"Burn More Calories" with Brian Freeman, MD

Brian Freeman, MD, co-founded Energesis to help overweight people lose weight by growing their energy-burning brown fat. Experiments in mice have shown this approach works with GLP-1 drugs such as Wegovy in accentuating weight loss. Great chat with a compelling repeat founder.

Highlights:

  • Sal Daher Introduces Brian Freeman

  • Energesis: The Problem it's Solving

  • "... What we're doing is we're acting on those cells and basically nudging them to make more mature brown fat cells, so that the mass of the brown fat cells increases..."

  • "... That's pretty much it. We're trying to recapitulate cold exposure in a pill. That's right..."

  • "... one of the issues with weight loss due to, let's call it caloric restriction ... The body doesn't take it lightly because we've evolved not to starve, right? ... The normal physiologic response to that is to reduce metabolic rate. That makes it harder and harder to lose weight as your weight goes down, and it makes it very difficult to keep that weight off..."

  • Further Thoughts on Energesis

  • Brian's Entrepreneurial Journey

  • "... What if you could magically make everybody in America lean overnight, think of what that would do to healthcare costs. It would be reduced by at least two-thirds..."

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Transcript of “Burn More Calories”

Guest: Brian Freeman, MD

Sal Daher: Hey, this is Sal Daher. I'm delighted you found the  Angel Invest Boston Podcast in which I interview people who know a lot about building technology startups. I now have a Substack about losing and keeping off 100 pounds of body weight in my 60s. It's called Aging Fit, and my goal is to build a community of people interested in keeping fit as they age. Look for Sal Daher on substack.com. Daher, by the way, is spelled Delta Alpha Hotel Echo Romeo. Enjoy the podcast.

Sal Daher Introduces Brian Freeman

Welcome to  Angel Invest Boston, conversations with Boston's most interesting angels and founders. Today, we're very privileged to have with us Brian Freeman, MD. Welcome, Brian.

Brian Freeman: Thank you. Thank you for having me, Sal.

Sal Daher: Brian is not just an egghead. By the way, when I spelled his name, I spelled Brain Freeman. He's a fellow MIT grad, and he really is a brain. MD, practicing neurologist. He has been involved in starting companies before, and he is working right now with Olivier Boss, his scientific co-founder, on a very, very interesting addition to the armamentarium for fighting against obesity.

It's going to be a tremendous conversation, very timely. As I said, Brian is also an MIT grad, beaver power. Okay. Brian, explain to us what Energesis is doing, what problem it's solving and how it's solving the problem.

Energesis: The Problem it's Solving

Brian Freeman: Okay. All right. Energesis is addressing the obesity pandemic. We can address type 2 diabetes as well. What we're doing is, it's quite a different approach from what most companies in the space are doing. We are targeting something called brown fat or brown adipose tissue. The reason I think that's interesting in the big picture is that all of the therapeutics that are either on the market now or in development pipelines are trying to reduce energy intake.

They're basically appetite suppressants for the most part. What we're doing is on the other side of the energy homeostasis equation, if you will. We're increasing the expenditure of energy from the body.

Sal Daher: Homeostasis for the software engineer types here is the natural process of trying to reach an equilibrium in the body. When things are out of whack, try to get back into whack. Please continue.

Brian Freeman: Okay. All of our body weight is a dynamic equilibrium, like you were just saying, between energy in and energy out. If you want to cause weight loss, you got to hit one of those things. That's it. Those are the only two ways to do it. You can reduce energy in or you can increase energy out. Like I said, everything that's come and some things have gone already off the market and then there are lots of things in development pipelines now are looking at reducing energy intake. What we're doing is on the other side. It's quite differentiated in that aspect.

Sal Daher: Excellent. Excellent. Now, brown fat, there's a certain morality play involved with fat characters. Brown fat is the good fat. White fat is the bad fat, especially if it's around your organs or interstitially inserted into your organs and muscles and so forth, where it leads to horrible results. Brown fat is something that aids in the metabolism of fat, right? It allows you to burn the white fat more efficiently. It's a natural thing.

