Geoff

Dr. Ethan Weiss, thanks for coming by the office.

Ethan W.

It's my pleasure, good to be here.

Geoff

So you have an interesting background. You have a clinical cardiology practice, you have a research background as a publishing academic, and you recently stepped into the entrepreneurship space with Keyto, spelled K-E-Y-T-O, which is a keto diet breath meter and app, supporting app. A lot on your plate, but just I think it would be helpful to give context for our audience. How did Ethan Weiss, maybe 20 years ago, get along this path?

Ethan W.

So, the short answer is, my dad is a cardiologist, and so I grew up around medicine, and grew up around science. But I was an atrocious science student in high school. I mean, I was actually pretty much of a mediocre student throughout high school, and I went to college thinking that I was going to do something non-scientific, and definitely non-medical. I had no interest, and at that time felt like I had no aptitude to do any of it.

And so I went to a small liberal arts college up in New York state, and initially intended to study music, but pretty quickly found out that I didn't have the talent to do that. So I think it was only because I was in that environment where there really was no science. I think they've actually really bolstered their science in the past 25 years since I've been gone, but at that time, really, there were hardly any science majors. And so I think it was friendly and nonthreatening to me, so I decided to take a couple science classes and ended up finding at that stage of my life, without the pressure of being in a super hard charging, all boys private school in Baltimore, that I really liked it.

And so I just sort of did one of these, I'll do another one, I'll do another one, and then I thought, well gosh, if I'm liking the science, I'm pretty good at it, maybe I should just do medicine. So I ended up going straight through to do medical school. But it still, when I got to medical school I was one of 10 non-science majors in my class, and we were quickly allocated to the bottom of the class. It was sort of a funny adaptation going to medical school at that time, because we were ranked, one through whatever it was, 120, and I think most of us were used to being toward the top of our class, and by definition, you take 120 kids who are all at the top of their class, someone's not going to be at the top of their class.

And so those of who had not studied science ended up clustered at the bottom, and it was pretty much a struggle that I actually, legitimately almost failed out of medical school. I was really doing quite badly, and I went to visit a dean, or maybe he asked me to come visit him, and so I said to him, "What do I do to not fail out?" And he said, "Well, I think you just need to slow this down. Get your hands on things." So he recommended that I go work in a lab in the summer, between first and second year, and so I thought, "Okay, fine, I'll do whatever you say." And so I called 25 different people.

Back then, it was actually a call, there was barely email, this was the summer of 1992. And I got 24 straight nos. When they heard my story of this quasi-humanities major, came from Vassar College who's failing out of medical school, they were not super excited to have me in the lab. And long story short, I finally found this young assistant professor who was working in... He was a psychiatrist who was working in neurosciences who agreed to take me. And really, the truth is, within a week I had discovered my passion in life, which was science. I really fell in love with the lab, I fell in love with the culture, I fell in love with the whole thing, and I liked working with my hands, and all that stuff.

And basically, I went nuts and went back to this dean, and I said, "I need to go to graduate school," and he said, "Whoa, slow down cowboy. Do more than two months in a lab." So anyway, I ended up taking a year off, and had a really good experience, and I came to this fork where I had to decide, was I going to actually do graduate school, and gave it some consideration. But got a lot of...

Geoff

Get the M.D. on top of the...

Ethan W.

Yeah, so I had my M.D., and at the time where I was a student you could pretty... I wouldn't say easily, but it wasn't that hard to be able to add... to get into the Ph.D. program. Whether I could have found funding for that was a different story, but I think I'd gotten enough traction that my mentor said, "Look, if you want we'll sponsor you, and if you want to stick around and do a Ph.D., go for it," but I was getting to a point where I was sort of like, "Eh, I'm in my mid to late 20s, and maybe it's just better to go on."

Asked a lot of people, and specifically asked, am I going to be able to do science as an M.D. only scientist, and those people said, "Yeah, sure, it's just really going to be the quality of your experience." And so, I ended up not doing that, I did my internal medicine residency back at Hopkins, and then came to San Francisco 20 years ago, summer of 1998. And I came here to do a combined research and clinical fellowship in cardiology. So that was sort of the long-winded version of how I got to be where I am.

Geoff

And now I would say that you're probably one of the more respected folks in the space of keto, cardiology, especially in the tech world that we live in, in San Francisco. So it's kind of a cool story to go from, I guess, a humanities major, through not knowing that he really likes science, that now being a leading voice in science taught leadership, I would say.

Ethan W.

That's very kind. Look, I mean my background was important, and I think one of the things I try and tell my kids... Actually my older daughter is a freshman in high school, and in her high school they have these electives, and her elective her first trimester was improv. And she was super bummed, and I was like, "That's the greatest thing ever." You probably couldn't design a better skill to have. In whatever career you end up having, the ability to be able to have an impromptu conversation off the cuff, and not struggle and be able to do that is super important. So I do think my humanities background, maybe not the music, but being able to write, and think critically and stuff, that was all super important for me.

Geoff

Yeah. I think one of the things that is especially interesting for our audience is that most of our listeners are either up to speed on the ketogenic diet, or probably practicing the ketogenic diet, or fasting, or some variation of optimizing metabolism. But I think your background as a cardiologist is especially interesting, because we've had folks in nephrology, folks in internal medicine, or with weight management, but not a lot of folks with cardiology experience, prescribing and investigating the ketogenic diet. So I would say that standard medical practice is still low-fat diet. I think if you talked to a cardiologist 90% of them would say, "Eating high fat, that's crazy, you're going to give your patient a heart attack." I'm sure that was probably your background and training.

Ethan W.

It was my background as a child.

Geoff

How do you go from the status quo, or the standard recommendations of a low-fat, high grain whatever diet, to looking at keto as a viable, not just option, but something that's beneficial for these types of patients?

Ethan W.

I mean I literally grew up in a home where my dad was and is, remains a cardiologist, and at that time, growing up as a kid in the 70s and the early 80s, it was pretty clear, like the American Heart Association, all the different ADA, everything else, viewed fat as the evil. And that certainly was ingrained in me, and I think it's ingrained in our culture. It's actually difficult to unlearn this concept that fat could be anything other than poison. I mean that was really the way we were raised, and what I think, what I try to explain to people, is that nutrition is one of the rare examples of a true zero sum game.

If you have a certain number of calories that you're going to eat during the day, some fraction of those are going to be broken down into the three macronutrient categories. You're either going to be eating protein, carbohydrate, or fat, and so if you're going to limit your fat intake, and most people have a relatively consistent and moderate protein intake, then by definition what you're doing is increasing your carbohydrate intake. And so I ate a ton, I mean I had a ridiculous amount of carbohydrates as a kid. I remember, I probably had two or three Cokes a day, and Doritos, and chips, and just ridiculous amount of carbohydrates, which probably were labeled as heart healthy. I mean I'm not even joking.

Geoff

Yeah, that's probably true, yeah.

Ethan W.

I even vaguely remember, when I got to San Francisco in the early 2000s, having conversations with friends of mine. This one endocrinologist, I remember specifically who worked in the lab that I was doing my post-doc in, and we were talking about, I think it was right in the peak of the Atkins Diet craze, and I remember thinking, "That's insane. These people are killing themselves." And I remember when Dr. Atkins died, and he died of a heart attack, there was this whole... And I remember having this almost I told you so moment, it was really... But again, this is all based on opinion, and the absence of any real strong, robust data. Or if there are data, the data are really observational and pretty flawed. And I think the story really for me begins and ends with the flaws in nutritional epidemiology. And so we'll get there eventually, but I think it's really important to stay humble about what we do and what we don't know, and the reaction from me now, having embraced an openness to other nutritional approaches and lifestyles, I don't want to make the same mistake that our predecessors made, in assuming that this is the right way forward.

Geoff

The end all be all. Yeah.

Ethan W.

I mean, we don't have data yet to support the idea that, say, the ketogenic diet is going to improve risk for cardiovascular disease. We have some data I think that are pretty good, that it certainly can moderate the effects of Type II diabetes, but I want to be super careful and not jump to making the same mistakes that people made in the past. But I got here sort of... Well I mean, the path is actually sort of simple, right? I got interested...

