08:21 Mate or fight, right?
2:08:23 Eat or don’t eat.
2:08:25 There isn’t a whole lot of middle ground.
2:08:26 I think it is more nuanced.
2:08:28 It is female-male.
2:08:35 But as you pointed out in humans, you’re going to say, okay, potential mate, potential foe, collaborator, friend, unknown person.
2:08:43 So there are other recognitive pathways feeding into your initial binary classification of female or male.
2:08:47 So it’s not a simple go-no-go decision in humans.
2:08:52 In the mouse world, it’s simpler, at least in the assays that we design.
2:09:02 So in the instance I was telling you about, if you take the male mouse, the sex recognition happens in the first 5 to 10 seconds.
2:09:03 Just like in humans.
2:09:04 Just like in humans.
2:09:05 It just instantly knows.
2:09:07 If you can make the distinction, your brain makes it automatically.
2:09:07 Right.
2:09:10 So first 5 to 10 seconds, right?
2:09:14 And that signal of female or male persists for about 90 seconds.
2:09:17 And it’s much larger facing a female than a male.
2:09:26 So if we artificially, optogenetically activate these cells in the male brain only for 90 seconds and then give him a male,
2:09:31 for the next 15 to 20 minutes, he thinks it’s a female and he’ll try and mate with him.
2:09:39 So that recognitive process has induced a state in the male that says it’s a female.
2:09:46 Although the sensory input that’s coming in, the pheromones that are coming in, the size, the way the animal’s walking around, all screams male.
2:09:48 He thinks it’s a female he tries to mate with him.
2:09:50 So he’s different even though the outside world isn’t.
2:09:50 Right.
2:09:58 And if we inactivate these cells, if we silence these cells or if we kill the cells, and again, we’re talking of, you know, maybe 2,000 cells.
2:10:01 If we kill the cells, he cannot recognize females from males.
2:10:04 Typically, he prefers the smell of a female.
2:10:06 That preference is gone.
2:10:12 And because he can’t say that’s a male or a female, he neither mates with females nor attacks other males.
2:10:14 He will interact with them.
2:10:16 He’ll hang out with them.
2:10:16 He’ll be pretty chill.
2:10:18 He simply won’t mate or fight with them.
2:10:33 So that says that there are some hardwired things, in the mouse brain at least, right, where you can sort of convert those with experiments into yes, go, no, go signals.
2:10:46 But I imagine if you set up more complicated assays, where if the other male is a sibling, then you won’t attack the male, but you won’t mate with them either, as long as you don’t sort of touch the neurons.
2:10:53 So right now, we’re just trying to understand the basic decisions these cells are making, the basic sort of information they’re processing.
2:10:58 And that seems to be, you know, go, no, go, mate, don’t mate, fight.
2:11:07 It seems you want context to matter, but not when survival and reproduction are critical.
2:11:16 I like watching nature shows for a variety of reasons, but there’s an incredible one where these hyenas are attacking a lion, and they’re trying to rip off its testicles.
2:11:22 It’s a pretty convenient way to limit lion numbers, as long as they’re going to kill this lion and eat it.
2:11:26 But even if they don’t succeed in that, they try and castrate the animal.
2:11:29 And another male lion shows up.
2:11:32 And it’s really interesting, because typically those lions would fight.
2:11:40 But in this case, the second male lion is willing to risk his fertility and his life in order to protect the other.
2:11:42 So there’s this higher order calling, right?
2:11:50 It’s like suddenly he has a mission that overrides his desire to be the dominant lion, and it’s just about preserving lions more generally.
2:11:51 That’s right.
2:11:59 Pretty incredible that, you know, as unsophisticated as the lion brain may be, it’s able to just completely switch over.
2:12:13 And I raise this because what you’re describing and what this nature show reveals is that it’s almost like hormones activate circuits, activate repertoires of behaviors.
2:12:23 That we’re sort of like a repertoire machine as opposed to like just having like switches in the brain, which is how we were talking about them earlier.
2:12:27 It’s tempting to think about them as switches, but the context really matters.
2:12:29 Context matters.
2:12:34 And, you know, people have, Tinbergen, for example, has proposed that there’s a hierarchy of behaviors, right?
2:12:39 So you have mating, aggression, protection of young, or defense from predation.
2:12:51 So all of those are sort of have nested regulatory structures, one imagines, as you pointed out with this lion, that if you have a different context, then a different set of behaviors is sort of, you know, activated.
2:12:54 And the same thing’s true for, you know, even aggression, right?
2:13:03 If you take these VMH cells that we’ve talked about before, if you activate them, the animals will attack other males, or females for that matter, or a glove for that matter.
2:13:09 But if you change the context that the animal’s in, your experimental animal’s in, and you activate these cells, he may not attack.
2:13:17 Because in this case, the context is overriding activation of these cells and telling him, no, it might be too dangerous, do not attack.
2:13:25 So if you put him in another resident’s cage, in a different animal’s cage, so it’s no longer his turf, and you activate the cells, he’s much less likely to attack now.