Polar bears have a lot of brown fat, and they are able to consume enormous amounts of food, and then burn their white fat to keep themselves warm. It means that the polar bear irradiates, turns his white fat or her white fat into heat and dissipates it through heat, therefore allowing it to eat more. This is the desideratum of everybody, to eat a lot and not gain weight.

The hope here is to activate your brown fat to increase the equilibrium of brown fat and white fat in the body. Therefore, it'll help people lose weight by not just eating less, but also by increasing their metabolism.

Brian Freeman: That's exactly right. All mammals have brown fat. It's a mammalian adaptation. Its function is to create heat when the ambient temperature is too low. It also has another function, which is to dissipate excess calories.

This is interesting. I think a lot of people are not aware that brown fat is turned on by cold exposure, but it's also turned on by eating. It's also turned on by any stress, including exercise. It's stimulated to become active many times throughout the day, and you don't need to have an external stimulus to get brown fat action.

All mammals have it, and we have it. We actually have more in the winter than we do in the summer. That can be shown with PET scans or other methodologies used to image how much brown fat mass there is. I guess one thing that I should point out about brown fat is that there's really two ways to, quote, "enhance it." You can either turn it on acutely through a cold exposure, for example, or with a drug like norepinephrine, for example.

You can try to recruit more of it to increase the mass of it. That's what we're trying to do. There were attempts decades ago in pharma to try to activate brown fat, and that worked brilliantly in laboratory mice who are basically living in the cold, as far as mice are concerned.

[laughter]

Sal Daher: They prefer a very warm environment.

Brian Freeman: Exactly. For them, a normal animal housing set of environmental conditions was cold, and so they maintain a large mass of brown fat. When you acutely stimulate it, you get a nice boost in energy expenditure. In humans, that's not the case. We've been very clever at engineering our environment so that we're comfortable, thermally comfortable all the time. The result of that is we feel good, but most of our brown fat wanes away. You always have the capability of making more, but we don't carry around a lot of it because there's an energy cost to doing so.

Sal Daher: It's exactly what it does. This burns off energy. I just want to follow two tracks here. One, I want to pursue the mechanism of activating the brown fat. First, I just want to say that extra calories in the body ends up as adipose tissue in the organs and in the muscle. In the organs, it can eventually lead to impairment of the pancreas and producing insulin. It can impair liver function, and it can make you insulin resistant.

If you have enough fat in the muscle, the muscle is not able to take in glucose in the presence of insulin. I borrow-- I think, Peter Attia had this idea of the insulin being like a straw that you put into the cell in order to get sugar into the cell, get glucose into the cell to power the cell, to allow the cell to make ATP to run itself. ATP is the universal fuel for cells for those who are not biologists.

Brian, when I was at MIT, you didn't have to take biology. Two semesters of calculus, two semesters of physics, one semester chemistry, no requirement of biology. They thought high school biology was perfectly enough. I'm sure, by your time, everybody had to take two semesters of biology as well.

Brian Freeman: Yes, yes.

Sal Daher: Anyway, getting back from this digression, so the idea here is that, it has this brown fat and this miraculous, miraculous action. Now, you say activate the brown fat. Are you growing new cells of brown fat? Are you expanding the existing brown cell fats, just making them larger, more active? What is it your molecules are doing?

"... What we're doing is we're acting on those cells and basically nudging them to make more mature brown fat cells, so that the mass of the brown fat cells increases..."

Brian Freeman: Okay. We all maintain a reservoir of brown fat precursor cells or progenitor cells, which are essentially adult stem cells that are committed to becoming brown fat cells, mature brown fat cells. That's the only thing they can become. What we're doing is we're acting on those cells and basically nudging them to make more mature brown fat cells, so that the mass of the brown fat cells increases.

There's a drug that's been on the market for decades called erythropoietin or Epogen. It's used in patients with anemia, often cancer patients, who don't make enough red blood cells. That acts on the precursors for red blood cell formation. We're very much analogous to that, except we're acting on a different kind of tissue lineage. The idea is to make more of the mature cells and increase the brown fat mass so that, whenever it's turned on, you get a boost of energy expenditure.