So for the past 15 years, I've been working in a lab. My lab has been focused on trying to understand basic mechanisms of metabolism. And I think about five or six years ago, I woke up one morning and thought, "Gosh, this is really fun. I really love going to work every day, and we get to do..." It's basically like I'm getting paid to play, and it was that enjoyable for me. But in terms of impact, it felt... I struggled with this idea that there were probably 30 people in the world who really were paying attention to what we were doing, and the question of what we were going to leave behind really bothered me. So I started to think, "Well, how could I start to explore having an impact more than just on these 35 people who care about the work that we're doing in the lab?" And so got interested in sort of, let's think about nutrition, nutrition is one of these things, we can apply nutrition to huge numbers of people.

Geoff

Everyone eats.

Ethan W.

Exactly. Everyone eats, and it's super important, and, oh, by the way, if you think about as a practicing cardiologist, if you look at the landscape of how we treat or prevent cardiovascular disease these days, we really have the sort of standard medicines, procedures, surgery, and I think we're getting to a point now, especially in this country, where the economic landscape dictates that it's getting harder and harder to justify development of new therapies, because of the cost.

And you can use examples, my favorite example is the development of this class of medicines called PCSK9 inhibitors, which are cholesterol medicines, which were developed over the past 15 years. And those drugs have had... I mean it's probably the best story from concept, discovery, biology, all the way through the clinical program, best story that I've seen in my career, and yet the drugs are sort of a commercial flop, and you could make a lot of excuses for that. But for me, the hard, fast reality is that the economic reality of today is that it's really hard to justify paying for them. So that's how I got interested. I ended up doing a bunch of advising for companies, and eventually I got introduced to Virta, which is based here in San Francisco. And they're applying the ketogenic diet to patients with Type II diabetes, and so I've been advising them for two years now, and that's where I really got to know, that's where I really began to do a deep dive on keto.

Geoff

I think that's an interesting full circle journey, going from being raised by a cardiologist, who probably was steeped into that dogma of AHA, ADA, seeing that fat was evil, to, okay, being open minded, and just kind of going through Virta, just reading like, "Oh, let's actually look at all the literature here," and the literature for Type II diabetes is pretty compelling, right?

Ethan W.

Yeah, and I give Steve and [Sommi 00:12:54] and those guys a ton of credit for bringing me on board. Because at the time, I'm naturally pretty skeptical, but at the time I certainly wasn't, I was no advocate. In fact, I was definitely going into this with eyes wide open, and thinking, "All right, well..."

Geoff

I'm going to call BS on you guys.

Ethan W.

No, but I mean look, the truth is, I got introduced to them through Bob Kocher, who's a partner at Venrock, he's an investor, and I think he led their series A. And Bob's a physician, and Bob told me when we first met, he said, "You're not going to believe the results these guys are having," and he said... And this stuck with me, and I think he's largely right. He said, "Their results are unparalleled in terms of diabetes treatment or reversal, or whatever name you want to call it, next to anything other than bariatric surgery."

And obviously, bariatric surgery's not something you can apply, or want to apply, to 80 million people. It's incredibly effective at managing diabetes in certain people, but it's not going to be for everybody. But that stuck with me, and so I went into this thinking, "Okay, well this is an interesting approach for diabetes management, but what the hell are we doing to cardiovascular risk on the side?" And so it definitely was this very slow, deliberate, and very thoughtful bit by bit, me digging in, learning about the history of keto, going back hundreds of years, to really doing a deep dive on their data. And that continues to this day, I still am learning so much, it's been really fun.

Geoff

Yeah, curious to hear a little bit about the cardiovascular side of the story, because obviously cardiovascular disease is the biggest killer of Americans, by far. I think cancer's number two. So, I think within how keto can apply to cardiovascular disease there's the cholesterol story, and I think another big biomarker that people care a lot about is calcium coronary artery scores. Curious to hear about your experience, or your best practices around, what are the biomarkers that you care about as a clinician for cardiovascular risk, and how does diet impact some of those biomarkers? How do you think about it?

Ethan W.

Yeah, this could be a very long discussion, so just jump in and interrupt me. And I'll introduce it by saying that I'm a little bit of an anomaly when it comes to the low-carb keto world, because of my feelings about cholesterol. So, I have come a long way in understanding the benefits of low-carb, or of keto in health, and I have hope around what we might eventually demonstrate in terms of cardiovascular health, but I am not giving up on the so-called cholesterol hypothesis. I'm still a firm believer that the cholesterol, whatever form you want to call it, is a fundamental, an important, if not the most important, risk factor in developing cardiovascular disease. So you want to talk about cholesterol first, or calcium, or do both, or...

Geoff

I think those are probably the two big biomarkers that people talk about for CVD, so I think we can go one at a time, sure.

Ethan W.

So, cholesterol for me is, like I said, I want to be super clear, I am not of the camp that cholesterol is not important as a risk factor. That said-

Geoff

Both LDL and HDL, you still look at total.

Ethan W.

No, I think we've sort of come to a general understanding that HDL is probably a marker of risk, but not itself contributing to risk. In other words, it used to be thought that HDL was good cholesterol, so the higher the HDL, the HDL was actually performing some protective mechanism in terms of returning cholesterol out of the artery wall. And that was the teaching forever, and in fact when I was growing up, and when I was a medical student, the dogma was, all right, LDL is bad cholesterol, HDL is good cholesterol, that's the one that you want to get it up however you can do it. Whether it's through exercise, alcohol, or drugs, you want to get HDL up, and then don't really pay attention to triglycerides. It's just sort of a non-factor.

And I think what we've learned, largely through the work of my colleague in the human genetics world, and Mendelian randomization and other techniques that they have, is that it turns out HDL itself is not causative, HDL is just a marker, so it doesn't mean that it doesn't confer... That if you have a low HDL, it doesn't mean your risk is definitely higher than it would be, but getting your HDL to go up doesn't improve your risk at all. And we've now demonstrated that through multiple mechanisms, including I think three different classes of drugs that have all failed. And if anything, yes, they raise the HDL beautifully, but if anything, not only do they not reduce the risk of cardiovascular disease, they make it worse.

So I sort of stick HDL aside. Triglycerides is fascinating, because these Mendelian randomization studies have now shown that triglycerides is indeed causal, looks to be causal, and that's fascinating especially for somebody who's interested in keto, because one of the things that happens in keto is your triglycerides come down. Almost virtually, people see this decrease in triglycerides. So I think if you're looking at just the sort of basic, fasting lipid profile, where you get a total cholesterol, and an HDL, and a triglycerides, there are a lot of people out there, including friends of mine, who think that that's worthless. I love the idea that we can get information out of anything, and so I think it's certainly not the most sophisticated information, but it's actionable, and I think the number that I pay attention to now, in that basic lipid profile, is the non-HDL cholesterol. So, total cholesterol minus the HDL.

And that includes most of the sort of atherogenic particles, and other things that people pay attention to. So if you're only getting a fasting lipid profile, the number that I care about is non-HDL. It doesn't mean I don't pay attention to LDLC, I do, but the number that I care about is non-HDL. And of course, I do pay attention to triglycerides. There's obviously a wealth of other ways to dig down, and drill down into the lipids, and I think-

Geoff

You could spend a masterclass on it.

Ethan W.

We won't do that today, but I think the truth is, if you step back and you're honest about the data right now, the data don't support, at least in a robust way, that any of those measurements add anything to heart outcomes. It doesn't mean that they won't, they might at some point. Again, there are arguments among experts, people who are far more expert than I am about which of these markers is more or less predictive. But I think the people that I respect the most seem to think that the data, the information you get out of non-HDL is roughly equivalent to the information you get from Apo B, which is a sort of atherogenic component of lipoprotein.