2:13:33 And then there are these experiments, right, that females will kill the offspring of other females.
2:13:35 Females will kill the offspring of other females.
2:13:36 Right.
2:13:43 Unless certain conditions are met, like they’ve already had a litter of their own, they’ve happily raised that litter.
2:13:46 Or they’ve been hanging out with the other female and her pups for a while.
2:13:53 It’s worth mentioning because, you know, I’m not trying to equally distribute violence here, but so often we think about, you know, males and violence.
2:13:58 But maternal aggression is one of the most robust things one will ever observe.
2:14:05 But female-female aggression does exist, and it usually exists in the context of who gets to have and raise successful offspring.
2:14:09 That’s when you see real nastiness emerge.
2:14:22 Yeah, which is, you know, in the context of sexual behavior, we’re yet to get this guest on here, but there’s someone out there that studies female sexual behavior in an interesting way in terms of somewhat evolutionary terms.
2:14:40 But saying that, you know, one of the more pronounced effects that you see is, depending on whether or not someone has had and raised children, how they behave towards other women, or the more salient experiment.
2:14:54 And I need to verify this is actually true, that when apparently there’s a study where they sort of scale the level of attractiveness of women coming in to get a haircut from another heterosexual woman.
2:15:08 And the more attractive a woman is who comes in to get her haircut, the more hair the hairstylist, the female hairstylist cuts off, almost as if there’s a competition and they’re trying to actually damage the competition.
2:15:32 And then other examples where the whole notion of women shaming other women for being promiscuous, the notion being, well, if men can get sex without having to invest much, then that will change the standard of what men expect and will make it less likely that they’ll be able to find a, you know, a safe, happy mate situation to raise kids.
2:15:38 I mean, these are the ideas that spin in the background and you kind of go, okay, well, that’s a just so story.
2:15:48 I probably could explain those data five different other ways, but then you hear the animal data and you go, wow, a lot of this is really about extension and preservation of our species, you know?
2:15:50 All right.
2:15:51 More questions.
2:16:00 This is interesting given our earlier discussion of periaqueductal gray and its involvement in sexual behavior and in pain management.
2:16:07 Is there a difference in the way that males and females experience and attempt to relieve pain?
2:16:14 Do we know anything about the interaction between hormones and pain management as it relates to males and females?
2:16:23 There are a lot of reports saying that males and females have different pain thresholds, but I think it’s been really challenging to dissect out where those differences arise from.
2:16:25 I mean, that’s all I have to say.
2:16:26 So I don’t know much about this.
2:16:30 Because people will say because of the pain of childbirth that women have a higher pain threshold.
2:16:35 And that’s been revealed in some studies, at least to my knowledge.
2:16:39 But that could also be because they’re in a different hormonal state than having a baby, you know?
2:16:40 So.
2:16:42 A lot of natural endorphins released.
2:16:43 Presumably, yeah.
2:16:49 There were a lot of questions about environmental toxins in food, in water.
2:17:09 You know, some of this gets to the atrazine data from Tyrone Hayes from Berkeley who years ago said that atrazine present in the water and that frogs were being exposed to was causing an inversion of sexual behavior in these frogs and disrupting sexual differentiation.
2:17:14 That was, you know, taken and run with in a variety of directions, some accurate, some far from accurate.
2:17:22 But I think nowadays people are very concerned about endocrine disruptors, especially during pregnancy and in early childhood.
2:17:34 And a lot of people are speculating as to whether or not this is one reason that there’s a fair amount of discussion about confusion about gender identity and sexual differentiation.
2:17:35 What are your thoughts on this?
2:17:49 Is it conceivable that things in food, in the environment, which act as endocrine disruptors, are smearing some of the previously clear outcomes for human fetuses?
2:17:58 I think you have to ingest large amounts of these hormones at the right time to, or these modifiers, these modulators to have an effect.
2:18:04 So I don’t know what the kinds of exposures there are, you know, with plastic bottles and whatnot.
2:18:07 I mean, maybe, but it’s, you’d have to have a large exposure.
2:18:09 That’s not to say it doesn’t happen.
2:18:13 There might be species in which it’s really sensitive, so it could happen.
2:18:15 Here’s one thing I know for sure.
2:18:27 Our former friend and colleague, Ben Barris, right, who was born Barbara Barris, was an identical twin, has an identical twin sister that is perfectly happy being a woman.
2:18:31 Ben was definitely not happy being a woman from an early age.
2:18:33 Switched to being Ben.
2:18:48 And for a long time, and I know this because he told me directly, but it’s been documented, he claimed that his mother was treated with an anti-miscarriage drug that had androgenic, pro-testosterone properties.
2:18:57 And he thought that perhaps that had an impact on his gender preference, which is interesting, right?
2:19:03 Because he’s speaking to hormonal influence on gender preference that at least his idea—
2:19:03 Gender identity.
2:19:11 Right, and he can’t know, but he was an MD and a PhD, and he was thoughtful about the biology of sex differentiation, obviously.