Sal Daher: Basically, you're triggering a natural process that the body would trigger if it was exposed to cold. Basically, you don't have to take cold showers to get more brown fat.

Brian Freeman: That's right. That's essentially right.

Sal Daher: Yes, cold showers in a pill.

"... That's pretty much it. We're trying to recapitulate cold exposure in a pill. That's right..."

Brian Freeman: That's pretty much it. We're trying to recapitulate cold exposure in a pill. That's right.

Sal Daher: Right. Right. That is really brilliant. Now, I understand that what your company has is a platform for discovering very interesting compounds. This is only the first combination of compounds that you have stumbled upon. Would you care to discuss a little bit about your platform, what it entails, or would you rather not discuss that?

Brian Freeman: No, I'm happy to discuss this. This is where the company started. We have patents filed on this, patents that are issued. My scientific co-founder, there's actually two of them, one is in Switzerland, one is here, Olivier Boss, who you mentioned.

Sal Daher: What is the name of your other co-founder?

Brian Freeman: Jean-Paul Giacobino. G-I-A-C-O-B-I-N-O.

Sal Daher: Okay, Giacobino. Olivier Boss is O-L-I-V-I-E-R, Boss.

Brian Freeman: As in my boss.

Sal Daher: My boss, yes. Please explain your molecule search platform.

Brian Freeman: Right. Right. Our scientific co-founders, Olivier Boss and Jean-Paul Giacobino, discovered the first known progenitor cell for brown adipocytes or brown fat cells. It's a human cell. The idea was, could we use this as the core of a discovery platform where, essentially, we can throw compounds at these cells and see which of those compounds turn them into functional, mature brown fat cells?

Schematically, it's very simple, but it took quite some time to develop this into a high-throughput platform. We've now used this idea, this discovery tool, and thrown several different kinds of compound collections at it to see if we could discover molecules that have this property of recruiting new brown fat cells. We've looked at biologics. We had a nice discovery there.

We have an active small molecule program. Then we also have screened approved drugs, previously approved drugs. We screened about 1,250 of them. That has actually become our most advanced program because these are known safe drugs that we can take into the clinic.

Sal Daher: Listeners should know, biologics, these are biological compounds that are made by cells, and they're usually proteins, but the process for production is a little more involved. The small molecules are chemicals and the production there is easier, they scale faster and so forth. We've had Todd Zion on the podcast, who is on the board of Energesis. He talked about his bioreactor and the kind of stuff that goes on in the bioreactor and the ecosystem around making proteins and so forth.

In this case, you don't even need to do that. Basically, it's chemical reactions to make the small molecules which are existent, which have been tried in humans before. Am I speaking out of turn if I say that you're actually able to create a really interesting effect with lower dose than is customarily given with these molecules?

Brian Freeman: That's right. Initially, when we looked at previously approved drugs, we found a handful that seemed to have this property that was previously not known about these drugs. We looked at them in animals, and we found that they caused weight loss. Particularly when combined into two-compound combinations or two-drug combinations, we found that we could increase the efficacy without affecting the safety.

Once we saw that, we thought, okay, well, let's see if we can reduce the doses of one or both of these drugs and try to maintain the efficacy, but potentially improve the safety window by giving lower doses. What we found is that, with one of the drugs that's in our lead combination, we were able to reduce the dose by about half. With the other drug, we were able to reduce the dose by about 75%.

Sal Daher: Whoa.

Brian Freeman: Yes. It's actually much lower now. That sent us off in a new direction, which was, okay, how is this working? If it's only present in one quarter of the dose, then it's supposed to hit the target. What's going on here? Two years later and a lot of work later, we identified the target that is important for what we're doing, which is a different target than this drug is approved to hit. That's been a journey, but it's been very helpful for us because we've identified this novel target for obesity that mediates energy expenditure.