And whether or not that is more or less equivalent to LDL particle number is a debate that I don't think we can have today. The other thing that's emerged in the past few years that I was initially skeptical abut, that seems to be also causative, against supported by human genetics as well as epidemiology, is LP-a. So when I see a patient for the first time, at the basic level I at least get a fasting lipid profile, paying attention to HDL, I'm not starting to get Apo B more, and patients who want it, I'll do a particle analysis, and then I'm getting LP-a as well. So that's sort of the cholesterol panel for me. Obviously, in some or most people, we're also getting a HSCRP to look for inflammation as well. So that's sort of the basic risk assessment blood test panel that I'll do, and we can-

Geoff

When you have a keto intervention, typically in my experience, just on myself and just seeing folks, people in the community sharing their blood and lipid panels, is that you would typically see HDL go up, you would see triglycerides go down, and sometimes LDL would go up on keto. So it'd be interesting to hear how you integrate that with those typical results of someone on a ketogenic diet with your understanding of cardiology, for assessing risk here.

Ethan W.

Yeah. There's a tremendous need to be able to really hammer this down, and kind of understand it. And I think the first step is to understand what are the changes, and the second step is to understand what's the impact of the changes? Understanding the impact of the changes clinically is going to be a longer investment, that's going to take a longer time. But I think Virta's done a really nice job looking at the changes in their population. They've done it on a population basis, and they haven't... And I think it's important to recognize that if you look at the sort of, what are the mean changes in any of these markers across hundreds of people, you'll see things move.

But any one individual might have more or less of a change, and I want to come to really talk about what happens, because there are people who, I think, are referred to in the community as hyper-responders, and I think it's really important to address that. Because there is a subset of people who clearly will have... I think nobody would argue that the markers, at least the traditional markers the way we look at them, go wacky in the wrong direction.

But I would say on average if you look at the population, with what Virta has published, and I think, and I believe it... data, I think, are really robust... is that what you see is, as you said, an increase in HDL, decrease in triglycerides, a slight increase, about 10% increase in LDLC, but no change in Apo B. And if you do a particle analysis, it looks like what you see is an increase in the so-called pattern A. So you see an increase in these big, fluffy LDL particles, and a decrease in the small particles, which again, to my lipid colleagues, like Ron Cross and others, those are the more atherogenic particles.

So it looks as if the hint is that what you're seeing is a change, again, on a population basis, you're seeing a change that seems neutral at worst, but maybe even protective, in terms of reducing atherogenic lipoproteins. So that's something, I think, that's comforting, on population basis. So what do you do with this individual? So you have a patient who comes to see you in the office, and I have a lot of them, and they say, "I went on keto, and my LDL particle number went from 600 to 1200, and my Apo B doubled," whatever it is. And so what do you do with that? And that to me is the important question in this field, and what I tell people is, you have four choices.

Basically, you come to me, Geoff, and you say, "My cholesterol went whackadoodle when I went on keto," and I say, "All right Geoff, you got four choices." And so your first choice is ignore it. There are people out there who are able to talk themselves into thinking this is meaningless, there are people out there who are able to say, "Okay, well I have a calcium... " we'll come back to calcium in a second, but they're willing to say, "All right, I have a calcium score of zero, I'm 55 years old, and so that's comforting, and so I'm not going to ignore it, but I'm going to set it aside and maybe we'll repeat the calcium score again in a few years. But I'm going to put it in a drawer."

So option one is ignore it, or put it away for a little while. Option two is quit keto, right? No one wants to do that, or at least... I shouldn't say no one. Most people who go on keto and like it don't want to stop. They like how they feel, they like the effect, they like the weight loss, they like the other metabolic benefits, but it's always an option. Option three is to make a shift in the ratio of your saturated fat to monounsaturated fat intake. And I think that to me is the simplest, and most attractive option. It would be hard to do if you were a carnivore, but I think it would be relatively easy to do otherwise. And so again, because on keto, because nutrition is zero sum, on keto you have to increase your fat intake way above what we're all used to, and way above what we were all ingrained and conditioned to think is normal. You're going to have to derive those plants from other sources, probably more plant based sources.

Geoff

Nuts-

Ethan W.

Yeah, nuts, avocados-

Geoff

Avocados. Right.

Ethan W.

Olives, olive oil, fish, really rich in omega-3's and things like that, as opposed to eating, you know, fatty steak, or pork and stuff, all day long. So that's the option. The fourth option, which I think we could also spend 40 hours talking about, but I don't want to dismiss, it's just funny how the world has come to see this as evil. Fourth option is to take a cholesterol lowering medicine, and I know that seems like craziness to so many people, it's so funny how there's this wild skepticism about this, but statins specifically, as a class of medications, are probably the best studied medication in the history of pharmaceuticals.

There's probably never been a better studied drug class. It's been around since the late 1980s, and arguably, several hundred thousand patients have gone into large randomized controlled trials, with outcomes. So is there potentially some bias, of course, are there side effects, probably, but they're really powerful medications, and I think... I'm fond of saying, while they certainly have effects on lipids and lipoproteins and other things, their biggest effect is that they reduce your risk of having a heart attack. So I reserve that for people who are... Again, you're making trade-offs all the time in medicine, it's one of the things you learn early on, is you're constantly going to make trade-offs, so if somebody comes to me and says, "I love this keto thing, I'm really worried about my cholesterol, I don't want to change the way I want to eat," then an option is to take a statin.

Geoff

Look at statins. Yeah, which is interesting. I don't want to get too derailed with statins, but it seems like it's one of the areas in the low-carb, keto community where it's like, oh, statins, lot of side effects. I mean how do we steel man that argument? It's that the research might be biased, the raw data has never been fully published, and while there are small cases where it seemed like there was positive effects, it would just average out in the population size, or a lot of people with side effects, with muscle pains and all that. It would be kind of the steel man way of presenting why statins aren't that great. And the original inventor of statins, I believe a Japanese scientist, ended up saying that he didn't believe in statins anymore. So I guess if that's the steel man argument, how do you counter the steel man argument of...

Ethan W.

I guess I should say the other thing to me that's so fascinating is how these Venn Diagram circles of the low-carb, keto community and statin skepticism, how there's so much overlap between the two of them. And it's something I talk about, and think about a lot, and I'm not sure I have a very good explanation. There are lot of theories, but forget that for a sec. So again, short of vast conspiracies involving just, countless, hundreds of thousands of people, and academic institutions... It would have to be a tremendous bias. I think I'm less willing to buy into that, so I believe the data in general sort of at face value are legitimate and real.

Are there examples where people cook things and all this other... Of course. But I mean we're talking about a huge dataset, with multiple different... You know, five, six, seven, eight, nine different pharmaceutical companies, hundreds of different academic investigators, so it would have to be a really vast conspiracy. In addition, statins are now all completely generic. So there's no financial conspiracy. I mean if there were a conspiracy 20 years ago, then that conspiracy's long over.

Geoff

Incentive to economic rent is now gone, right, yeah.

Ethan W.

That's gone, so I think where things get really complicated, and where I have genuine disagreement... healthy, and thoughtful disagreements with even colleagues of mine... is over the differences between primary and secondary prevention. So I don't know how much people pay attention to that, but the bulk of statin data that's been published has been published in what we call secondary prevention population. So, people who've had a heart attack, or have the equivalent of coronary artery disease, get randomized statin or placebo, and then you follow them for X number of years, you look at the difference in outcomes.

And I think there's very little debate, even among the most skeptical statin skeptics, that statins are effective in secondary prevention. So then the question... And I think where things have gotten more complicated is in primary prevention, say somebody like you or me, who's never had a heart attack, may have risk of having a heart attack, so what's the role of statins in preventing our first heart attack. And because the risk of heart attack in anyone in the primary prevention world is lower, by definition, it's harder to design trials to enroll bigger populations.

Trials have to last longer, so I think I will be the first to admit that the quality of the data in the primary prevention population is worse. But does that mean, and is there any biological plausible explanation for why... Let's just say I have a heart attack tomorrow. So today I'm in the primary prevention population, tomorrow I'm in the secondary prevention population. Why would there be any difference in the ability of the statin to reduce my risk tomorrow, versus today? So I think it's biologically difficult to understand, other than just sort of the basic statistics, that the event rate's going to be higher in the secondary prevention population, so therefore it's easier to design trials that are properly powered. Again, you sort of get in this thing...

Geoff

There's a nuance to that, and there's that subtlety, yeah.

Ethan W.

