Hookworms: Can parasites improve your health?

[Kristin] (0:00 - 0:04)
It's very sexy to have planned what to do with your missing data ahead of time.

[Regina] (0:05 - 0:10)
Forget the flashy car, forget the, you know, the flowers, you just need to show Kristin some missing data protocol.

[Kristin] (0:10 - 0:12)
Exactly, and I'm all over that, yes.

[Regina] (0:13 - 0:15)
It's like a little bit aphrodisiac, right?

[Kristin] (0:15 - 0:44)
Absolutely. Welcome to Normal Curves. This is a podcast for anyone who wants to learn about scientific studies and the statistics behind them.

It's like a journal club, except we pick topics that are fun, relevant, and sometimes a little spicy. We evaluate the evidence, and we also give you the tools that you need to evaluate scientific studies on your own. I'm Kristin Sainani.

I'm a professor at Stanford University.

[Regina] (0:45 - 0:50)
And I'm Regina Nuzzo. I'm a professor at Gallaudet University and part-time lecturer at Stanford.

[Kristin] (0:51 - 0:56)
We are not medical doctors, we are PhDs, so nothing in this podcast should be construed as medical advice.

[Regina] (0:56 - 1:12)
Also, this podcast is separate from our day jobs at Stanford and Gallaudet University.

So, Kristin, in today's episode, we are going to talk about worms. Did you know that some people out there infect themselves with hookworms on purpose for their health?

[Kristin] (1:12 - 1:29)
Well, I only know about this, Regina, because you told me about this, and I have to say my gut reaction on this was, that is disgusting.

[Regina]
Did you do that on purpose?

[Kristin]
Yeah, that was a pun.

I have to say right from the outset. I am not a creepy-crawly bug person. This episode might make my skin crawl. I don't like worms.

[Regina] (1:29 - 1:42)
I kind of love bugs and worms. This has good science behind it, so maybe that will make up for it.

Your skin crawling, but your brain is all, you know, a flutter with good stuff.

[Kristin] (1:42 - 1:44)
Yeah, you're not going to woo me into liking worms.

[Regina] (1:45 - 2:23)
So we are going to be focusing on one randomized controlled trial for this in Australia, and they tested this hookworm therapy on participants who were at risk for type 2 diabetes, and the claim that we're going to look at today is just the goal of the study, which is, one, is it safe to do this, right, is it safe to infect people with hookworms, and two, if people could actually tolerate having hookworms in their gut for two years. But the eventual goal is to see if this can help people lose weight, you know, improve their insulin sensitivity, reduce their blood pressure, all those good things.

[Kristin] (2:23 - 2:25)
This is an alternative to Ozempic.

[Regina] (2:26 - 2:40)
Who needs drugs when you have bugs? We could sell that.

So statistically, what are we going to cover?

Early-stage randomized trials and also worms, not the statistics part, and worm sex lives.

[Kristin] (2:41 - 2:43)
Regina, I'm impressed that you got the sex in there.

[Regina] (2:44 - 2:54)
Thank you. I had to work really hard for it.

I wrote about this for Reader's Digest, by the way, back in 2016, not the worm sex, but the research on worms.

[Kristin] (2:54 - 2:56)
Oh, so that's how you got into this hookworm thing.

[Regina] (2:56 - 3:03)
Hookworms and a lot of other weird things in this article, actually. The piece was called, What Happens When Scientists Experiment on Themselves.

[Kristin] (3:03 - 3:05)
Oh, those are fun stories.

[Regina] (3:05 - 3:06)
Yes.

[Kristin] (3:06 - 3:08)
I want to read this article now. You're going to post it in the show notes, right?

[Regina] (3:08 - 3:12)
Post it in the show notes. Uh-huh. So, you want to hear some before we get to the worms?

[Kristin] (3:12 - 3:13)
Oh, of course.

[Regina] (3:13 - 3:58)
So, Sir Isaac Newton.

[Kristin]
The apple-on-the-head guy.

[Regina]
The calculus guy, too.

Yeah, yes. In the 1600s, he had this theory about how the eye works, and he tested it out by sticking a darning needle into the back of his eye socket and poking around until he saw colors.

[Kristin]
Okay, so the other thing that bothers me besides creepy, crawly bug things is I'm very sensitive about my eyes, so you are really making my skin crawl. So, why would he do that?

[Regina]
He had a theory about how our eyes see images, you know, how the retina flips things around. You might remember that from high school physics.

[Kristin]
Uh, no.

[Regina]
Yeah. Well, it's cool, and he turned out to be right. We should probably put in here a blanket statement.

I think, do not try this at home.

[Kristin] (3:58 - 4:04)
Absolutely. Do not try any of this at home, especially worms and poking things in your eyes. Yes.

[Regina] (4:04 - 4:05)
Want another one?

[Kristin] (4:05 - 4:06)
Oh, yeah. Absolutely. Yeah, yeah.

[Regina] (4:06 - 4:41)
In the 1980s, everyone thought that stomach ulcers were caused by stress and spicy food, bad day at the office. But there was this young Australian doctor who was pretty sure all that stuff had nothing to do with it, and he thought it was bacteria. No one believed him, so he first made sure that he had no ulcers, right, got some medical imaging, and then drank this whole cup full of broth full of the bacteria.

[Kristin]
Gross. Gross.

[Regina]
But it worked.

[Kristin]
He got ulcers?

[Regina]
He got, well, his wife stopped it early.

Oh, yeah.

[Kristin] (4:41 - 4:41)
Oh, good. Because women are smarter.

[Regina] (4:42 - 4:48)
Because women are smarter. He was, within a week, he was vomiting, and his stomach was inflamed. I know.

That's why she was like, okay.

[Kristin] (4:49 - 4:51)
But it was enough to show this causal connection.

[Regina] (4:51 - 4:55)
He made his point. And then he took antibiotics, and then poof, it was gone.

[Kristin] (4:55 - 4:56)
Oh, wow. It was better.

[Regina] (4:57 - 5:01)
2005, he shared the Nobel Prize after he did this self-experimentation.

[Kristin] (5:01 - 5:02)
Self-experimentation. Wow.

[Regina] (5:02 - 5:07)
I know. I love it. Okay.

That makes you happy enough we can go into the worms?

[Kristin] (5:08 - 5:10)
Tell me about the worms.

Obviously, I'm thinking somebody infected themselves.

[Regina] (5:11 - 5:13)
Yes, they did. 2004, British immunologist.

[Kristin] (5:14 - 5:15)
Yeah.

That's actually really recent.

[Regina] (5:16 - 5:16)
It is recent.

[Kristin] (5:16 - 5:31)
Is this even allowed to experiment on yourself?

[Regina]
That is a great question. I looked it up.

So it's controversial. Yeah. Some people say, fine, go ahead, experiment on yourself all you want, but you don't get to have it published in a scientific journal.

[Kristin] (5:31 - 5:35)
It's a little like doping in sports. You don't want to incentivize it, right?

[Regina] (5:36 - 5:36)
Yeah. Why not?

[Kristin] (5:36 - 5:44)
Because then everybody has to do it, right? In order to win your Nobel Prize and get published, you don't want it to be a requirement that you give yourself worms.

[Regina] (5:44 - 5:46)
It does set quite a bar, doesn't it? Right.

[Kristin] (5:46 - 5:48)
Okay. But 2004, somebody did this.

[Regina] (5:49 - 6:15)
2004, British immunologist, and he wanted to do a study with hookworm therapy for patients with asthma. And the UK Bioethics Committee was like, you are not putting hookworm parasitic larvae in people.

[Kristin]
Good for them. I agree.

[Regina]
You are not doing this. So he infected himself.

[Kristin]
Oh, wow.

[Regina]
And it showed that it was safe. No ill effects. He was okay.

And that he was okay. And they said, okay, go ahead.

[Kristin]
Oh, he got his study approved.

[Regina]
He got it approved.

[Kristin] (6:15 - 6:18)
Ooh. Well, they did incentivize then because he was able to do the study.

[Regina]
Yes.

[Kristin] (6:19 - 6:23)
What was the name of the scientist again?

[Regina]
David Pritchard. So he will come up again, actually.

[Kristin] (6:23 - 6:24)
Okay. David Pritchard.

[Regina] (6:24 - 6:32)
Because he's still involved in this. So they're still studying this. I looked at clinicaltrials.gov and studies not just in Australia, not just the one we're talking about.

[Kristin] (6:33 - 6:34)
Other ones. Other people picked up on this.

[Regina] (6:35 - 6:41)
Netherlands, Denmark, England. Not in the U.S., though.

I'm sorry. You cannot sign up.

[Kristin] (6:42 - 6:44)
Oh, darn. I was going to rush out and sign up for that clinical trial.

[Regina] (6:44 - 6:53)
You were going to rush out there. They're studying things like celiac disease, multiple sclerosis, ulcerative colitis.

[Kristin] (6:53 - 6:56)
Oh, those are all autoimmune diseases. So they think it fights autoimmune disease.

[Regina] (6:56 - 7:05)
They do. That's the idea. They do.

We will talk about that in a moment. But before we do that, there are people that are doing this to themselves, as I mentioned. So we can still get you your worms.

[Kristin] (7:07 - 7:09)
Wait, what? Not just the scientists, like people at home?

[Regina] (7:09 - 7:11)
People are doing this at home. Yes.

[Kristin] (7:11 - 7:12)
Because they're bored?

[Regina] (7:12 - 7:15)
You can mail order hookworms on the internet.

[Kristin] (7:15 - 7:18)
You're kidding. Is that even legal?

[Regina]
It's a gray area, actually.

[Kristin] (7:19 - 7:19)
Really?