Coincidentally, it's dovetailed perfectly with what we have found on the nominal small-molecule studies that we've been doing because we initially did high-throughput screening of thousands of compounds, which we did in collaboration with the NIH. We had a handful of hits that came out of that and have studied those to determine, well, what are they hitting? Are they hitting something else? Are they hitting something that's known?

It turns out they're hitting the same thing that this previously approved drug is hitting. It makes us confident that this is a real target for obesity. That's what our novel chemistries are revolving around now, that novel target.

Sal Daher: Very interesting. By the way, shout out to Ty Danco for putting Brian in touch with Michael Mark, who put Brian in touch with me. Shout out to Ty, who's an angel investor, a former angel investor, who's very, very helpful. He was in charge of Techstars in Boston at one point, and he's a great guy. He's been on the podcast.

By the way, listeners should know that the reason I'm so informed about this is that I spoke with Brian during the summer when Brian Freeman presented at Walnut, and there was quite a bit of interest. I'm not speaking out of turn to say that there's quite a bit of interest, and Walnut is pursuing conversations with Energesis. I think so this is an opportune time for more people to learn about this very, very intriguing startup working in a really important space.

Now, the obesity space is taking all the oxygen in the room, so to speak, in pharmaceuticals. that's the only thing people want to talk about because the cost of obesity to society is so massive, and the potential of alleviating that somehow with a pharmaceutical intervention is very appealing. How does your choice of small molecules that have already been studied really well and are well-tolerated by human beings, how does the addition of that to this incredibly busy space, how does it play in that?

Brian Freeman: That's a great question. To get back to this discussion about energy intake and energy expenditure, everything that's out there on the market now, these drugs are called GLP-1-

Sal Daher: Agonists.

Brian Freeman: -or GLP-1 receptor agonists or GLP-1 analogs. GLP stands for glucagon-like peptide 1. The initial drugs that came onto the market were GLP-1 analogs, and there are now so-called dual agonists, for example, Lilly's tirzepatide, also known as Mounjaro, is a dual agonist that's hitting GLP-1, and it's hitting another receptor. There's a couple of companies that are even working on triple agonists, which are hitting GLP-1 and a couple of other receptors.

The long and short is that, what's on the market, what's in the development pipelines, these are mostly GLP-1 drugs, and they work. They work, but like I was getting into before, they're really affecting energy intake, they're appetite suppressants. They do cause a good amount of weight loss, and they're very popular as a result.

Where do we fit into all of this? What we're doing is we're increasing the body's energy expenditure. It's a different approach, so it could be used in combination, but there's more to it than that. This is actually extremely timely because, I don't know if you saw, but yesterday in  The New York Times, there was an article about why some people are not achieving their weight loss goals on Ozempic. This is something that I've been talking about-

Sal Daher: No, I didn't see that.

Brian Freeman: -with people for a year or so.

Sal Daher: What's going on there?

"... one of the issues with weight loss due to, let's call it caloric restriction ... The body doesn't take it lightly because we've evolved not to starve, right? ... The normal physiologic response to that is to reduce metabolic rate. That makes it harder and harder to lose weight as your weight goes down, and it makes it very difficult to keep that weight off..."

Brian Freeman: Yes, which is one of the issues with weight loss due to, let's call it caloric restriction, because it could be due to drug treatment with Ozempic. It could be due to simple dieting. There's a normal response to that. The body doesn't take it lightly because we've evolved not to starve, right?

Sal Daher: Right.

Brian Freeman: The normal physiologic response to that is to reduce metabolic rate. That makes it harder and harder to lose weight as your weight goes down, and it makes it very difficult to keep that weight off. This is a concept in the scientific obesity circles called the adipostat or the weight set point. Basically, your metabolic rate goes way down.

This is documented with semaglutide, which is Ozempic. If you go off the drug, your weight will go right back up, and it may actually go above-

Sal Daher: Beyond that.