2:19:13 So it’s conceivable, right?
2:19:17 He passed away in 2017, so I can’t get his thoughts on this now.
2:19:27 But, you know, he was pretty vocal about the fact that he thought that there were things that—medications and other things that could certainly impact gender identity.
2:19:32 What you’re referring to was a pretty powerful hormonal modulator that he was exposed to, right?
2:19:44 So that is a very different dosage than, you know, you might presumably get from these days from environmental, you know, plastics with modulators that could impact hormone signaling.
2:19:48 That’s a pharmacological dose you’re presumably exposed to.
2:19:49 Right.
2:19:55 And I think that’s a big question nowadays, to what extent these endocrine disruptors are impacting the fetus.
2:20:02 I mean, it has been shown that microplastics are present in the first fecal matter that a baby, you know, excretes.
2:20:13 Whether or not those microplastics are effective endocrine disruptors in the sense that they are causing androgen disruption or estrogen disruption isn’t clear.
2:20:15 Lots to consider.
2:20:18 I mean, there are so many conflicting data.
2:20:22 You know, it’s easy to paint a picture where it’s all about endocrine disruptors pushing things one way or the other.
2:20:28 But our colleague, Mike Eisenberg, has done studies showing that, indeed, testosterone levels and sperm counts are dropping.
2:20:31 But according to data from his lab, penis sizes are going up.
2:20:42 So, you know, the data don’t always fall squarely into like a news article type framework, you know.
2:20:46 And typically, news articles on this stuff pick one or the other side to push for.
2:20:53 What do you want to know most going forward about how sex differences in the brain come about?
2:20:55 Like, what are you most excited about lately?
2:20:57 There are many questions, right?
2:21:06 One is, we still don’t have the identity of all the different social behaviors that animals engage in, that mice engage in, the innate behaviors, right?
2:21:09 So, what are these circuits?
2:21:11 How do they interact with each other?
2:21:17 So, if you’re mating, how do you assess threats and stop mating, for example, right?
2:21:18 So, that’s one level of question.
2:21:20 What are the circuits and how do they interact with each other?
2:21:30 And at the same time, how are they interacting with higher order circuits that, you know, let you navigate, let you make decisions?
2:21:34 What is interaction between cortical cells and hypothalamic cells?
2:21:35 So, that’s a big question, I think.
2:21:45 The other is this thing, this plasticity, this adult dynamic circuit feature that we and others have run into in the female brain, how widespread is it in the brain?
2:21:50 Do males also have such dynamic plasticity in the adult animal?
2:21:50 We don’t know.
2:21:55 And if so, what are the conditions in which the male brain rewires?
2:22:05 And, you know, females undergo different, as we’ve talked about, undergo many different life stages that are pretty unique to females, right?
2:22:08 Lactation is one of them, menopause is another, pregnancies is another, ovulation is another.
2:22:16 So, how are these circuits different across these stages compared to, say, the female who’s not gone through any of those yet?
2:22:22 Those are very interesting questions, especially given the divergence of life choices that you see out there now.
2:22:27 Not everyone is getting married, having kids, and doing that.
2:22:31 I mean, many people still are, but my understanding is birth rates are going way down.
2:22:36 So, certainly some people are opting out or, for whatever reason, aren’t having kids.
2:22:45 Nirao, thank you so much for coming here today, for sharing with us all your incredible knowledge and experiments.
2:22:55 For me, it was especially gratifying because I think these topics are not just timely, but it’s fundamental to who we are.
2:23:03 I mean, as you pointed out, perhaps one of the most important distinctions that we make in life is determining, like, who we are and who others are.
2:23:16 And the male-female distinction is a critical one that arises at least as early as conception in terms of the chromosomes are involved.
2:23:18 And then the hormones are acting on that, of course.
2:23:21 So, I want to thank you for the work you’re doing.
2:23:23 You do really hard experiments.
2:23:24 You do beautiful experiments.
2:23:26 They’re super clean.
2:23:30 And you get really incredible outcomes, which you shared with us today.
2:23:35 It’s also wonderful that you took the time to be a public educator.
2:23:45 Come here and share with us on this set of not trivial topics when it comes to navigating the landscape of sex and gender and hormones and all this stuff.
2:23:47 So, you’re brave.
2:23:52 And we appreciate your bravery and the way you approach these questions.
2:23:52 Thanks, Andrew.
2:23:53 It’s a pleasure being here.
2:23:54 Thanks for having me on the show.
2:23:55 Yeah.
2:23:56 Well, we’ll have you back again.
2:23:59 And thanks for also being a Bulldog owner.
2:24:01 I love that you got it.
2:24:01 Bring Cooper.
2:24:03 That you got Cooper.
2:24:05 And next time, bring him.
2:24:07 He’s an amazing French Bulldog.
2:24:11 And, you know, just makes me appreciate you that much more.
2:24:12 Thank you, Andrew.
2:24:16 Thank you for joining me for today’s discussion with Dr. Neerao Shah.
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