[Regina] (7:19 - 7:26)
There is no specific law that says you cannot buy hookworms and put them on yourself. Because why would anybody think to write that law?

[Kristin] (7:27 - 7:30)
There's lots of things where it's not a specific law, but you still know you shouldn't do it.

[Regina] (7:31 - 7:43)
Some of the sites I found like only take payment in Bitcoin. That should tell you something. Dark web.

So I found all of this through this fascinating site online, Helminthic Therapy Wiki.

[Kristin] (7:43 - 7:47)
Oh, this is where people go if they want to get mail order hookworms.

[Regina] (7:47 - 7:52)
No, they just give you the information. And then you have to go to these various sites.

[Kristin] (7:52 - 7:53)
Do not do this at home. I should say this right now.

[Regina] (7:53 - 7:55)
We are not advocating this.

[Kristin] (7:55 - 7:55)
Not at all.

[Regina] (7:55 - 8:04)
We're not endorsing this, but it's quite fascinating. So it has hundreds of personal stories from people who have tried this, testimonials.

[Kristin] (8:04 - 8:05)
I want to hear a few.

[Regina] (8:06 - 8:22)
Yeah, of course. I thought you would. OK, here's one.

It's now been a bit more than six months since my initial inoculation, and I'm now the proud mom of a family of hookworms. And the results I have seen have been amazing. I stopped taking one of my asthma medicines completely.

[Kristin] (8:22 - 8:23)
Oh, wow.

[Regina] (8:25 - 8:43)
OK, another one. You might like this one more.

I'm a year into treatment and I truly appear to be physically aging backwards. I barely recognize myself in pictures from a year ago. My skin, hair, and nails have changed.

I'm more well-nourished and my outside reflects that.

[Kristin] (8:43 - 8:45)
That sounds a little hyperbolic.

[Regina] (8:45 - 8:45)
Right.

[Kristin] (8:46 - 8:54)
I would love to age backwards, but I'm not sure that's possible.

[Regina]
They're fans.

[Kristin]
Yeah, they might be overselling it a bit, but OK.

[Regina]
But there's like hundreds of these.

[Kristin] (8:54 - 8:58)
Right. So people really think that this is doing something helpful for them.

[Regina] (8:58 - 9:14)
There are a lot of autoimmune disorders out there, and we'll talk about why, what the link is, but there are a lot of people struggling with it and they don't have a lot of good treatments for Crohn's disease. All these things are chronic. They're ongoing.

So you can imagine that people might try something.

[Kristin] (9:14 - 9:14)
Yeah.

[Regina] (9:15 - 9:16)
Why not?

[Kristin] (9:16 - 9:21)
If you want to get rid of the hookworms, if you try it and you don't like it. Do you have an option to get out of it?

[Regina] (9:21 - 9:23)
Good point. Deworming. You take medicine.

[Kristin] (9:23 - 9:24)
OK. Good to know.

[Regina] (9:25 - 9:26)
And it kills the worms.

[Kristin] (9:26 - 9:30)
But Regina, how does this even work? So you mail order hookworms and are you eating them?

[Regina] (9:30 - 9:35)
No, those are tapeworms. Tapeworms you get from eating like undercooked meat.

[Kristin] (9:35 - 9:45)
So I was thinking that the weight loss is because the worms are eating your food. Am I on the wrong worms?

[Regina]
Yeah, wrong worms.

[Kristin]
Yeah. So you're not losing weight because the worms in you are eating your food?

[Regina] (9:45 - 10:17)
No, they're sipping your blood. So the danger is anemia because maybe they're gulping instead of sipping your blood.

And you don't get hookworms from eating. The hookworms come in through your skin. So people who infect themselves on purpose usually put them on their arm.

[Kristin]
Oh.

[Regina]
But out in the wild, you usually get them by going barefoot on soil that's been contaminated where these little baby worms are living. And they literally burrow into your foot.

[Kristin]
Ew.

[Regina]
Yeah, it's supposed to be quite itchy in there.

[Kristin] (10:17 - 10:31)
OK, you're making me a little worried, Regina, because my kids and I, we like to go barefoot around the house and in our backyard. Should I be worried?

[Regina]
Do you have indoor plumbing?

[Kristin]
Yes, we do have indoor plumbing, yes.

[Regina]
Do you use it?

[Kristin] (10:31 - 10:56)
Yes.

[Regina]
Then you are OK because it spread through poop.

[Kristin]
Oh.

[Kristin]
When the hookworms are having sex in your gut, they're making eggs. They're actually making 10,000 eggs a day. And then you poop these eggs out.

And then when they're out in the soil or in your carpet, the eggs hatch into baby worms. And then when you're stepping on them barefoot, that's when they get into your skin.

[Kristin] (10:56 - 11:01)
Hopefully not poop on the carpet. Can the eggs hatch in your gut? Like, are you getting baby hookworms in your gut?

[Regina] (11:01 - 11:18)
Good question. No, they cannot hatch inside your body.

The conditions need to be just right for the eggs to hatch. So they cannot actually hatch on your carpet. I was joking.

They need warm, damp, sandy soil. Like, they've evolved for very particular conditions.

[Kristin] (11:19 - 11:29)
So when people are doing this at home, however many hookworms they put on their arm initially, they infect themselves with initially, they're never going to have more than that in the body. Is that correct?

[Regina] (11:29 - 11:36)
Exactly. They live their whole lives in your gut. You are their forever home.

And they cannot multiply.

[Kristin] (11:37 - 11:42)
And how long do they live?

[Regina]
Three to five years.

[Kristin]
Oh, that's pretty long.

So they're pretty hardy.

[Regina] (11:42 - 11:43)
Yeah, they are.

[Kristin] (11:43 - 11:52)
Another question for you, Regina, if you are infecting yourself with hookworms at home, is there any risk of you spreading this to other people in your household?

[Regina] (11:52 - 12:19)
Very good question. No. So again, as long as you've got indoor plumbing and you are using it, you are okay. And the hookworm infections, they're mostly a problem in developing countries. With sanitation issues.

I should point out that the baby worms that you're getting, if you mail order these or in research, they do not come in poop. You are not getting feces in the mail.

[Kristin]
Excellent.

[Regina]
They come in like distilled water.

[Kristin] (12:19 - 12:28)
So you're getting a little jar of worms in the solution. And you are just putting this solution on your skin. And about how many worms are you getting?

[Regina] (12:29 - 12:31)
10 or 20 is what people tell me.

[Kristin] (12:31 - 12:34)
Oh, okay. Not too many. And that's all you have for the next three to five years.

[Regina] (12:35 - 12:45)
Right. Anything more than 30, just to put this into context, is considered like a high infection. And if you have a thousand of them, that's when you're getting into like dangerous territory.

[Kristin] (12:45 - 12:57)
Oh, okay. So this is why this might be really bad in developing countries because you're not controlling it at 10 or 20. You might have a lot more because you're being infected constantly from the environment.

And that's what puts you at risk of the anemia.

[Regina] (12:57 - 12:59)
They can sip too much of your blood.

[Kristin] (12:59 - 13:02)
Can you see the worms when you put them on your skin?

[Regina] (13:02 - 13:29)
They are barely visible. I looked it up. They're measured in micrometers.

And you can put two of them on the tip of a sharpened pencil. They itch. So you know they're there.

They itch and they just go right in there. They go through your bloodstream. They got quite a journey.

Your lungs and then into your esophagus. And you kind of swallow them. And that's how they get through to your GI tract.

[Kristin] (13:30 - 13:34)
That sounds really disgusting. So can you feel them? Do you feel it when you're swallowing them?

[Regina] (13:35 - 13:58)
They're still really tiny at that point, like half a millimeter. So you do not even notice. And it's from there.

They go through your stomach and they go to your small intestine. That's the first part of your intestine. Takes them about a week to get there.

And your intestine is where they live. And they use their little cutting plate mouth things to dig into your intestinal wall to hold on.

[Kristin] (13:59 - 14:00)
This is not making me want one more, Regina.

[Regina] (14:02 - 14:09)
The idea is so your intestine can't squeeze them out when it digests food going through.

[Kristin] (14:09 - 14:14)
Oh, they hook on. And that's why they're called hookworms. Oh, I just learned something.

Thank you.

[Regina] (14:15 - 14:21)
They hold on for dear life. And that is their forever home. But they do move around from site to site in your intestine.

[Kristin] (14:21 - 14:23)
It's not a permanent hook. It's a reversible hook?

[Regina] (14:23 - 14:29)
Yeah, I guess they unhook and then move somewhere else, new neighborhood, so they don't get bored.

[Kristin] (14:30 - 14:35)
And of course, they need to move around so that they can have sex with other hookworms in your gut.

[Regina] (14:35 - 14:37)
There you go. This is where the party happens.

[Kristin] (14:37 - 14:52)
All right, Regina, that's the background on worms. But tell me, why do people think this does something beneficial for you? Like, what is the biological theory behind why people think this might help to fight diabetes or for weight loss?

[Regina] (14:52 - 15:27)
Well, scientists actually started talking about this in a rigorous way in the 60s and 70s. There was a letter in Lancet in 1968 where a doctor in Nigeria just published a letter. So it wasn't a study.

And he said, hey, I've noticed that there's not a lot of autoimmune disease in tropical Africa. Very little rheumatoid arthritis, ulcerative colitis, lupus. Even after you adjust for age, even in non-rural areas, he said it's strikingly low.

And he hypothesized maybe it has something to do with parasitic infections.

[Kristin] (15:27 - 15:37)
I mean, there might be a lot of other reasons that you would have less autoimmune disease. Like maybe you're not eating a Western diet. And maybe, I think with diabetes especially, Western diet has a lot to do with it.