I think from my standpoint, again, I think the data are relatively incontrovertible that statins prevent heart attacks. Do they prevent them entirely through reduction of LDL cholesterol? Absolutely not. I think again, that's part of the reason why I like when people refer to statins as heart attack prevention pills and not cholesterol pills, because they probably have a lot of other pleiotropic effects, including effects on inflammation in the vessel wall, or there are people who think they're plaque stabilizers. There was a time in the 1990s where people thought the statins prevented against sudden cardiac death, that they were stabilizing from an arrhythmia standpoint. So I think it's a really complicated and energized, and sometimes religious discussion, and I don't want to piss people off, but I think... I will say this. I came to the low-carb keto thing with a tremendous amount of skepticism, and over the past five years, I've grown to embrace it now, really spend my life-

Geoff

Looking at it.

Ethan W.

With it. And so I just ask people to have the same open mindedness when they approach the cholesterol question, because I think the data there are really strong and compelling. So I'm not going to change anyone's mind, and I'm certainly never going to push anyone to take a pill they don't want to take. So we can talk about side effects. Now I think side effects are super interesting when it comes to statins, and my take on it is that we don't really have sufficient data today to tell you anything other than the one consensus agreed upon side effect is you increase your risk of developing Type II diabetes. You sort of disregulate your insulin/glucose homeostasis to some degree by taking a statin.

Everything else, I'm not saying it doesn't happen, but everything else has not been born out. And partly it's been the way that the trials were designed, so most of these big statin trials were designed with a run in period. So if you and I get randomized to one of these big statin trials, we both will... Let's say you get randomized to placebo, I get randomized to statin, we're both going to take statin for three or four weeks before we start. And if you develop any side effects, you're out of the study. So in some ways, what they did was flush out all the people who were going to have any side effects, and so that's why when you look at the data, there isn't really ever a difference between placebo and statin, when it comes to side effects.

Geoff

Right, because they flush them all out.

Ethan W.

That's a little bit of a false, so I think there are a couple studies that are ongoing now that should begin to answer the question of, what is the true incidence of, say, muscle related side effects, which is the most common thing I hear about. The cognitive stuff will also always bother people, I don't know how we're going to answer that one, but those are the main ones. But everything we do, as I said before, in medicine is a trade-off. And so it's just about having this conversation about what are the risks of this, what are the risks of this, and how do you want to proceed?

Geoff

No, I think that's a well nuanced position there. I don't want to forget about talking about calcium, so let's touch on calcium. So again, I think if you don't think LDL or HDL or cholesterol is a big marker, I think folks in the low-carb keto community will say that calcium is the biomarker of choice, we should look at calcium. What are your thoughts there? Obviously it could be useful, right?

Ethan W.

Yeah. So calcium, coronary artery calcium, the amount of... So it was, I think, first seen on chest X-rays, and then this guy, I think his name is actually Dr. Agatston... if you get a calcium score, it'll come out in Agatston units. He figured out a way to quantify the amount of calcium. It's been studied for a long time as an epidemiological marker for cardiovascular risk. So the more calcium you have in your arteries, the higher your risk. And the reason for that is that for reasons that we don't totally understand, as plaque progresses-

Geoff

They get calcified.

Ethan W.

It gets calcified, right. You can see that on an X-ray. So the story with calcium is very much the story with a lot of things for me. I started off as a skeptic. In fact, I remember getting patients coming to see me in the office with a calcium scan, and they were scared, because their calcium score was super high. And I remember thinking, "Gosh, I wish I never had this."

And for the longest time I never ordered one, I only saw them from patients who were referred to see me in the office. And I never could understand why anyone would order them. And I think it's, again, over the past five years, probably independent from anything having to do with nutrition, that I've started to appreciate that they're actually very useful in helping us define risk. And that's my job as a preventative cardiologist, my job is to help define what's your risk, as best we can, what's your risk of having a heart attack?

So I've started to use them a lot more. I tend to use them in two main areas. So the amazing thing is that there was tons of skepticism about calcium scans in the cardiology community, so much so that I think even to this day they're not reimbursed by any commercial payer, and they're not reimbursed by Medicare. So that's a whole different story, you can actually talk about the economics of why they're so cheap, but if you order one today, the patient has to pay out of pocket, because it was considered to be scientific, or research.

So remarkably, even just now two months ago, the American Heart Association published their new set of guidelines, and in that set of guidelines they included for the first time ever, they included calcium score as another way to assess risk. And that's the first time that's ever happened, and so I think we're going to see a lot more calcium score. So when do I use them? So I use them in the traditional, standard, let's say you take a patient with intermediate risk... So we bucket risk, in cardiology we bucket risk as being, like everything else in medicine, low, medium, and high. And we do that based on a calculation of your 10 year risk of having a heart attack, and low is less than 10%, intermediate is 10 to 20, and high is above 20.

And so the traditional way to use calcium is to, say, take somebody who's intermediate or low-intermediate, or even high low, so somebody in the sort of 7 to 15% range, and do a calcium score on them, and you can help make a decision about whether you want to be a little bit more aggressive in prevention. I still do that, but the two places I really use calcium score, one is in older people who have wacky lipids, who either don't want to, or have had a bad problem with taking statins or other cholesterol medications. So we've learned a lot about the value of a calcium score of zero. And while a calcium score of zero is not 100% guarantee you're never going to have a heart attack, especially in older people, where you'd expect that if they have plaque, that by the time you get to be 60, 65, 70, 75, that that plaque would be calcified.

So a calcium score of 70 in an older person is extremely reassuring. So the classic example is, you take somebody who's got super high LDL cholesterol, say 250, 70 year old man, and they have a calcium score of zero. I'm comfortable now stopping the statin in that patient, if that's what that patient wants to do. Again, that's relatively controversial, and certainly not guideline driven today, but I use a calcium scan score of zero in an older group of people to help have comfort over not treating.

The other place I use it is in younger people, where a 40 year old should have no calcium, because if you look at the population curves, you'd expect to have no calcium up until, I think, 40, 41. So if somebody comes in, and they've got other risk factors, let's say they've got a strong family history, and their numbers are all pretty wacky, and they want to know, "Well, guidelines don't say that I should start prevention therapies until I'm 40, I shouldn't even be doing any of this stuff until I'm 40, what do I do? I'm 38 years old, my dad died of a heart attack, my uncle, my brother..."

I'll do a calcium scan in that person, and if they have calcium, that to me is very telling, and that sort of lights the fire that, hey, look, we want to be super aggressive. However we decide to approach prevention, whether that's nutrition, or lifestyle, medication, or something else, let's be super aggressive.

Geoff

Yeah, I think that's super helpful, that's like a good 101 on calcium for our listeners here. So I want to move topics to Keyto.

Ethan W.

Yeah.

Geoff

The new venture, here. So clinical practice, research, and you started advising at Virta, got really deep into the keto space. What inspired you to team up with the team here, and launch Keyto? Congrats on the launch-

Ethan W.

Yeah, thank you.

Geoff

So you're just closing the pre-sales shortly, right?

Ethan W.

Yeah, it's been crazy, and super fun. Like I said earlier, I got to this point in my career where I really wanted to think about impacting more people, and got turned on to this, what's going on at Virta, and was really taken by the results that they've had. In common with that, I think, over the past three or four years I've become personally really fascinated with the power of trying to find ways to modulate human behavior to impact human health.

And again, it comes back to this economic reality that we're not going to be able to treat 80 million people with metabolic disease, however many million people with NAFL or NASH, or all these other things. We're not going to be able to treat them all with expensive drugs, and devices, and surgery, so how can we enable people to be able to make the changes in their lives that they want to make, but they haven't been able to? And it comes back to this idea that people come to see me in the office, and they say consistently, "Ethan, I am fat, and I want to lose weight," and my response to them over the 25 years I've been seeing patients has always been the same. Which is, "Okay, well just eat less and exercise more." Which is basically the equivalent of me just punching them in the face, because they come back six months later, and nothing-

Geoff

I'm trying to, I'm trying that.

Ethan W.

Has changed.

Geoff

Or it's like, yeah, be smarter. Yeah, how?

Ethan W.