Brian Freeman: -where you start because your metabolic rate is now lower than it was when you started. Like I said, this can happen with just simple dieting as well. What if you can come into that situation with a drug that could directly increase metabolic rate? That's what we're doing. We could be used just with simple dieting, or we could be used in combination with the Ozempics and then Mounjaros and produce much greater weight loss. We've actually shown this in the lab.

Sal Daher: For me, my audience knows that I'm keeping off a hundred pounds of body weight. What you're talking about, adipostat, is very true. Your body wants to get back to its original body weight, its original weight. I got to work like the dickens. It's been 660 something days that I've walked more than 10,000 steps.

Brian Freeman: It's amazing.

Sal Daher: Just before the podcast, I was pumping iron here. I'm working out all the time. Then I watch my calories like crazy with my fitness pal, and I'm weighing myself obsessively almost. Well, once a week I weigh myself just to keep on top of that to prevent my body from going back because it wants to go back to that weight. I have to be pushing against this loaded spring all the time.

A solution like the one of Energesis, which is really interesting because, at Energesis, you're making your body burn more energy, that would be really great. I haven't taken the GLP-1 agonists. My reservation about that is there've been some indication that GLP-1 agonists are helpful in addiction settings, in curbing people's appetite for drugs. It makes me wonder what appetites it's curbing.

[laughter]

Sal Daher: Is it going to curb my reproductive appetite? This is a children's show here, so we don't go more than that --

Brian Freeman: It's a family program.

Sal Daher: Yes, family program. Let's not be more specific than that. Is it going to curb my enjoyment? For example, this afternoon I had a delicious guava. I was hungry. Okay. I sat down. Guava is a marvelous fruit, high in fiber, really high in potassium. It's very low in calories, and it's just tasty. I love guava. I'm Brazilian by birth. We used to eat this all the time, but I enjoyed my fruit because I was hungry.

I know people who are on Ozempic, you're like, "Would you like some?" "No, thanks." They're dyspeptic. They're literally dyspeptic. That for me is not-- but something that would help in terms of speeding up of turbocharging my body's consumption of calories, that would be cool. I'd consider that.

Brian Freeman: Yes. We think that what we are doing is resetting or lowering this adipostat, this weight set point so that people who do lose weight, would not have the drive to regain that weight because the body would be resting at a lower body weight. There is actually a lot of evidence now in animals and in humans as well that the more brown fat mass you have, the lower your weight, the higher your metabolic rate is, and also the higher your temperature is.

There are now very careful studies of temperature over the course of the day. It requires many measurements throughout the day over time. It's believed that the obese actually have a slightly lower body temperature. We're talking about fraction of a degree, but that is a reflection of a lower BAT mass and a lower metabolic rate. That temperature in the obese is abnormal because they don't have the brown fat mass to create what is a normal temperature.

Sal Daher: Interesting. Interesting. As a physician, you know that the average normal body temperature of human beings has dropped.

Brian Freeman: That's right. 

Sal Daher: I wonder if that has to do with our being fat in addition to our not being constantly fighting off some horrible infection.

Brian Freeman: That is a really interesting question. I don't know.

[laughter]

Sal Daher: That's a cool thing. 98.6, that was maybe a century ago when they did these measurements. We usually run a little cooler than that.

Brian Freeman: Yes, right.

Sal Daher: We probably don't have like an infected tooth or something, like most people had in those days.

Brian Freeman: Right.

Sal Daher: How did humanity survive? [laughs] Fascinating, Brian. This is really, really fascinating. The idea is playing on the other side of the equation, playing on the side of raising output of heat from your body, raising your body temperature, that means you can spend less on heating your house.

Brian Freeman: That's right. Well, it goes both ways. Maybe we should lower the temperature in our house and create more brown fat and, I guess, lose weight.

Sal Daher: I think it's probably the shock is what gets you producing that--

Brian Freeman: Just to be clear, we're talking about maybe a fifth of a degree in body temperature. You need very specialized equipment to detect this. It's not anything that would affect enzymatic function and normal cellular processes. We're not talking about that kind of temperature.

Sal Daher: Yes. His body temperature got so cold that the lipids became stiff, wouldn't flow.