[Regina] (15:37 - 15:44)
And then they noticed when they dewormed the population, then metabolic diseases, autoimmune went up.

[Kristin] (15:44 - 15:53)
Right. But again, maybe at the point where you've got people coming in, public health and deworming, that's the point at which the country is developing. And they're also getting a McDonald's down the road.

[Regina] (15:53 - 16:11)
Right. Obvious problems with this, which is why they started looking at the mechanism. So they were doing things in mice. And I'm going to give you what I think is a big picture of this, realizing I am not an immunologist.

So inflammation, autoimmune diseases, are basically chronic inflammation sometimes they're called. Like type 2 diabetes.

[Kristin] (16:12 - 16:21)
Right. I hear this thrown around, chronic inflammation, inflammatory reaction. Sometimes I think people just throw this word around without having any clue what it actually means.

So can we unpack what we even mean by that?

[Regina] (16:22 - 16:39)
It's a real thing. I mean, yes, people throw it around as a buzzword. But it just basically means that your immune system is activated.

And they call it inflammation, flame. Because one of the things that happens when your immune system is activated, like fighting off a cold virus or something, it sends more blood flow to the area.

[Kristin] (16:40 - 16:41)
It gets red and hot. Right. Hot.

[Regina] (16:42 - 16:42)
Inflamed. Yeah.

[Kristin] (16:42 - 16:47)
So I'm thinking like you've got a cut on your arm and it gets infected. It gets red and hot. And that's the inflammation.

That's it's inflamed.

[Regina] (16:48 - 16:53)
Yes. So it's not fun. You want this big response to fight off these invaders.

[Kristin] (16:53 - 16:56)
It doesn't last. If your body fights it off effectively, it goes away.

[Regina] (16:56 - 17:04)
Goes away. But chronic inflammation is when your immune system is constantly activated in small ways. Like all the time.

[Kristin] (17:04 - 17:05)
Right. When it shouldn't be.

[Regina] (17:05 - 17:09)
Right. So before we get to worms, though, can we talk about fat?

[Kristin] (17:09 - 17:10)
Sure.

[Regina] (17:10 - 17:17)
You've probably heard that having a lot of fat around your waist is more dangerous than having like a lot of butt fat.

[Kristin] (17:17 - 17:21)
Oh, sure. Yeah. The apple shape versus the pear shape.

It's bad to have too much around your middle. Yep.

[Regina] (17:22 - 17:41)
This is dangerous because it's a different type of fat. Your abdominal fat actually talks with your immune system. And when you have too much of it, it kind of flips a switch and the fat tells the immune system to gear up and get ready for a fight.

It turns up the immune system.

[Kristin] (17:41 - 17:46)
Is it like when you get too much fat around there, your body is kind of seeing it as a foreign invader?

[Regina] (17:47 - 17:58)
Right. They're not really sure why your body is doing this, but this inflammation makes everything go haywire. It also interrupts the signaling between your cells and the blood sugar and insulin.

[Kristin] (17:59 - 18:01)
Oh, this is where you get the insulin resistance with diabetes.

[Regina] (18:01 - 18:43)
Right. And it's this feedback loop, right? Because the more insulin resistance, the more it keeps trying to shove the blood sugar in there and the more your blood sugar rises and the more you're gaining weight.

It goes around and around and around. So where do the worms come in?

Where do the worms come in? This is fascinating. So your immune system handles different types of foreign invaders in different ways.

So if you have bacteria or viruses in your body, your immune system puts this all out blitz war. And that's why you feel so horrible when you're sick.

Your immune system is calling all the troops and that's because bacteria and viruses are fast and dangerous.

[Kristin] (18:44 - 18:49)
Right. Your immune system is saying, we have got to get rid of this quickly because these things could kill you quickly.

[Regina] (18:49 - 19:01)
Right. But with a blitz war, it's also easy for things to get out of control. Your immune system can get too ramped up with its enthusiasm, like the cytokine storm with COVID-19.

[Kristin] (19:02 - 19:06)
Oh, right. When the immune system was getting overactivated and that could kill you.

[Regina] (19:06 - 19:26)
Right. This is the type of immune system response that happens in a small way with his abdominal fat.

[Kristin]
Got it.

[Regina]
It's doing that. It's turning up that inflammation. But the immune system does not handle all foreign invaders this way.

It recognizes worms as being a different type of invader.

[Kristin] ] (19:26 - 19:36)
Oh, because they're a parasitic infection.

Right. So it gets the idea that a parasite maybe is not trying to kill you quickly because it wants to live off of you and therefore wants to keep you alive. Right.

[Regina] (19:36 - 20:00)
It wants to sip on your blood. So your body activates a different type of immune system. It's more like a ground war.

[Kristin]
Oh, slow acting army. That's fascinating, actually.

[Regina]
This immune system, it says, hey, guys, calm down.

It calms down the immune system. It's like, hey, guys, thanks for all your bombs, but we don't need you here. We just want to keep an eye on this.

[Kristin] (20:00 - 20:13)
Oh, interesting. So you've got this inflammation coming from the abdominal fat. But if you've got a few worms in there, maybe the idea is the body says, hey, actually, it's just a parasitic infection.

So let's calm everything else down.

[Regina] (20:14 - 20:23)
Yeah. So they call this other type of immune system anti-inflammatory and it might interrupt that cycle that we were talking about. It's at least plausible.

[Kristin] (20:23 - 20:51)
Yeah, that's biologically plausible. But what's the evidence? Can we talk about the study now?

[Regina]
Yeah, let's talk about the study.

[Kristin]
All right. First, I think we need to take a short break, though.

Regina, I've mentioned before on this podcast, our clinical trials course on Stanford Online is called Clinical Trials, Design, Strategy and Analysis. I want to give our listeners a little bit more information about that course. It's a self-paced course.

[Regina] (20:52 - 21:00)
We cover some really fun case studies designed for people who need to work with clinical trials, including interpreting, running and understanding them.

[Kristin] (21:00 - 21:29)
You can get a Stanford professional certificate as well as CME credit. You can find a link to that course on our website, NormalCurves.com. And our listeners get a discount.

The discount code is normalcurves10.

Welcome back to Normal Curves. Today, we're looking at the claim that hookworm therapy is both safe and tolerable.

[Regina] (21:29 - 21:32)
I think we are ready to talk about the actual study now.

[Kristin] (21:32 - 21:34)
Oh, you told me there was going to be a randomized trial. I'm all excited.

[Regina] (21:35 - 22:05)
Randomized trial. 2023, published in Nature Communications. Yes, I thought it would be good to have a nice recent one.

16 authors. First author was a PhD student at the Australian Institute of Tropical Health and Medicine. This was at James Cook University and this was for her PhD dissertation.

The senior author is a research fellow there and is big into worms because he has a TEDx talk called Worming Your Way to Health.

[Kristin] (22:05 - 22:08)
Oh, I'm going to have to go watch that now just out of pure curiosity.

[Regina] (22:08 - 22:23)
I recommend it because he actually shows a video of two worms in a person's intestine, female who had just eaten, who's lying around satiated, happy, and a male who is trying desperately to mate with her. Yes, so you get to see.

[Kristin] (22:23 - 22:25)
Some people might want to see that.

[Regina] (22:25 - 22:27)
Hookworm porn. Yes, right there.

[Kristin] (22:29 - 22:33)
Are we putting a link to that?

[Regina] (22:33 - 22:42)
We are definitely putting a link to that one. Yes. I don't encourage you to search for hookworm sex videos because then it's in your Google search history and then goodness knows what you're going to get.

[Kristin] (22:44 - 22:45)
You don't want your dates to see that.

[Regina] (22:45 - 22:47)
Yeah, well, gosh, what are they going to sell you?

[Kristin] (22:48 - 22:51)
Well, these dark web sites where you can buy your own hookworm, right?

[Regina] (22:51 - 22:54)
That's what they're going to sell you. And sex toys at the same time.

[Kristin] (22:55 - 22:58)
All right, let's get back to the study, though, Regina. How big was the study?

[Regina] (22:59 - 23:13)
40 participants. They were all at risk for type 2 diabetes.

[Kristin]
A lot of them are overweight?

[Regina]
Overweight, obese. They needed to have an abdominal circumference and a waist circumference of at least 35 inches for women and 40 inches for men.

[Kristin] (23:14 - 23:14)
Pretty big, I think.

[Regina] (23:14 - 23:19)
Plus insulin resistance, problems with blood cholesterol.

[Kristin] (23:20 - 23:20)
They are on the path to diabetes.

[Regina] (23:20 - 23:56)
Yes. I think they call it metabolic disorder.

[Kristin]
Pre-diabetes?

[Regina]
Pre-diabetes, there you go.

They were randomized to either one of two doses of hookworm therapy or a placebo. And we'll talk more about that in a minute. But I wanted to mention the primary and secondary outcomes.

So, they clearly delineated them in the paper, which was great. The primary outcomes were basically just safety. Does the delivery method work?

And can people tolerate it? Can people handle having this for two years? Right.

So, the secondary outcomes, those were like weight.

[Kristin] (23:57 - 23:58)
Right. Did their weight change.

[Regina] (23:59 - 24:05)
And blood markers, metabolic health blood markers, like cholesterol and insulin resistance and all of these things.

[Kristin] (24:06 - 24:09)
So, Regina, was this a phase one trial? It sounds like it.

[Regina] (24:10 - 24:14)
It was, you can tell. Talk for a minute how you can tell just by the outcomes I described.