So how do we... We're stuck with this idea of how do we, people want to do this. There's no doubt in my mind that people want, they don't want to feel the way they feel, or they way they've felt. So I think what we were missing were the tools to be able to enable individual people to be able to make the changes they want to make in their lives. And so I sort of got fascinated with this, how can we modulate human behavior? And part of it came from this reality of having teenage daughters, and I got stuck on this idea, I remember having this awakening a few years ago, when my daughter... my now 15 year old daughter... got Snapchat. And I remember watching the incredible, incredible addiction that she had to this platform, and thinking, "I've seen this before."

When I was a resident in Hopkins, and I was taking care of countless numbers of heroin addicts, I'm seeing the same behaviors in my daughter, my teenage daughter, who's trying to get to her device, to be able to interact with her friends, that I saw in these people who were trying to get heroin to be able to satisfy their addiction. And I think it wasn't an accident this time, this was engineered addicted. I think one of the things that we've learned now, especially today in 2019, is that Silicon Valley has done a spectacular job over the past 20 years of learning how to engineer addiction. It's the basis of how a lot of these companies have come to exist.

And so, could we harness the power of that for something good? And again, I don't want to say that there's nothing good about Facebook, and I love Twitter and stuff, so I do think there's good in what Silicon Valley's done, or what we've done in the past. But could we turn it toward something that we haven't yet turned it to? Specifically, could we turn it towards trying to engineer positive addictions? Could we try and get people to help relearn how to live their lives?

And so a couple years ago, I got introduced to Ray Wu, you know, one of my two co-founders at Keyto, and he had just sold his company, and he and Leanne, our third co-founder, were working on something else. And we started going out to lunch, and talking about this very issue, and did a really deep dive on the behavioral economics, and thought, gosh, it would be fun to do something together. And I remember we would have these lunches over the course of months, and were always coming back to this idea. How can we do something? We just could never find the right hook. We could never find the right thing that would help, that you could give people the feedback that they needed to be able to make the changes they needed, to kind of relearn.

And I mean, we thought of everything, and I won't bore you with the details, but eventually the two circles converged. This idea that, hey, there's this super powerful intervention that I'm watching unfold at Virta. At Virta, at least they're applying that to people who are on the sicker end of the spectrum, and the amount of human capital that they deploy to treat these people is pretty intense, and therefore also pretty expensive. So it's not really as accessible to a average person. Again, their intervention is spectacular, but if you just take an average person who's non-diabetic, it's harder to access.

And I think what I heard over and over again when I saw, was that the benefits of keto are there for a lot of people, that a lot of people had a really hard time doing it. And so we sort of settled on this idea that, gosh, one of the things that's special and unique about keto, that's different from all other diets... or, I shouldn't say all, but most all other diets... is that it gives you this biomarker that you can follow over time, when you do it. And that can help you gauge your level of success, and it really helps to enable adherence. And that biomarker is obviously following your ketone levels. And so we did a dive on how do you measure ketone, and obviously your listeners are going to know that you can measure ketones blood-

Geoff

Blood, urine, breath...

Ethan W.

Yeah. Blood, urine, and breath. And actually, the publications go back now 100 years. There were publications describing gold standard measurements of blood, urine, and breath, and the performance of all three of them has always been about the same, in terms of assessing ketosis. It turns out that there haven't been very good devices to measure acetone in breath. So acetone, your readers probably know, the pathway. So we'll back up and we'll say that acetoacetate is broken down into β-Hydroxybutyrate, and acetone. And acetoacetate to acetyl-CoA.

Geoff

I think it's BHB to acetoacetate, to acetyl-CoA, right?

Ethan W.

So, acetoacetate to BHB, and then-

Geoff

Oh, because they can-

Ethan W.

They can interconvert, for sure, so in fact it explains the reason why if you take your product, that your acetone levels go up, which is a fun experiment to play around with. Yeah, we should definitely. But I think we have some anecdotes that that actually does happen, but in any case, the performance is pretty good, but the problem was that the quality of the tools to measure it were not very good, and they certainly weren't portable. So Ray and I, and Leanne, kind of thought about different ways to tackle this, and basically I won't bore you with all the details, but we stumbled onto some early technology that we were able to use in a pilot. Actually technology that you can buy on Amazon. And it confirmed to us that this could work, and so we set about trying to build a device that people could carry around and use all the time, and it would replace measuring your blood, or measuring your urine. And so that was the story of how Keyto was born.

Geoff

Yeah, and that is actually really funny, because that was part of my own personal journey, experimenting with the ketogenic diet. Probably three, four years ago now, where you start getting onto the diet, you want to measure your outcome, you want to track your progress, and so okay, you can either stab yourself, you can use these pee sticks, or there's breath meters. And I remember that it was intimidating at first for me to do finger sticks, because it's not painful, but it is a pinch. It is annoying. You've got to stab your self, you've got to get a little bead of blood out, and you've got to measure yourself.

So it was always interesting to me, can you make it easier for people to just measure their ketone levels? And here we get the trade-off, because a lot of the clinical research is focused on blood ketone levels, how did you come across thinking, okay, breath acetone is going to be an equally valuable marker for our customers, for our population, or was it an engineering trade-off? Where you guys thought, okay, finger sticks is only for crazy, hardcore people, either you have diabetes, or you're a weird bio-hacker who's down to stab themselves, and breath is going to be a lot more easy for people. Or do you see this not as a trade-off, where you think acetone can actually be more efficient as a marker for ketosis?

Ethan W.

So, I've tested myself, I don't know, thousands of times over the past few months, and I'll say that from my own personal experience, that I get as much or more information from our device as I do from blood. The concordance or discordance of those measurements is probably more dependent on biology than on the performance of the sensors. I'll say that, I won't mention any of them by name, but some of the commercial blood meters are as bad as any device I've ever used, and basically just sort of a random number generator.

I haven't used urine strips too much, but my experience is that they're also not very accurate, and so from my perspective, you hit on this idea that's not super painful, but it's enough of a negative stimulus that it makes you not want to do it. The other reality is that those strips are expensive, and depending on where you get them and which one you use, they can be really expensive. So there is a barrier to doing it regularly, and I think for that reason, a lot of people, except for the hardest core bio-hackers, are not doing it. It certainly is a barrier to mass adaptation on a sort of broad consumer basis. If you're thinking five years, or however many years into the future, hey look, Keyto could be something that my grandmother could do. It's hard to imagine...

Here's an example. We've been testing, everyone we can get our hands on has been helping us test these devices, including my children. I've not, to this day, yet made them prick their finger. I've thought about it a few times, but I'm just not going to, they wouldn't do it. And like you say, it's not like the most painful thing in the world, but they're just not going to do that. And so I think it is just enough of a barrier. So we were set on this idea. What we're trying to do is enable behavior change. So part of the behavioral science suggests that in order to do that, you have to make things fun, and pleasant, and you have to make people feel good.

And so even subconsciously, just this association you get, I know you probably get it too. I get this dread when I go to check my blood. Even though I've done it 10000 times, I'm still, just, "Ugh, I really don't want to do that." And so I think the same is true for urine, right, we have this association of urine as being dirty. Just walk around here in the tenderloin, you'll get this idea, urine is not something you want to bathe in. So I think we knew that if we could pull it off from an engineering standpoint, that breath was going to be optimal from a behavioral standpoint.

So the question was, could we make a sensor, or could we develop a sensor, that would be accurate enough. And so then the question is, accurate enough for what purpose? So the way I look at it is, number one, we're trying to make a consumer device that helps people, again, make changes in their life to achieve whatever goals they want. Whether it's weight loss, or optimizing their metabolic health, or feeling better, whatever it is. But basically, how can we help people adopt this lifestyle? And so that's number one. And I think that was our first goal, was let's make a device that's good enough for that.

And then secondarily, it would be great to be able to satisfy you. It would be great to be able to satisfy Peter Attia, and other people who are going to clearly be comparing our device to every other device out there. And obviously, that's the thing that keeps us a little bit up at night, we're a little... I would say scared is the wrong word, but we're interested in how people see this device at that level. But I think optimistic, again. And partly, because it's cheap, and because there's no barrier to use it, you can use it as many times as you want during the day, we're going to get a much richer dataset. And so I think what we'll learn is that some of the differences that you may see between, say, two assays, are probably more a function of biology than they are of the assay or the sensor itself. But that's something we're super excited to learn, and going forward, I think as a company we want to invest in the science, in actually doing the studies to say, all right, let's see how it compares.