[laughter]

Brian Freeman: That's right.

Sal Daher: That's not a concern. I find this, the possibilities of Energesis, really extremely exciting as I explained. Perhaps they're my own weird thoughts about this, but just the idea that your appetite is not affected. It's just you burn more energy. You're more alive, so to speak. My sainted mother passed away. She had a lot of problems with weight loss. Weight is highly genetically determined. As a physician, you know that very well.

The concordance between identical twins raised apart is up to 90%. Amazing how much genetics plays a role in weight. My mom used to say, "Oh, I have slow metabolism." She gained weight. She used to be very thin, but then she put on a lot of weight. She used to complain about slow metabolism. She would've been very happy with the possibility of this.

Brian Freeman: [chuckles] She was probably right.

Sal Daher: She was probably, yes. Well, she also had an injury in her leg, which prevented her from being physically active. She would've been unbelievably active person, except that she had a weak foot that she couldn't do things with.

Brian Freeman: Oh, yes, that certainly didn't help.

Sal Daher: This is something, back in the '50s, they didn't take care of it, and the tendon was destroyed. It was horrible. An injury like that can cause follow-on problems in your health because you don't exercise as much.

Brian Freeman: Absolutely, yes.

Sal Daher: This is really promising. Brian, what other thoughts would you like to get out to our audience of angels and founders about Energesis?

Further Thoughts on Energesis

Brian Freeman: Well, first of all, I think everybody's aware of this, but the obesity landscape has really radically changed in the last few years. Investors, I've heard about it, the public knows, but that's been very. very good for us actually. We've been working on this for quite some time mostly via NIH grants. We've had some DOD grants. We've had a couple of early-stage research partnerships with large pharma.

It's really only in the last, say, three years or so that people are starting to understand that obesity is not a lifestyle choice. It's is a medical problem, and it can be addressed pharmacologically. That the GLP-1 class of drugs has been great for that. That's been good for us as well because we're targeting obesity. People get it, it can be addressed. You have your reservations about GLP-1s, and anybody should have reservations about being on a drug for a long time.

Sal Daher: Any intervention.

Brian Freeman: Of course, of course. Yes.

Sal Daher: Except exercise.

Brian Freeman: There you go.

Sal Daher: That's the the panacea.

Brian Freeman: Right, right. The GLP-1s, they obviously reduce food intake. There have been a lot of concerns recently about this issue of muscle mass. You're pumping iron in between podcasts and that's what my--

Sal Daher: It's my second today.

Brian Freeman: That's the right thing to do. If you lose weight via caloric restriction, whether it's dieting, whether it's Ozempic use, or some other way, about 75% of that weight is going to come from your fat, and about 25% is going to come from muscle mass. There's concern, particularly in large pharma, about what is this going to do, particularly to people who are a little bit older, have less muscle mass to begin with.

It's not a particularly good scenario, particularly if people get on these drugs, they lose muscle, then they regain fat. Then they go on the drug and lose more muscle. It's not a particularly good set up.

Sal Daher: It's a ratchet effect.

Brian Freeman: Exactly.

Sal Daher: The fat comes back on, but the muscle is difficult to build at old age.

Brian Freeman: Exactly. Pharma is concerned about this. We always look at body composition when we do animal studies to see where is the weight coming from. It's all coming from the fat. We don't see any change in the muscle mass. That is what you would expect with recruiting brown fat or enhancing brown fat function. It's another clinically important I think differentiating factor.

Whereas, the GLP-1 drugs cause weight loss. We cause weight loss, but we cause weight loss of a different flavor. I don't think it's a worrisome kind of weight loss. It's brown fat-mediated weight loss, that's physiologic, if you will. 

Sal Daher: Yes. No, no, I see the possibility here. Instead of taking a high dose of Ozempic or Mounjaro or any of these drugs, you might take a smaller dose and take the two compounds that you have, it doesn't have a name yet, but this combination, it would allow you to have a lower dose. Then the weight loss, some of it would be mediated by reduction in appetite. There's slight reduction appetite, slight reduction in eating, but some of it would be just more burning off of calories.