[Kristin] (24:14 - 24:32)
Right. I think a lot of people aren't aware that clinical trials have these different phases. And you always like to start in a very small group of people just to make sure it's safe, which makes sense, right?

We don't want to expose thousands of people to something if we're not sure it's safe. And also, at that stage, often they're not really sure what's the right dose.

[Regina] (24:33 - 24:48)
So, it helps to work out dosing too. Yes, yes. Phase one is not designed to show effectiveness.

So, if you see results for a phase one trial, you really should be thinking, okay, just is it tolerable? Is it safe? What were the adverse events?

Not did it work.

[Kristin] (24:48 - 25:01)
Right, which I think people have trouble getting their heads around. It's like, no, we're not trying to see if it works. And they say, why would you do a study and not see if it works?

Because before you even can get there, you have to know it's safe, tolerable, and what dose to use.

[Regina] (25:02 - 25:11)
And sometimes if we're talking about delivery method, if we're talking about hookworms, can we actually put some baby hookworms on an arm and have it do anything?

[Kristin] (25:11 - 25:20)
You need to inject it. You need to swallow it. All these kinds of things.

We talk a lot about phase one clinical trials and the different phases of clinical trials in our clinical trials course in Stanford Online.

[Regina] (25:23 - 25:25)
It's important for people to understand where it fits in in the whole pipeline.

[Kristin] (25:26 - 25:26)
Yes, exactly.

[Regina] (25:27 - 25:50)
So sometimes you hear about phase 1A and 1B.

[Kristin]
I can never remember which is which, Regina.
[Regina]
The different dosages.

So phase 1A is usually just testing one dosage. Okay. And phase 1B is testing more than one dosage.

And this was a 1B. So this tends to be usually no more than 100 people, 20 to 100 people is phase one clinical trials. And this was 40.

[Kristin] (25:50 - 25:59)
This was 40, right. Okay.

[Regina]
And they gave two doses of the hookworms.

[Kristin]
Right. Regina, do you mind if we do a little statistical detour here and talk about the different phases of clinical trials?

[Regina] (26:00 - 26:06)
Good idea. Let's use a nice example. How about the Moderna COVID-19 vaccine?

[Kristin] (26:07 - 26:17)
Oh, yeah, this is really interesting because the COVID vaccines, they went through all of these phases. But I think a lot of people aren't aware of that. They aren't aware of what happened behind the scenes.

So let's talk about it.

[Regina] (26:17 - 26:24)
Yeah. So they did have a phase one clinical trial. They had 45 people and they tested three doses.

[Kristin] (26:24 - 26:25)
They did a phase 1B.

[Regina] (26:25 - 26:35)
Yeah. And they wanted to see whether it actually triggered any immune response.

So forget about does it prevent COVID or not. Does it actually do anything inside your body?

[Kristin] (26:36 - 26:37)
And is it safe.

[Regina] (26:37 - 27:02)
And what kind of adverse events do you have? Right. And they used that information then to refine what dosages they wanted to continue testing to test for efficacy.

Because, OK, low, medium, high, which one is getting us the right amount of immune response with the least amount of adverse events, you know, side effects. So in the U.S., most of the phase one trials proceed on to the next phase.

[Kristin] (27:02 - 27:02)
Oh, OK.

[Regina] (27:02 - 27:04)
They use that information to inform and refine.

[Kristin] (27:05 - 27:07)
At least it seems to be safe enough so we'll keep going.

[Regina] (27:08 - 28:09)
Right. About 70 percent in the U.S. continue on.

[Kristin]
So then did they move on to a phase two?

[Regina]
They went on to a phase two. Now, this is where it starts to get slightly bigger. Usually it's about 300 people.

Moderna trial had 600.

[Kristin]
OK. Yeah.

[Regina]
And here is where they said, OK, let's start refining the dosage. Maybe that high was a little too high.

[Kristin]
Right.

[Regina]
And the low was a little too low. Right. So let's take that medium dose and then split it out and try out two doses.

And so here we start to test efficacy. So this is not bringing it to the entire population. But we're starting to look at, OK, we have an idea, a little bit of the dosage now and that it actually has some sort of reaction in the body.

Now let's see whether it actually works. And to continue to look at safety. Of course.

That's primary. That's the idea behind phase two. And here, only about one third of treatments move on from this in the U.S. So it gets a little bit more stringent.

[Kristin] (28:09 - 28:13)
Because now you're looking to see that it does something. If it's safe but doesn't do anything.

[Regina] (28:13 - 28:14)
Doesn't do anything.

[Kristin] (28:15 - 28:16)
We're not going to make a lot of money off of this.

[Regina] (28:16 - 28:37)
Right. You have to see whether it's practical. And then phase three, this is where we usually hear about them in the media.

This is where most trials we're hearing about are the phase three trials. We hear a large group of people, different regions, different types of people. We want to broaden it out.

[Kristin]
And here is where we are confirming efficacy.

[Regina]
Yes. That is the goal.

I mean, we're still looking at safety.

[Kristin] (28:37 - 28:39)
We're still going to monitor for safety, of course.

[Regina] (28:39 - 28:45)
We're going to monitor that. But hopefully, we're pretty sure about that. And now we can focus on does it even work?

[Kristin] (28:45 - 28:48)
Does it work? And does it work well enough that you would give it to people? Is it cost effective?

[Regina] (28:49 - 28:52)
Right. And this is usually what you need for approval.

[Kristin] (28:52 - 28:53)
For the FDA.

[Regina] (28:53 - 28:59)
FDA approval in the U.S. Typically, these are only up to about 3,000 people. But Moderna had 11,000.

[Kristin] (28:59 - 29:00)
Wow.

[Regina] (29:00 - 29:15)
Yeah, they were testing it big. Here, only about a quarter of these phase three clinical trials are successful.

And then we have phase four. Sometimes we don't hear about these, but this is the monitoring. Post-approval. What's happening in the population?

[Kristin] (29:16 - 29:25)
You keep checking to make sure some very, very rare side effects that maybe you can't pick up in a trial with 10,000 or 3,000 people. You need 100,000 people to pick them up.

[Regina] (29:25 - 29:32)
But they're severe. So we really want to know about them. But very rare.

Or it takes a little while for them to show up. Yeah. So you're following them a longer time.

[Kristin] (29:32 - 29:41)
All right, Regina. So that's the background on clinical trial phases. And that situates us because the hookworm trial that we're talking about is a phase 1B.

[Regina] (29:41 - 29:48)
Phase 1B, which is a long way from here. Your doctor is going to slap some hookworms on your arm.

[Kristin] (29:49 - 29:52)
So nobody's going to be recommending this to you when you go to the doctor yet.

[Regina] (29:52 - 29:59)
But it really is worth it to invest in a good phase one clinical trial.

[Kristin] (29:59 - 30:05)
Oh, they're super important.

Why would you go spend money on a 10,000 person randomized trial that's doomed to fail when you could have figured that out in 40 people?

[Regina] (30:06 - 30:21)
And you can find problems and then refine it. Refine the dosages. Refine the treatment.

Delivery method. Yeah.

So that's how this fits in. We've got phase 1B. What other things, Kristin, did we talk about in our course?

[Kristin] (30:22 - 30:24)
Oh, sure. Randomized trials. So we talked about randomization.

[Regina] (30:25 - 30:37)
First of all, I should point out you really want randomization when you're talking about hookworm therapy because you don't want to allow people to choose whether I am adventurous, I choose hookworms.

[Kristin] (30:38 - 30:41)
You would choose the hookworms and I would not. Not that I'm not adventurous, but I'm not adventurous when it comes to worms.

[Regina] (30:41 - 31:14)
Worms, right, in your body. So they did block randomization here. It's actually a good sign.

It means that they have put some thought into this. Here they block randomized blocks of six on a two by two by two ratio. It just means I am going to, before the next six people arrive, I am going to use my computer program or whatever to randomize two people to the high dose, two people to the low dose, and two people to the placebo.

And that's it. So what it does is really ensure that you have good equal representation among the groups.

[Kristin] (31:14 - 31:14)
Yes, exactly.

[Regina] (31:14 - 31:24)
And they did that very well. They had 13, 14, and 13 here. So what else did we talk about in our course?

This is testing your memory.

[Kristin] (31:24 - 31:30)
Oh, my goodness. What did we teach in our course? I'm really curious here, Regina, what was the placebo?

[Regina] (31:30 - 31:33)
Placebos are so fascinating. This is the fun stuff. I love talking about placebos.

[Kristin] (31:33 - 31:36)
How do you convince people that they got worms when they didn't?

[Regina] (31:36 - 31:47)
I know. It's so important to have that, right? Here it was Tabasco sauce.

Hot sauce. They put it on a bandage. And it burns and itches.

[Kristin] (31:48 - 31:50)
And you can't see what's under the bandage.

[Regina] (31:50 - 31:51)
You can't see what's under the bandage.

[Kristin] (31:51 - 31:54)
So they feel this tingly burning and they think they're getting the worms.

[Regina] (31:55 - 32:04)
It's a good one. It's a good placebo, yeah. Because I've seen other clinical trials on hookworms and they just use water because they said, oh, you can't see it. It's underneath the bandage.

[Kristin] (32:04 - 32:07)
But if you don't feel anything, you know you didn't get the hookworms.

[Regina] (32:07 - 32:10)
So I thought hot sauce was a good thing.

[Kristin] (32:10 - 32:26)
Good design. Even in this trial, the outcomes are pretty hard end point. You either lost weight or you didn't.

It's not in your mind. But your mind can affect whether you lose weight. So if you think like, oh, I'm getting these worms and I must be losing weight.

Maybe you just subconsciously. You eat better. You exercise more.