Geoff

Yeah, no, I think that's exciting for me, because I think the first thing I used was a breath meter, but then I didn't know how to compare a random acetone level to what the clinical studies will show, which is blood BHB. And I think that I saw some of your preliminary data where you're starting to somehow map that number in a way that could be actually translatable. And I very much can re-echo your experience around some of the devices, a certain brand that comes to mind, it markets like a cheaper ship, it's just like really, really inconsistent for us. It's almost like a random number generator, and if you're demonstrating something like an exogenous ketone, where you expect to see some changes, and you're just doing random numbers, it's very embarrassing when you're like, "Ugh. This meter's not really working."

Ethan W.

I think, and again, something we think about a lot, people put trust in you. And again, I'm not saying that the people are fraudulent, that they're going out there to try and trick people, but you want to be able to trust the number that you're getting. You don't want to prey on people, so it's disappointing that there are these devices out there, a lot of them, it's not just in our space, but they're probably in a lot of spaces. It just makes you think like, we should have a healthy amount of skepticism about these numbers that we're getting that we see as ground truth, but they're not.

And so then the question is, well what is ground truth? And again, for me I go back to the science. The science is, if you take gold standard assays for all three, they perform the same. So, that tells that if you can develop an assay that's good... and by the way, doing this with breath is no simple feat. There's a lot of factors that go into this measurement, some of which we understand, a lot of which we probably still don't understand. So it's going to be a great learning process for us going forward. But I think so far, again, for the time frame that we did all this in, we're really happy.

Geoff

Can you walk us through some of the engineering, and some of the sensor technology behind the device? It'd be helpful, and interesting.

Ethan W.

Yeah, I mean it's a fascinating story, and basically... I'll try and tell it quickly. I kind of mentioned that there was this sort of existing technology. If you go online, and you Google, how do you measure breath acetone, you'll see stories that people have been using old early version of consumer alcohol breathalyzers to measure acetone. And the reality is, when people figure it out, is that these early sensors, even in police breathalyzers back in the 1970s, were not specific for ethanol as a volatile organic compound, that they were nonspecific and they could detect any volatile organic. So I've heard stories that may or may not be true that people in the 1970s and 80s on Atkins or keto would get pulled over and get arrested for drunk driving when they hadn't had anything to drink, because they'd blow into that breathalyzer.

Geoff

That's funny.

Ethan W.

So when we started to get serious about doing this, we actually bought, I probably personally bought, every alcohol breathalyzer that is sold on Amazon, and tested them all. And we saw, yeah, absolutely, this pattern is true. These early cheap ones, it has to be a cheap one. It had to be a $10 or $15 one, which sounded so strange. But that's because the new ones were engineered-

Geoff

Ethanol specific.

Ethan W.

To be specific for ethanol. And so these early ones, if you blew into it and you were in ketosis, the thing would go off and it would start beeping and going crazy. And so it turns out that Ray, my partner and co-founder, his family's originally from Taiwan, and his uncle is there, and works in manufacturing. And he had this contact, this group of people who were developing a consumer alcohol breathalyzer for Asia, and they had one of these early sensors, for whatever reason. So they sent it to us, we blew into it, and lo and behold, we could detect acetone.

So we thought, well, this could be a fun go-to market thing for us, just as a V1. Well, to make a long story short, it would've worked fine, but we were able, the sensor company that was providing them the sensor had a sensor that was actually, they had been developing specifically for acetone. Just coincidentally. So we were able to swap the sensor, and not have to restart the whole manufacturing process. And these sensors are, I mean you can use whatever fancy terminology you want, but these are incredibly, incredibly sophisticated nano-sensors, and I'm not a physicist, and I'm not an engineer, so I'm not going to try and explain how the whole thing works, but basically as acetone binds to it, it changes the electrical conductivity of it, and that's basically how they work.

And so we sort of stumbled into this existing acetone sensor, and were able to kind of get this thing up and going. So for the past three or four months what we've been doing is trying to understand this beast, and trying to figure out what it means, and how to calibrate it, and we've spent a lot of time working on it, and I think we're pretty satisfied with where we are today.

Geoff

Ray actually sent me a screenshot of some of Peter Attia's testing data, so it's pretty interesting to see how the different measures he got, caught up with the different brands of blood sensors, and all that. So it is interesting to see that from what I saw your meter is quite sensitive, and quite consistent, which is good to see.

Ethan W.

Yeah, and he has, I mean Peter has an early, early version of our device, so I actually just sent him a new one. He's in one of his one week keto, one week fast, one week keto sandwich things, and so I think he's just starting the fast this week. So his numbers are going to go sky high, but I mailed him a new device just to kind of see. So at the end of the three weeks we'll end up crunching all the raw data, I promised him we'd send him the raw data and see what things look like. So it'll be kind of fun, and one experiment, and Peter's smart, one of the smartest people I've gotten to know, and so it'll be fun to see what that looks like.

Geoff

So to give our consumers a little bit of a preview of how this would work, so you breathe into the meter, the Keyto meter, and you'll get a score from zero to what, 10?

Ethan W.

Yeah, I mean it's a work in progress. Right now, zero to 10. I think we're sort of settled on eight. It's a trade off, right? I mean we want people to feel good, we want to optimize for the behavior, but we also want people to feel good and confident about the actual reading. So we're going back and forth about what the number is, but I think the current, as of today, it's eight.

Geoff

Okay, got it. So I can see the engineering trade off, where I think for the consumer that's looking to lose weight, you just need to know if you're in ketosis or not, kind of almost like a binary almost. But for someone who is trying to maybe be a bio-hacker, or understand their biomarkers a little bit more, with more fidelity, maybe you'd want some nuance, and some way to translate that to a blood BHB marker or something, right?

Ethan W.

Absolutely. And what's interesting is, there's probably more than you'd think on the consumer side. I would have thought maybe it is just a binary thing, or maybe it would be three categories for just an average consumer who wants to lose weight, but the truth is, this gamification that happens is so ridiculously powerful, and people get obsessed with wanting their scores to go up. And I know there are people out there who say, "Don't chase the ketones," all this stuff, but the truth is, that's the hook. That is the Snapchat equivalent.

If you can get people to focus on trying to get that number to go up, and not focus on their scale, and not... By definition what they're doing to get that number to go up is going to be super, is going to be productive for them. So that's what we've seen, and so you have to give people a little bit of that reward, that they have to get that dopamine surge, they want to win. And so we're working on all kinds of ideas around group chat, and leader boards, and challenges, and other ways to really take advantage of our natural inclination as human beings to want to compete with one another, and to one.

Geoff

Yeah, I know that personally. I mean I think we've done keto challenges just in the group in the past. I know our producer Zhill was in on one of the challenges with me, where we would do two finger sticks twice a day, one in the morning, one in the evening, and we'd have to go above a certain number, and we'd ratchet that up-

Ethan W.

What number?

Geoff

I think the first week was above 0.5, the second week was above 0.8, and the third week was above 1.0. And every time that you would go under your score, we would put $10 into a pot, and then go from there. And it was just a fun challenge, where yes, you end up ketone chasing, which probably isn't necessarily the goal for you, but it's a natural way to maintain motivation and it's a fun way to compete.

Ethan W.

It keeps people engaged, and the other thing that it does, and again we're seeing in our, you know, we have these alpha and beta testers who are out there using our thing in the real world. And the other key element that we haven't talked about is the social support. And that to me is one of the critical elements, that if you look across any nutritional intervention, if you want to predict success, having support, whether that's in the form of a health coach, or some other professional, or a peer, or a friend, or a relative, that's really important.

And so what we're seeing now is that the people who do the best are the people who exist in these groups where there's a ton of support. So if somebody's new, and they're just getting started, there's a whole group of people there to say, "Hey, look, don't worry about this, or if you have this side effect don't worry, we'll help you through this, and don't forget not to eat too much protein, don't forget you really need to work on..." So, and then you get on top of that, you layer on top a little bit of competitiveness. Like my wife has just started in the past week, she finally said to me, "Ethan, I'm going to, I feel like I should try this." And she's naturally a pretty competitive person, and she ended up, we have this group, I think there are nine of us that are friends, and she ended up at the top of the leaderboard. And right now, the current version of the app sends a push notification to everybody in the group when there's a new leader, and so last night she ended up on top, and she was gloating, and telling everyone, check out the new leader and stuff. So she was pretty excited.