[Regina] (32:27 - 32:27)
Yeah, exactly.

[Kristin] (32:28 - 32:31)
So we don't want that because then it's not the effect of the worms.

[Regina] (32:31 - 32:38)
Placebo effect is when you think, OK, I'm having good things happening. Yeah, I'm improving. There's also something called the nocebo effect.

[Kristin] (32:39 - 32:45)
Which is a fascinating concept. Regina, I would be at risk here of the nocebo effect.

[Regina] (32:45 - 32:46)
Explain what the nocebo is.

[Kristin] (32:46 - 32:54)
If I enrolled in this trial and I thought I might have gotten worms, I am going to think bad things are happening to me because of the worms.

[Regina] (32:55 - 33:00)
For two years you're going to picture the worms in your gut. Whether or not they are there.

[Kristin] (33:00 - 33:05)
Right. So anything bad that might happen to me, I might attribute to the worms. Even if I just got the Tabasco sauce.

[Regina] (33:05 - 33:15)
Right. That's the nocebo effect. And this is especially important with this randomized trial.

Right. Because I'm looking at adverse events.

[Kristin] (33:15 - 33:16)
That's the thing I'm looking for.

[Regina] (33:17 - 33:28)
I need to protect against that. Kristin, we talk a lot about placebos in our clinical trials course. Maybe we could take a moment and talk about a few of our favorite examples of placebos in clinical trials.

[Kristin] (33:29 - 33:31)
Absolutely. This is worth going off on a little tangent.

[Regina] (33:31 - 33:35)
How about you do sham surgeries? You do that great in the course.

[Kristin] (33:35 - 33:58)
Yeah, Regina, sham surgeries are fascinating. It might help to take a specific example. So there's a surgery that is commonly done to treat arthritis in the knee.

And it involves scraping out the cartilage in the knee joint, scraping out some debris, basically. People do feel better after the surgery, but we're actually not sure that it's doing anything biologically. We're not really sure why or if it works.

[Regina] (33:59 - 34:06)
Is it the cleaning out of the debris that makes people feel better or just the experience of having your knee cut open?

[Kristin] (34:06 - 34:35)
Right. You think you got treated and therefore you feel better. So if we wanted to do a good trial to test whether this specific surgery was actually helping people, we would want a control arm.

But if we just use a control arm where people don't get surgery, that doesn't guard against the placebo effect. So we want a good placebo. And a good placebo here would actually be to do a sham surgery.

And what that means is they give you anesthesia, they open up your knee, but then they don't do the scraping part and they just sew you back up. They don't do anything.

[Regina] (34:36 - 34:44)
It's so weird. It's not actually a sham in a way. It's real surgery.

They open you up. They just don't do whatever they were going to do to your joint.

[Kristin] (34:44 - 35:15)
Right. They don't do the cleaning out of the debris or something. And you might wonder, like, how is this ethical?

How are you going to allow people in a trial to operate on somebody for no reason? I mean, operating has risks. The problem is that a lot of these surgeries, like this kind of knee surgery, where we don't really know if or how it works, we actually don't know that we aren't already doing sham surgery on lots and lots of people.

That's why you want to test it against a placebo, against a sham surgery, to prove that it's actually doing anything beyond the placebo effect.

[Regina] (35:15 - 35:26)
Anyway, placebo effect is so important. In our clinical trials course, we also talked about how important this is for testing psychedelics, for looking at psychedelics in a therapeutic sense.

[Kristin] (35:26 - 35:30)
Oh, I love this story in our course, Regina. Everybody should just go to our course just for this story.

[Regina] (35:30 - 35:54)
The background is that investigators are looking at psychedelics for therapeutic use, not just for fun, you know, to help treat PTSD, depression, anxiety, eating disorders.

[Kristin]
Can you say what are psychedelics?

[Regina]
Like LSD or psilocybin, that's the stuff in magic mushrooms, or MDMA, that's Molly, or ecstasy.

[Kristin] (35:54 - 36:06)
I've heard of these kinds of treatments being used for things like PTSD, but how do you do a good clinical trial here? I'm a little skeptical, right? Because how do you do a placebo?

People will know these are pretty powerful drugs. They'll know if they're on them, right?

[Regina] (36:07 - 36:38)
You would think so. But what they have found out is that you can actually fool people into thinking that they are on a psychedelic trip. So just like a sham surgery, they take people on a sham psychedelic trip with absolutely no psychedelics involved.

[Kristin]
OK, explain that more, Regina.

[Regina]
Right. In the course, I talked about this one study where they fooled an entire group of people.

They told them that it was a real study that they might get the psychedelic or they might not, but really no one got the psychedelic.

[Kristin] (36:38 - 36:39)
Everybody got the placebo.

[Regina] (36:40 - 37:15)
Everybody got the placebo. And they had like, you know, the hippy trippy room with the cool posters and the mood lighting and the trippy music. They had people walking around and saying, oh, my God, your pupils are so enlarged.

You know, like the whole thing. People came out of there absolutely convinced that they were on a trip. They asked the researchers, where can I get a hold of this?

Because I just feel amazing and that was life changing. what the mind can do. Even participants who had experience with psychedelics.

[Kristin] (37:15 - 37:18)
No way. Because I can imagine if you don't know what it feels like, you're like, oh, yes, oh, right.

[Regina] (37:19 - 37:22)
Oh, no, no. The mind is so powerful.

[Kristin] (37:22 - 37:31)
Hence the necessity of placebos. So I guess they were doing this so they could come up with a good placebo for a trial on one of these psychedelics. Amazing.

[Regina] (37:32 - 37:32)
Right.

[Kristin] (37:33 - 37:42)
All right, Regina, so that's our little tangent on placebos. But let's get back to the hookworm trial now. You said the placebo was Tabasco sauce.

What were the active treatments, though?

[Regina] (37:42 - 37:48)
They got either 20 baby hookworms or 40 baby hookworms.

[Kristin] (37:48 - 37:58)
That's the low dose and the high dose.

[Regina]
Mm hmm.

[Kristin]
Regina, you mentioned that if you're getting above 30, that's starting to get where it might be dangerous, might suck too much blood. So were they worried about giving people 40 hookworms?

[Regina] (37:58 - 38:22)
Yeah, they were. And now they're going to be closely monitored. So it's not like they're just putting it in there and sending them off.

But remember, the whole point of a phase one trial is to see how high is too high.

You kind of want to brush up against the boundaries of what is tolerable but effective.

Kristin, interesting side note. You ever wonder where those baby hookworms came from in the first place?

[Kristin] (38:22 - 38:25)
Well, I hadn't up until now, but I'm curious, where did they come from?

[Regina] (38:25 - 38:38)
They came from eggs that were donated from volunteers. And the volunteers had been intentionally infected with hookworms and those hookworms came from David Pritchard.

[Kristin] (38:38 - 38:41)
Oh, the original guy, the self-experimenter.

[Regina] (38:42 - 38:52)
Yes, that is the one. So these worms are like the grand baby worms of the original worms from David Pritchard.

[Kristin]
Oh.

[Regina]
Who got his out in the wild.

[Kristin] (38:52 - 38:52)
Okay.

[Regina] (38:53 - 38:59)
And he is responsible for a lot of the hookworms that are out there used for research.

[Kristin] (38:59 - 39:08)
So like he passed on his worms to some people and then those people infected themselves and took their poop and then sent it to a lab to be cleaned up and then sent it out for research?

[Regina] (39:08 - 39:21)
It's beautiful. Science is beautiful.

The other thing that they do is separate the eggs from the poop, carefully incubate them, hatch them, lovingly go through and find the most vigorous, active, happy worms.

[Kristin] (39:21 - 39:29)
Wait, so that's somebody's job like to look under a microscope with the tweezers and pick out the juicy ones and then discard the rest? Yeah. I do not want that job.

[Regina] (39:29 - 39:37)
Yeah, it seems like it would kind of be fun. Yes, you, you and you, not you, but if you're only giving them 20 or 40 at a time.

[Kristin] (39:37 - 39:41)
Right. You want to know that they're going to hook on and not just, you know.

[Regina]
You don't want the lazy ones.

[Kristin] (39:41 - 39:42)
Survival of the fittest here.

[Regina]
Right, right.

[Kristin] (39:42 - 39:43)
You want the fit ones.

[Regina] (39:43 - 39:43)
Right.

[Kristin] (39:43 - 39:51)
All right, another thing we talk about in our course, Regina, blinding.

[Regina]
Blinding.

[Kristin]
You don't want people to know that they got the placebo versus the active treatment.

[Regina] (39:51 - 40:07)
So this one was double-blinded.

[Kristin]
Oh, great.

[Regina]
Yeah, which is very nice.

Sometimes they call it masking, so this was double-masked. There was only one of the 16 co-authors who knew what was underneath those bandages. He was the one that prepared all of the treatments.

[Kristin] (40:07 - 40:13)
So somebody had to, like, put the hookworms or the Tabasco sauce on the bandages and then they put them in some envelopes.

[Regina] (40:14 - 40:17)
Sealed, opaque envelopes with the number, the randomization in there.

[Kristin] (40:17 - 40:29)
So even the person putting the bandages on, you don't want them to know because they might react in a certain way that gives it away. It's like, oh, I'm touching the worms.

Right, yeah, so that's how I would react if I were the one putting the worm bandage on you.

[Regina] (40:29 - 40:38)
Right, and so none of the people that were collecting the data knew either. If they know, they might be treating the particular worm differently.

[Kristin] (40:38 - 40:49)
Sure, if somebody comes in and you're asking them about adverse effects and you know they have the hookworm, it's natural that you would ask more questions related to the hookworms. If you know somebody got Tabasco sauce, you're not too worried.