Geoff

So I know you've been eating keto for the last couple of years now, right?

Ethan W.

No, I started about a year ago.

Geoff

Okay. So I think it would be helpful just to get a sense, what does your typical meal look like, are you heavily meal prepping? When you go out, how do you deal with ordering keto in restaurants?

Ethan W.

Those are great questions. So I've been doing 16/8 for the past five years, and I still do that.

Geoff

Teah.

Ethan W.

And I find that now doing keto, that's just like a incredible, much easier. Not that I ever struggled too much, I mean I would occasionally get a little bit hungry around 11:00, but whatever anyone says about keto, whatever potential metabolic or energy benefits it has, it's hard to not say that it reduces hunger. I just, I'm not hungry. I'm never hungry in the afternoon, but I find myself less hungry in the morning.

So I mostly don't eat breakfast, I do make myself lunch every day, and it's the first time I've ever done that in my life. Even when I was a kid, my mom would make my lunch, or I'd buy lunch at school, I just never did that, and that's a big deal. I mean the fact is, what I'm making when I get up in the morning, is a salad, and I'm putting in that salad some mix of grains, vegetables, I'm putting cheese, some nut, macadamia, walnut, whatever it is. I'm putting a protein, whether that's salmon, or chicken thighs, or whatever it is in there on top, and an avocado almost every day. And then I keep bottles of olive oil in my office, and so-

Geoff

I was going to say, you're probably drenching that with oil right?

Ethan W.

I just dump it on there, and I love it. And the truth is, I've been eating this way for almost a year, and I really don't, I'm not bored. And now I'm making salads for my wife, and my kids, so I need to figure out a way to optimize the production line a little bit, because it definitely is a 15 and 20 minutes every morning. But it's a fun 15, 20 minutes, and I love to cook. So that's, I'll eat two meals a day, so that's one. And then at dinner, again, I cook. I've always cooked more than my wife has, and I've always cooked some, but I've gone from, I would say maybe making 20 to 25% of my meals on a weekly basis, to making 80 to 85, maybe even sometimes 90%.

So I'm making dinner most nights, and again there it's whatever protein. My younger daughter's a vegetarian so it's a little bit complicated, sometimes we'll make her something else, but it's going to be whatever meat, fish, seafood, all the way up to pork, or lamb. Last night we had lamb burgers, and then some roasted vegetable on the side. And then at night, my treat before I cut myself off at eight o'clock is I'll have a couple squares of dark chocolate. And I drink, I have two glasses of wine, usually two glasses of wine a night, I'd say. It's unusual if I don't have two. I just like to drink wine.

So when I started this, I had two nonnegotiables. I had a few that were sort of, I can't believe I'm ever going to negotiate, but I had two absolute nonnegotiables, they remain the same. So that's coffee, and alcohol. If somebody told me, "You would add five years to your life if you gave up coffee and alcohol," I'd say, "No way, you can have the five years." So those are the two, and so I do, obviously I still drink coffee, now I drink black coffee, and I drink a couple glasses of wine.

Geoff

Okay. So that sounds like that's not even... It sounds quite sustainable, quite happy.

Ethan W.

It is. So the travel thing is hard, at the beginning it was really hard, like that, I think... And one of the benefits of having this is that it's a real time... not real time... it's sort of a relatively real time feedback mechanism. So what I found was that this was really helpful in learning kind of where are hidden carbs. So I had a couple of experiences where there's a big thing of food trucks outside my office at Mission Bay, and every once in a while I'd end up working late and not having a meal there, so I'd have to go out and get something.

So I remember one night I went to get poke, and I was like, "All right, well this should be great, it's just going to be tuna and salmon and a bunch of vegetables." But of course the sauce has just gobs and gobs of sugar, and the next morning, my ketone level was in the garbage. And so for me it was a learning experience, like all right, well avoid that sauce. And so I sort of now pack a little bag when I'm traveling that is full of nuts, other... I'll have a dried salami, or some other thing if I'm starving and I can't find a meal on an airplane that's reasonable. If it's pasta, then I'll just eat the nuts and have a little salami or something.

Geoff

Yeah, no I think you bring up a really good point, that check-in, that validation is so important. When people ask me, "Why do you wear CGM," or, "Why do you finger stick yourself," well at one level, at a certain point you know, probably what your diet will do to you, but it's always these hidden things. These confirmations, where you need that personal feedback to make sure you're actually continuing with a virtuous cycle.

Ethan W.

That's the key, and I think you hit on it, because if you're making all of your meals, you probably don't need it, because you know what you're putting into it. But even those of us who make the majority of our meals, and I think I'm unusual, and I think Ray is unusual, most of the world does not make most of the food they put in their bodies. So if you're going out there and putting your trust, and there's not a label on it, you're at the whim or the mercy of whoever it is that's making it. So this is a way of kind of learning.

And so it's not instantaneous feedback, but that's enough that you're not going to go back the next day. I've had the experience enough times, I had it with chicken wings, I've had it, one night I think one of my favorite stories is my kids, early on, when I was starting to do keto, said, "Dad, let's order pizza." And I said, "There's no way I'm ordering, I'm not having pizza." And they said, "Well, please, please, please," so I looked at the menu, and found, all right, well I'll have chicken wings. And the next morning my numbers fell into the garbage again. I went and looked at the leftovers in the fridge, and they were breaded, and probably had a lot of sugar on them in the sauce and stuff. So that's a pretty important, even today, even though I'm pretty sophisticated, I think, when it comes to knowing what to eat and what not to eat, I still really depend on that for learning.

Geoff

Have you guys experimented with exogenous ketones with the Keyto meter?

Ethan W.

I haven't personally tried it yet, although I'm going to. Whether I do it here today is a different story, but a few of us, a few of the members of our team have tried it, and again, what I've heard is that it does make your score go up, which is not, I guess, shocking.

Geoff

Which is consistent with our understanding of how ketone esters or ketone salts would affect acetone production. It's not as acute as you would see in blood, but you will see acetone being breathed out as... I think it's something like, showing up in 15 minutes in your blood is about 90 minutes, or 120 minutes, into it, so...

Ethan W.

Yeah, it's really interesting. If you look at the pathways in a biochemistry textbook, it doesn't look like they should go backwards, but they're clearly an interconversion. And we're learning so much about this biochemistry now that I think we'd all thought this was all salt and settled, but there's obviously a lot more to learn. Acetone itself was always thought to be inert, and not really a fuel source, but it turns out that acetone itself can be converted to acetate, and acetate can be a source of energy for cells. So I think there's a lot out there that we're still hoping, or we're still needing, to learn.

Geoff

Or how people were expecting it's like a signaling molecule, I mean it's interesting work there.

Ethan W.

Yeah, tons. Same with BHB. As you guys know, there's clear evidence that it's able to signal, and so the questions of what it's doing, and again, now that we know that there is conversion between, say, β-Hydroxybutyrate and acetone, it's not even necessary for acetone itself to be signaling, or to be doing anything biologically, but the fact is we know that there's this equilibrium, and they go back and forth, so.

Geoff

Right. So what are the important things to know about Keyto? So it's on pre-sales now, that wraps up in...

Ethan W.

I don't know, I mean I think-

Geoff

And when do you guys go to market, when do you guys go to launch? What are the details here? How do people learn about the product?

Ethan W.

We are on Indiegogo now, you can find the device there, and you can pre-order it on Indiegogo. I think our plan, last I checked, was they were going to go live with our own website in the end of January, and how we sort of approached the launch, that's a work in progress. But if you go to our website, is GetKeyto.com, and if you go to that you'll be moved to the Indiegogo for now, where you can pre-order it. I think as of this morning there were about 9000 devices that were sold, which is great, it's exciting for us.

Geoff

That's huge. That's massive.

Ethan W.