[Regina] (40:49 - 40:52)
Can I tell you about just a couple of other cool things that they did? You are going to like this.

[Kristin] (40:52 - 40:54)
Yeah, this is sounding like a well-done study.

[Regina] (40:55 - 40:56)
This is such a well-done study.

[Kristin] (40:56 - 40:59)
It makes us so happy because normally we're talking about not well-done studies.

[Regina] (41:00 - 41:10)
I know. This is why I wanted to talk about this. It's such a great example.

First thing they did, they pre-registered the study and they also published their protocol. Oh, I love this.

[Kristin] (41:10 - 41:27)
So this means if somebody reviewed their protocol, not you just made up anything and stuck it on the website somewhere, but somebody went through it, it's also pretty easy for me to then go find their protocol later after they publish their results and I can go and check and see did they actually stick to their protocol. And Regina, did you check?

[Regina] (41:27 - 41:36)
I did. I checked their registration and their published protocol and their publication. Good smoothing.

Yeah, and it was good. They did a really good job.

[Kristin] (41:36 - 41:37)
They stuck to it.

[Regina] (41:37 - 41:41)
There were a couple of things like they said they were going to get abdominal waist circumference.

[Kristin] (41:42 - 41:42)
Oh, with the tape measure.

[Regina] (41:43 - 41:54)
But they did not do that. But these were all secondary outcomes. And in a phase one trial, that's less important.

I want to make sure that they actually got all the data and all of the adverse events that they were looking for.

[Kristin] (41:54 - 41:59)
Yeah, the important things are the primary outcomes. Right, right. The others maybe just, you know, somebody lost the tape measure and that's it.

Right, right.

[Regina] (42:00 - 42:05)
The second thing they did, they shared their data.

[Kristin]
Oh, can we play with their data?

[Regina] (42:06 - 42:18)
We can play with their data.

It's great.

They have this great spreadsheet and it's just available online. This is open access, by the way, so everyone can go and it's just available from the journal website and I downloaded it. It has all these tabs and it has the data.

[Kristin] (42:19 - 42:26)
I could use that in class.

My students might find that interesting.

[Regina]
Oh, absolutely.

[Kristin]
Yeah, anything that makes their skin crawl would probably wake them up, too.

[Regina] (42:26 - 42:28)
You can hand out like gummy worms, you know.

[Kristin] (42:28 - 42:30)
Oh, that's so fun. Oh, my God, I'm going to do that.

[Regina] (42:31 - 42:40)
I'm going to show up for that one.

Third thing that they did, they thought through what to do about missing data. They put it in the protocol.

Ahead of time.

[Kristin] (42:41 - 42:43)
Ahead of time. Oh, my heart is all a flutter.

[Regina] (42:44 - 42:47)
I know. I mean, it's a very unsexy thing to talk about missing data.

[Kristin] (42:47 - 42:51)
Oh, it's very sexy to have planned what to do with your missing data ahead of time.

[Regina] (42:52 - 42:58)
Forget the flashy car. Forget the, you know, the flowers. You just need to show Kristin some missing data protocol.

[Kristin] (42:58 - 43:00)
Exactly, and I'm all over that, yes.

[Regina] (43:00 - 43:02)
It's like a little bit aphrodisiac, right?

[Kristin] (43:03 - 43:03)
Absolutely.

[Regina] (43:03 - 43:13)
It's like, I'm feeling a little hot and bothered right now. Mmm, tell me about imputation, baby. Oh, that's kind of dirty, actually.

[Kristin] (43:14 - 43:17)
Yes. Yes, it is. Yeah, love it.

[Regina] (43:17 - 43:28)
The important thing is that they thought it through and they put it down ahead of time. So, I thought it was great. A lot of planning a clinical trial, especially a phase one, is thinking through these contingencies ahead of time.

[Kristin] (43:28 - 43:28)
Yes, exactly.

[Regina] (43:28 - 43:39)
Even if it seems like it might just be a rare event, they talked about what they would do if they needed to deworm people or unblind people, all of these things. It's just sitting down and doing it ahead of time.

[Kristin] (43:39 - 43:41)
No, that's super important, especially when you're giving people worms.

[Regina] (43:41 - 43:43)
Yes, when you're giving people worms, especially.

[Kristin] (43:43 - 44:06)
All right, so, Regina, now I want to know what were the actual results? What did they find? But first, let's take a short break.

Regina, I've mentioned before on this podcast our introductory statistics course, Demystifying Data, which is on Stanford Online. I want to give our listeners a little bit more information about that course.

[Regina] (44:06 - 44:17)
It's a self-paced course where we do a lot of really fun case studies. It's for stats novices, but also people who might have had a stats course in the past, but want a deeper understanding now.

[Kristin] (44:17 - 44:44)
You can get a Stanford professional certificate as well as CME credit. You can find a link to that course on our website, normalcurves.com, and our listeners get a discount. The discount code is normalcurves10.

Welcome back to Normal Curves. Today, we are talking about hookworm therapy and one of the early clinical trials for that.

[Regina] (44:45 - 44:55)
I think we are ready now for actual results. One of the first questions the investigator is answered is did the worms actually set up shop in people's guts?

[Kristin] (44:56 - 45:01)
Regina, did they actually stick around?

[Regina]
So, what the investigators did is check their poop.

[Kristin]
Well, that makes sense.

[Regina] (45:01 - 45:10)
They are looking for evidence that the worms are still alive and they found that 91% of people who got the hookworms did poop out eggs.

[Kristin] (45:11 - 45:16)
Oh, interesting. So, 9%, a few people, what, their bodies just killed off the worms?

[Regina] (45:16 - 45:29)
Yeah. So, remember, immune systems are still activated even with a small number of worms and your intestine is squeezing things through and maybe it was just too much for all the weak, pathetic hookworms.

[Kristin] (45:29 - 45:34)
Well, maybe the person with the tweezers picking out the worms didn't do a very good job on that batch.

[Regina] (45:34 - 45:55)
Maybe they got the runts of the litter accidentally. Right. So, second thing, was all of this unsafe?

Were there any serious adverse events? And good news, they didn't find anything serious that would require medical intervention. No anemia, no blood loss.

That was really the most dangerous thing they were worried about.

[Kristin] (45:55 - 45:58)
So, even in the high-dose group, they didn't see anything?

[Regina] (45:58 - 46:05)
No, no. So, that was good. They did report a lot of GI complaints, like bloating and stomach cramps.

[Kristin] (46:06 - 46:09)
Well, that makes sense because there's worms in your intestines.

[Regina] (46:09 - 46:15)
Right. So, in the hookworm groups, 44% of the people had GI complaints, a little less than half.

[Kristin] (46:16 - 46:19)
Okay. What about in the placebo group, though, Regina?

[Regina] (46:19 - 46:21)
Nothing. Zero percent in the placebo group.

[Kristin] (46:21 - 46:29)
Wow. That's interesting because we were talking about that nocebo effect, and it looks like people in the placebo group did not experience a nocebo effect, at least for those stomach issues.

[Regina] (46:30 - 46:35)
Right. No phantom sensations from phantom imaginary worms in the gut.

[Kristin] (46:36 - 46:39)
But it does do something, at least for some people, if you did get the worms.

[Regina] (46:39 - 47:15)
Right. Because it takes them a little while to move in and hook onto your intestinal walls and rearrange the furniture, make themselves at home.

[Kristin]
And how long does that moving-in period last?

[Regina]
Usually just the first few months, and then it goes away because your body gets used to it. So, there were 27 people who got hookworms. Twelve of them had these GI complaints.

Three asked to be dewormed. They couldn't handle it. Now, two of these were in the high-dose group, and only one was in the low-dose group.

So, small numbers here, but it is not looking great for that high-dose group.

[Kristin] (47:15 - 47:22)
That makes sense because you mentioned that's a pretty high-dose kind of pushing up against the boundary of what might be tolerable.

[Regina] (47:22 - 47:38)
Yeah. Now, they also wanted to see whether people actually managed to stick it out throughout the entire study. So, maybe they're not complaining about GI effects, but maybe they're just like really grossed out.

They don't make it to the end of the study.

[Kristin] (47:38 - 47:40)
This is the tolerability piece.

[Regina] (47:40 - 47:45)
Tolerability. So, in the hookworm group, 59% made it to the end.

[Kristin] (47:46 - 47:52)
Oh, only 59%. So, actually, a lot of people dropped out, but how did that compare, Regina, to the placebo group?

[Regina] (47:53 - 47:56)
62% in the placebo group made it to the end.

[Kristin] (47:56 - 48:07)
Oh, so pretty much the same.

[Regina]
Yeah. Right.

[Kristin]
So, that tells us that even though a few people dropped out because of the worms, in general, most of the dropouts were unrelated to worms.

[Regina] (48:07 - 48:14)
Right. It's a two-year study, so you're going to expect some kind of a dropout in there. People move away or they get busy with other things.

[Kristin] (48:15 - 48:15)
Right.

[Regina] (48:15 - 48:17)
Just random things.

[Kristin] (48:17 - 48:26)
Question for you, Regina. When somebody drops out from the worm group, do they tell them, hey, you have worms? Because you really should know.

[Regina] (48:26 - 48:47)
They absolutely unblind them at that point. They had all of this in the protocol. They offer them deworming medication and then pass them along to their primary care doctor.

So, no, it's not like, well, you may have secret worms in your gut or you may not and we'll never tell you.

[Kristin] (48:47 - 48:47)
Great, great. Glad to hear that.

[Regina] (48:48 - 49:11)
Okay. So, we've checked out delivery mechanisms, safety, tolerability. Last primary outcome, investigators looked at mood.