Yeah, it's really fun. So we're madly working on getting those orders filled, we should start shipping out to the first backers on Indiegogo in the next week or so, and then we'll get those orders fulfilled. We've obviously got more coming from Taiwan, and we'll start selling direct to consumers in the next month or so. I can't tell you how we're going to sell it yet, because we haven't decided. I think there's a healthy discussion inside the company about what the best business model is, and I'm not going to bore your listener with that discussion, although it's kind of interesting to think about.

Geoff

Maybe they'll have some feedback of how they best want to participate.

Ethan W.

Yeah, I mean the truth is, what we've seen is there's definitely interest. I mean I sort of always... Ray hates it when I bring up Weight Watchers, but I always use Weight Watchers as my frame of reference that people are willing to spend $20 to $30 a month for a program that they're largely not using. Like, Weight Watchers churns pretty quickly. I think the average customer is on there for roughly nine months. And people just don't even go on the app after a few weeks. And maybe that will change, but they've got a long history, and from my standpoint, there's not much new there. It's going to be the same thing.

So the fact is, if people are willing to spend that kind of money for something that doesn't work, then how much money are they going to spend for something that does work? I'm not the business guy. The good news is, I get to be the scientist, and the doc, and just sit around and try and sound smart, and let these guys handle the business discussions. But our goal as a company, and I think the principle is that we want this to be widely available. We would love this to be available to as many people as possible, and we don't want price to be a barrier. So currently, it's priced at $99, I think we'd aspire to have that come down, and I think we expect it will come down. How we'd sort of end up on what we land on with the eventual business model is something that's a work in progress.

Geoff

Cool. Very exciting. So beyond the initial rollout of Keyto, what are the big goals for you, 2019, whether with Keyto, the company, or with your research, or with your practice. Any broad things to look out for in 2019 from you?

Ethan W.

Yeah, I mean I had such a good exercise to do, and I wish I had had the time to really sit down and do that, but frankly I've been so busy. I basically have two jobs, right, so I'm a clinician, I've got patients. And I told Ray, my number one obligation is to my family. My number two obligation is to my patients. I've got this other job that I need to do as well, which is running a lab, and I'm also incredibly invested in keto.

So I'm doing a lot of different things, and I think for me, learning how to balance all that is hard. But this is my first time doing a startup, and as you guys know, it's a lot of ups and downs, and a lot of work that seems like it's done, and then it's not. And then work that comes out of nowhere, and so right now I'm just having fun and we've a great, amazing team. I mean, just really so blessed to have the best partners right now, and so I still am amazed at what we've been able to get done in such a short period of time with such a small group of people, and with such limited resources. So I think I'm excited about what to see going forward. I can't predict what's going to happen with me, or with Keyto, or with anything, or even with my lab, two months down the road. But it's definitely, I'm the most excited one to kind of see where everything ends up.

Geoff

Awesome. And then, for the folks that are interested in keeping track, you're on Twitter, so your handle is Ethan...

Ethan W.

@EthanJWeiss.

Geoff

EthanJWeiss.

Ethan W.

Yeah. And I would say I had a massive Twitter addiction. I still have a massive Twitter addiction, I just don't have as much time. I think part of my Twitter time has been taken up by Keyto, so-

Geoff

You're more productive.

Ethan W.

I'm still there, I still love it, and I still think it's the best medium for interacting with people, especially when it comes to things like science and medicine and things like that. I really can't say enough good things about that and what I've learned, the people I've met. I mean indirectly, I met Ray through Twitter, and there are a lot of other people that I probably... Actually, my lab is basically comprised of people I've met indirectly through Twitter. I really enjoy what I get out of Twitter.

Geoff

Yeah, I mean I think I saw, I sort of started following you through Twitter. I mean I think it is, is connects everyone.

Ethan W.

It's pretty cool, and it happens to also fit with my personality. I like to be crass, and irreverent.

Geoff

You like putting it out there.

Ethan W.

Yeah, definitely I do. But it's fun, I mean that's the beautiful thing about the medium is it's a really democratic, right. I mean I remember early on when I was still kind of getting to understand it, the fact that you could reach out and have a conversation with these people that should otherwise be inaccessible to you, that was pretty amazing. I mean I remember having, I won't name names, but I remember having legitimate Twitter conversations with people I was like, I can't believe this. And I'm sure there are people out there who have those conversations with me, I mean today, thinking the same thing, which is super strange, but the fact is, that's the beautiful thing. You can access anybody. Doesn't mean that they're going to respond all the time, but people do tend to respond. People on Twitter do tend to respond.

Geoff

That's one question that I've asked a lot of our previous guests. How do you think Twitter has changed science communication? Because I think on one hand, you see this polarization, you have people just arguing, it's almost a religious holy war for some of the nutrition/diet discussion, vegan, versus carnivore, versus keto, versus balanced diet. Do you think that's helpful, do you think that's productive? I mean obviously it sounds like you like the kind of argument, let's get it out there, duke it out, but do you think it polarizes the conversation?

Ethan W.

I do. It absolutely does. I mean just like it does in politics, or religion, or anything else, or sports, you can look at the places in the world where we as human beings tend to find this community, and identify with communities. And in the case of science, it's not healthy. So if you ever see a little planet, or a little piece of meat in my twitter handle, you have permission to hit me in the head with a baseball bat. I think I come at science as not something you advocate for-

Geoff

You're not partisan, right, you just want to see the data.

Ethan W.

You advocate for the truth. And I think I would hope that everybody else would take that approach of saying, "Look, all we all want, our shared common goal is we want to find out the truth. We want to find out the answers." If it turns out that the ketogenic diet causes people to die of heart attacks, I will be the first one to get out there and say we were wrong on this. Just like I'm the first one to say I was wrong on calcium scores, or I was wrong on LP-a, or I was wrong on keto in the first place.

So I just hope people can keep their partisan, dogmatic religiousness to places where like, sports. Where it's okay if you're a Philadelphia Eagles fan, and you want to hate a Dallas Cowboys fan, that's fine. But there's no room for that. But that said, it's awesome that you can have a healthy academic, intellectual conversation about something, and question data in real time. The discussions that could happen in twitter around science are amazing, and so I've learned so much. Much more than I ever did in any other way. Every day it's a learning experience for me.

And so you find people out there, people who are new to the medium, go find people out there who are your trusted source of information. Don't just find one, find lots, and cultivate the lists of people that you want to follow and get your information from. And there are tons. There's such good information. There's people out there who I can't believe how much they read, and so I every morning, my routine is, when I get up in the morning, the first thing I do is scroll through my Twitter feed, and I'll update on what are the newest scientific papers. And I've got a group of people that I follow really closely, and that's my way of keeping up with the literature, and that's not going to change anytime soon.

Geoff

Yeah. So that's good, it sounds like you have a productive way of using that platform, as opposed to getting too sucked into the distraction of it.

Ethan W.

Yeah, I mean it is... Look, the politics thing is a whole different world. I pat myself on the back, I've done a pretty good job of steering out of that mess. I was way stuck in that morass for, you know, after the election, and I think it got to be really unproductive, and bad, and I think it also started to erode relationships, and it was just definitely the wrong thing. So I basically stopped paying attention to politics as best I could, and it was one of the best things I ever did. And so I try really hard to avoid getting in politics on Twitter. Of course every once in a while you can't help it, but I try and stay away from that stuff as much as I can.

Geoff

Yeah. Well said, I think, on just not being partisan on dogma, but just actually finding truth. I think that's what all... I think scientists, that's the job of science, that's the job of creating products for people, and services for people. Making things that people want, and works for them.

Ethan W.

Yeah, absolutely. I mean when the people at my lab come to me, and they say, "Hey Ethan, I've got bad news, we got the wrong result," I say, "What are you talking about, the wrong... there's no wrong result. We didn't get the result that we expected to get, but this is learning. If we get the results that we expect to get every time, then we should stop doing the experiments, because it's a waste of time." Why even bother to go through the actual activity of actually doing it, because if you know what you're going to get, then don't waste your time. So our job is to be super thoughtful, and critical, and question, question, question, question, question, and be humble. Probably the biggest thing above all is be humble.

Geoff

Cool, we'll leave it at that. I'm really excited to try out the Keyto, follow Ethan @EthanJWeiss on Twitter.

Ethan W.

Awesome.

Geoff

Thanks for coming in.