It's what they called well-being and the idea that maybe because you're worried you've got worms in you and it's really bothering you and you're never leaving the house because it's all you can think about and you're worried and you're depressed.

[Kristin] (49:11 - 49:16)
Yeah. That might be me if I was in this study, right? A little like my skin crawling all the time.

[Regina] (49:17 - 49:32)
Yes. Now, there were no significant differences between the groups, but I found the patterns to be interesting. So, I'm going to talk about those anyway, just realizing there's no significant differences between the groups.

[Kristin] (49:32 - 49:45)
But, of course, we need to put out the big red flashing lights and remind people that these patterns may not be real. They may just be chance fluctuations, but I'm going to allow it here because it's a Phase I study.

[Regina] (49:46 - 50:15)
So, this is, I realize this is the sin of cherry picking, but I'm going to treat these as exploratory results, hypothesis-generating results, because they are interesting. So, thank you for allowing it. This is what they found.

Now, placebo group did not change in their well-being over time, but the low-dose group actually got much better at six months, and they stayed good. Their mood stayed good and even got a little better in the last year.

[Kristin] (50:15 - 50:21)
Wait, their mood improved from getting worms?

[Regina]
Isn't that fascinating?

[Kristin]
What, they weren't lonely anymore?

[Regina] (50:21 - 50:27)
This is actually interesting, Kristin, because this was during the pandemic and the lockdown, so you might be onto something.

[Kristin] (50:27 - 50:35)
Oh, they had a friend. Maybe they were talking to their worms. I mean, I talk to my dog all the time, so why not?

[Regina] (50:35 - 50:42)
Hey, Henry. Henry, hookworm. How you doing?

How was your date with Ruth last night? Did it go well? That would make me very happy.

[Kristin] (50:43 - 50:51)
We're joking a bit here, but, Regina, is there any actual biological reason why your mood might improve with worms? Like, maybe they lost weight?

[Regina] (50:51 - 51:16)
Yeah, they did lose weight. Good question. We're going to talk about that in a moment, but there's another possible biological mechanism here, and that is that depression is sometimes considered an inflammatory disease, just like type 2 diabetes, and people in recent years have been linking how chronic inflammation also affects brain biochemistry.

[Kristin] (51:16 - 51:20)
And so the idea is maybe you reduce inflammation that might also affect the brain? Interesting.

[Regina] (51:21 - 51:48)
Or it could be, like you said, they're healthier, they've lost weight, they just feel better. Right. So that was low-dose group.

Low-dose group got better, their mood improved. Now, high-dose group also improved, but not quite as much.

[Kristin]
That's kind of interesting.

[Regina]
Yeah, not looking great for the high-dose group, is it? It's a pattern that we're going to see throughout this, and that's why I said it's interesting to look at the pattern and see if there's some consistency there.

[Kristin] (51:48 - 52:05)
Right. Just want to remind everybody, though, that these patterns, again, could just be chance fluctuations. And I also just want to point out here, Regina, the point of looking at the mood was just to make sure that the people in the worms groups didn't have a detriment to mood or well-being, and it doesn't look like we're seeing that.

[Regina] (52:05 - 52:19)
Right, right. We can at least say there's no strong evidence that it made things worse.

[Kristin]
Right.

[Regina]
Okay, those were all the primary outcomes, the most important things investigators were looking for. Now let's move on to secondary outcomes.

[Kristin] (52:20 - 52:30)
These are actually what people generally care about, the kinds of things that we're going to be testing in a Phase III clinical trial. They aren't the point in Phase I trials, but they're interesting and we want to explore them.

[Regina] (52:30 - 52:46)
First thing, let's talk about insulin resistance. We're looking at people who are at risk for type 2 diabetes, and insulin resistance leads to diabetes. In the placebo group, insulin resistance actually got worse over time.

[Kristin] (52:46 - 52:48)
Well, they were aging, so…

[Regina] (52:48 - 53:03)
Right, not surprising, uncontrolled, they're not doing anything, things are getting worse. The low-dose group, insulin resistance improved within the first year. The low-dose group improved significantly compared with the placebo group, and they stayed better.

[Kristin] (53:04 - 53:09)
Oh, that's interesting. So maybe it's doing the things that that biology that you talked about?

[Regina] (53:09 - 53:16)
That's the hope, but for the high-dose group, they improved a little bit, but not significantly better than the placebo group.

[Kristin] (53:17 - 53:25)
Interesting, because if those biological mechanisms are really what's at work, then you would think it would work in both worm groups. So maybe it's just a chance fluctuation.

[Regina] (53:26 - 53:40)
Or it could be something about having too many hookworms, like, you know, it's fine if you've just got a small party in there, but if you've got a big crowd, it's not good. All right. Okay, let's talk about weight.

That was insulin resistance. Weight loss.

[Kristin] (53:41 - 53:44)
Well, of course, this is what people care about, right? The weight loss.

[Regina] (53:44 - 54:04)
Right. Well, hopefully they care about their health, too.

Let me say right up front, there was no statistically significant difference between the groups. Okay. But again, the patterns, the effect sizes, they're still interesting.

Okay. Placebo group gained a bit of weight on average.

[Kristin] (54:04 - 54:07)
Makes sense. People tend to gain weight over time. Mm-hmm.

[Regina] (54:07 - 54:28)
Low dose group lost weight. Oh. Every time point, six months, one year, 18 months, two years, they lost weight on average.

So it's neat because it's not just that they lost weight at the beginning of the study because their tummy was upset and they weren't eating and they gained it back. No, it was throughout the entire study.

[Kristin] (54:28 - 54:29)
Oh, good. Okay.

[Regina] (54:29 - 54:33)
The median weight loss over two years was about 10 pounds.

[Kristin] (54:33 - 54:44)
Oh, that's actually a lot because for most dietary studies, a 10-pound weight loss is considered good. I mean, things have changed a bit now because there's Ozempic, but still, 10 pounds, not trivial.

[Regina] (54:44 - 54:51)
In the end, six out of seven people that remained in that low dose group, six out of seven had lost weight.

[Kristin] (54:51 - 55:05)
I love that you're saying the actual numbers there, Regina, because that's really good to remind people there were only seven people left at the end. So we're talking about seven people.

Yeah. This is why this is not one of the primary outcomes.

[Regina] (55:06 - 55:31)
Right, right. Perspective on the entire group of that seven, one person lost 37 pounds.

[Kristin]
Oh, wow.

[Regina]
I know.

Like, that is a lot. That was low-dose group, though. High-dose group, what have we seen so far?

Oops, it looked like they actually gained a little bit of weight. A median of nine pounds. By the end of the study, only two out of nine in that high-dose group had lost weight.

[Kristin] (55:31 - 55:43)
I feel like I'm going to be a broken record here repeating myself, Regina, but so it's hard to know, right? This could be something real that has to do with low-dose better than high-dose. Could be just a chance fluctuation.

Nothing is statistically significant.

[Regina] (55:43 - 55:55)
Right, right. But it does fit in with small numbers. It does fit in with a pattern that we're seeing. And there is one nice thing they did here, I'd like to point out now.

They used non-parametric tests.

[Kristin] (55:55 - 56:09)
Oh, wonderful.

[Regina]
Yeah, I thought you would like that.

[Kristin]
Yeah, I mean, with sample sizes this small, you said only seven and nine left in the worm groups.

With samples that small, you should almost always just default to a non-parametric test.

[Regina] (56:09 - 56:16)
Maybe we should talk a bit about non-parametric tests and what they do. I'd love to. They did Kruskal-Wallis here.

[Kristin] (56:17 - 56:27)
Okay, Kruskal-Wallis. Sure, because there's three groups, and that is the non-parametric test for comparing a numeric outcome like weight loss between three groups or more than three groups.

[Regina] (56:27 - 56:33)
Non-parametric tests are lovely because they don't rely on data being well-behaved.

[Kristin] (56:34 - 57:25)
I like how you put that, Regina. Yes, these tests are great because they deal well with badly behaved data. Regina, in some future episode, we're going to have a nice discussion about when do you use non-parametric versus parametric tests.

I'm going to defer that for a future episode. But the reason that we want to use non-parametric tests in this case is because with a small sample like seven people, one individual can have undue influence on any parametric statistics. So, for example, if we wanted to calculate the mean weight loss in the low-dose group here, we would be averaging in a negative 37 with six other numbers.

That is going to distort the mean, and it's not going to be a good representation of what happened in the entire group. I noticed when you brought up the weight loss originally, Regina, you actually mentioned the median weight loss and not the mean because you knew that the median was more reflective of the weight loss in the group.

[Regina] (57:26 - 58:21)
Exactly. That is a great way to describe it. And I just want to demystify the parametric and non-parametric.

When we're talking about parametric tests, we're talking about the traditional statistical tests that people usually learn in STATS 101, t-tests, ANOVA. We call them parametric because they involve knowing a lot of parameters or numbers about what's going on with the data. And non-parametric tests are much more forgiving.

And I always think of the non-parametric test as being dogs and the parametric test as being cats because cats are really finicky. Everything needs to be just right. You have to be petting them in certain ways, certain places, right, or they yell and they scratch.

But non-parametric tests are dogs and they're forgiving. They're like, I love you, whatever. Scratch me all over.

You're my best friend forever and ever.

[Kristin] (58:22 - 58:29)
I love your analogy, Regina.

[Regina]
Thank you.

[Kristin]
I'm afraid that we might offend some cat lovers, so I just want to point out that we love all animals on this podcast.

[Regina] (58:30 - 58:46)
We do. It's just that they have different personalities and statistical tests have different personalities and it's good to know what you're dealing with because you're going to deal with a cat much differently than you're going to approach a dog and the same things here.

[Kristin] (58:46 - 58:50)
That's a great way to put it. Can we explain actually how these tests work, Regina?

[Regina] (58:50 - 58:59)
Let's do it. How about we just do one example with two groups instead of three. So, let's talk about low-dose group and high-dose group just to make it simple.

[Kristin] (58:59 - 59:33)
Yeah, that's a great idea just to simplify everything. The principles are the same whether we're talking about the Kruskal-Wallis test or the test that we use for two groups. It actually has two different names.

It's the same test. Well, it was just invented by different people around the same time.

So, one of the names is the Mann-Whitney U-test. I don't like that name. It's also called the Wilcoxon Rank-Sum test.

And I love that name because it tells you what the test does. It's not just some random person's name. I mean, they should get credit of course.

[Regina] (59:33 - 59:35)
Who cares about the people? What did it do?

[Kristin] (59:35 - 59:46)
Right. It's just much more descriptive to say what it does. So, it's the Rank-Sum test. So, you can guess what they're going to do.

They're going to rank and then they're going to sum. And by sum, I mean adding things up. Summing, adding.

[Regina] (59:46 - 59:49)
Okay. So, sum we get. Let's talk about ranking.

What do you mean by ranking?

[Kristin] (59:50 - 1:00:26)
So, imagine, Regina, we take all 16 people that are left in the low-dose and the high-dose groups and we combine them and then we line them up from the best weight loss to the worst weight loss. So, the person who lost 37 pounds, they're going to get a rank of one. They are at the front of the line and then we line up everybody else behind them.

And the person who did the worst, they're going to get a rank of 16. And everybody in the line, they're going to get that number, that ranking, rather than their actual weight loss. And, Regina, can you say a little bit about why those rankings are nice compared with the underlying number?

[Regina] (1:00:27 - 1:01:14)
Yeah. So, this is fun. It almost makes it like a reality show, right?

They're lined up and we've got the winner up front and the poor person at the end, number 16. And it's just like you were saying before, that one person who lost 37 pounds, if we're using the actual number in there in this parametric way, they are going to be hugely influential on the mean. Because one super big number in there is really going to make the mean much higher.

The ranks, though, the ranks do something clever. So, like you said, we've got that person who lost 37 pounds, the right in front. But they're going to be standing right next to the person who had the second highest weight loss, number two.

And in that case, it was about 20 pounds. So, instead of them being, you know, 17 pounds apart, they're just one unit apart.

[Kristin] (1:01:15 - 1:02:15)
All of these numbers are evenly spaced. So, none of the people have an undue influence on the statistics.

All right. So, we've ranked them. And now, guess what we do? Because it's the rank sum test.

It's a big mystery. We're going to sum them. We're going to add the ranks.

The key, though, is we separate the two groups. We take the low-dose group and we put them in one corner and the high-dose group in the other corner. And we have them sum or add up the ranks in their group.

And we're looking for which group has the lowest total. Now, there's a little trickery that has to go on here because the sample sizes aren't the same between the groups. So, we have to make a little mathematical adjustment for that.

And that requires some fun math behind the scenes. That math also allows us to get a p-value to say whether the two groups differ significantly in their sum of ranks. If anybody wants to do that actual math, it's some really fun algebra that I enjoy.

And I go through that algebra in my medical statistics program on Stanford Online. So, if you love fun math, I'm going to send you there.

[Regina] (1:02:15 - 1:02:24)
I love how you break it down in this intuitive way because the math is nice. It's like you get to see underneath the hood and it makes you understand everything better.

[Kristin] (1:02:24 - 1:02:32)
Right. Plus, algebra is just fun. All right, Regina.

So, they use these nonparametric tests in the worm study. And what were the results again, remind us?

[Regina] (1:02:32 - 1:02:41)
Mm-hmm. So, insulin resistance, they found significant differences between the groups. Weight loss, it did not make statistical significance.

[Kristin] (1:02:41 - 1:02:56)
Right. Right. So, again, the study wasn't set up to detect significant differences on secondary outcomes.

That's why we're going to need some follow-up studies. But they found that in general, the worms were safe and tolerable. So, are they doing follow-up studies?

[Regina] (1:02:56 - 1:03:04)
So, hold that thought.

Before we talk about the investigators, I want to talk about the participants. What happened to their worms? Aren't you dying to know?

[Kristin] (1:03:04 - 1:03:08)
Well, I assume that at the end of the study, they got dewormed.

[Regina] (1:03:08 - 1:03:26)
They did not.

[Kristin]
What?

[Regina]
The authors reported that people loved their worms.

They wrote in the manuscript and said, okay, yes, some people didn't lose as much weight as others, and they were disappointed, but they continued, they said, quote, with unabated enthusiasm.

[Kristin] (1:03:27 - 1:03:32)
Wait. So, they offered to deworm them, and they said no?

[Regina] (1:03:32 - 1:03:51)
Yes. All of the hookworm folks, except for one, opted to keep their worms. And the one person who did decide to deworm did it just because they had to do a medical procedure, and I guess doctors didn't want, you know, the worms around. They kept their worms.

They were unblinded. They were told how many they had, what group they were at, and they chose to keep their worms.

[Kristin] (1:03:52 - 1:03:56)
Wow. So, they liked having the worms. I'm kind of blown away by that.

[Regina] (1:03:56 - 1:04:17)
Fascinating. Okay. So, there's that.

I felt like that was the most fascinating part. Yes, yes. Okay, investigators.

Yes. What are they doing? I did notice that two of the authors had a conflict of interest.

Yeah. They are founders and shareholders of a company that's developing drugs derived from hookworm proteins.

[Kristin] (1:04:17 - 1:04:24)
Oh, so, they're trying to get around having to put creepy crawlies in yourself. Well, I applaud that.

[Regina] (1:04:25 - 1:04:34)
It seemed like the idea is not really geared towards, okay, you go to the doctor and they've got the vial of hookworms and they're going to slap it on you.

[Kristin] (1:04:34 - 1:04:44)
Yeah. It's like leeches or something. Okay. So, I see long-term we're trying to get a drug or some kind of treatment that mimics what the hookworms do to the body.

[Regina] (1:04:45 - 1:04:53)
Right. So, it looks like right now they're doing clinical trials with actual worms, but it looks like long-term they might want to ditch the worms. Okay.

[Kristin] (1:04:53 - 1:05:30)
That's nice that we're getting rid of the worms eventually. Great. All right, Regina.

I think now we're at the point in the episode where we can wrap it all up and rate the strength of the evidence for the claim. And the claim today is that hookworm therapy is safe and tolerable. And how do we rate strength of evidence in this podcast?

It's with our trademarked highly scientific smooch rating scale. It's like Amazon stars. One smooch means little or no evidence for the claim.

Five stars means strong evidence for the claim. So, Regina, kiss it or diss it?

[Regina]
I'm going to go with 4.5 smooches on this, Kristin.

[Kristin] (1:05:30 - 1:05:48)
Really?

[Regina]
Yeah. Only because in the claim I did not say what dosage.

And I'm thinking if I'm going to do mail ordering, you know, DIY, unless I'm not going to get 40. Because 40, that overall pattern just sounded like it was a little too much. But I'm going to go with 20.

Sign me up.

[Kristin] (1:05:49 - 1:06:27)
Regina, I'm going to go with five smooches here because it does appear that this is safe and tolerable for most people. I mean, a few people dropped out, but most people wanted to keep their hookworms. This doesn't mean I'm advocating this.

Do not try this at home. But it is an opportunity for me to give five smooches, which isn't going to come around that much on this podcast. I should add, though, that if you had done a different claim, if the claim was about weight loss or insulin resistance or mood, we do not have evidence that hookworm therapy does any of that.

But for the claim safe and tolerable, yes, five smooches. Because the claim itself is just not that ambitious, but in a good way of not being ambitious.

[Regina] (1:06:27 - 1:06:47)
Good way. Incremental progress. I think this really reflects how science is supposed to be done.

This was a good, well-done study, but it was a Phase I trial, and we need that first. And that actually relates to my methodological moral. Are we ready for the methodological morals?

[Kristin] (1:06:47 - 1:06:48)
What's yours today?

[Regina] (1:06:48 - 1:06:54)
Walk before you can run. Invest in simple, but high-quality Phase I clinical trials.

[Kristin] (1:06:55 - 1:07:06)
Oh, I love it. Absolutely, Regina.

[Regina]
Thank you. What about yours?

[Kristin]
Here's mine, Regina. When faced with small samples, you better rank and sum, baby.

[Regina] (1:07:07 - 1:07:09)
Rank and sum, baby.

I'm going to put that in a coffee mug for you.

[Kristin] (1:07:09 - 1:07:10)
Absolutely.

[Regina] (1:07:10 - 1:07:15)
Because that sounds almost dirty. It's a little suggestive. I love it.

[Kristin] (1:07:15 - 1:07:30)
All right. I have to admit, Regina, I started this episode really skeptical, and you have gone a pretty far way in convincing me that there might be something here, and that it might not be quite as icky as I think it is.

[Regina] (1:07:30 - 1:07:44)
No way. We're doing it. Next time I come visit you, I'm bringing hookworms.

[Kristin]
No, no, no. I don't think that's going to happen.

[Regina]
B-Y-O-H.

Bring your own hookworms. Hookworm party. We're doing it.

Get ready. I'm just warning you now.

[Kristin] (1:07:45 - 1:07:50)
Okay, Regina. This has been a lot of fun.

[Regina]
Thanks, Kristin.

[Kristin]
Thanks, Regina.