Brian Freeman: Yes, that's right.

Sal Daher: Then you reduce this problem of loss of muscle mass, and that's a more satisfying type of weight loss, a healthier type of weight loss. Of course, this is to be demonstrated. This has not been demonstrated in human beings.

Brian Freeman: Right. [chuckles]

Sal Daher: Make that caveat.

Brian Freeman: Disclaimer.

Sal Daher: Disclaimer, we don't want to have some speckled person from the FDA knocking on your door.

Brian Freeman: Yes, that's right. We've done these studies where we've combined our product candidate with semaglutide or with other GLP-1s. We always see there's actually a synergistic effect between the two, which is we didn't really know what to expect when we started doing these studies. What we found is that the weight loss efficacy is greater than the sum of the two individually.

We think it's because, this effect that I was referring to before where, we're increasing metabolic rate directly in the face of an Ozempic-mediated metabolic slowdown, which enables much greater weight loss. We see that every time we do these kinds of studies. We don't have this data in humans yet, but we have shown this repeatedly in animal studies.

Sal Daher: Yes. Semaglutide and Ozempic, using those names interchangeably, it's the same thing. Tirzepatide is the Mounjaro, which has, I guess, three modes of action.

Brian Freeman: I think it's two for tirzepatide.

Sal Daher: Okay. Yes.

Brian Freeman: The triple agonists are out there. Lilly has one.

Sal Daher: Coming as well.

Brian Freeman: Yes. Yes. Yes.

Sal Daher: It's almost like generative AI keeping track of this stuff. [chuckles] Not even close. Not even close. Tremendous. Brian, what I'd like to do, if you're game, is I'd just like to do a brief promo for the podcast. Then I want to talk a little bit about your journey from being a physician scientist to becoming an entrepreneur.

Brian Freeman: Sure thing.

Sal Daher: If you're excited about this conversation with this brilliant physician and researcher or any of the other conversations we've had, you can get us prioritized by the algorithms in the platform where you listen to podcasts. The first thing you should do is follow us so that our podcast shows up in your feed every week. Then take the trouble, write a few sentences. They have to be complete. They have to start with a capital letter and end with a period.

They don't have to be particularly grammatical. If you took the trouble to write, the algorithm is easily fooled into thinking this is important content because someone took the time to write, even if ungrammatically. Also, leave us a rating. My sainted mother always asked me, told me to ask for five stars. Dare to ask for five stars. That will get this content, which is so valuable for humanity because, who knows, what connections could be made if someone in industry hears what Brian Freeman is doing or angels somewhere who has a particularly helpful suggestion for this hears this is how humanity develops.

Help us in this effort here, in the stone soup effort that we call the podcast. Please do that. Brian, when the podcast launches, if you listen to the podcast, do the same thing on your app so that helps us get found. Anyway, so Brian, a person as brilliant as you can make very, very attractive compensation, not have headaches and worries. You don't need the headaches of being a founder. What got you into this idea of becoming a founder?

Brian's Entrepreneurial Journey

Brian Freeman: God knows.

Sal Daher: A physician. In this time, there are lots of jobs. Why go out and do this insane thing of starting a company?

Brian Freeman: I guess I can go back to my medical training. Well, as you said, at the beginning, I went to MIT. My undergraduate was in biology. Then I went off to Japan just because I was interested and did research there. This was through the MIT Japan program.

Sal Daher: Oh, yes.

Brian Freeman: Yes. I came back and went to medical school and then did my training in neurology at the University of Pennsylvania. It occurred to me, and I think this probably occurs to people in other specialties as well, walking around doing rounds on the wards, that the largest cause of morbidity and mortality in neurology stroke by far.

Sal Daher: Yes.

Brian Freeman: What underpins stroke? The number one risk factor for stroke is hypertension but diabetes is way up there, hypercholesterolemia. Basically, the metabolic syndrome is really what underpins this huge problem which is still the number three cause of mortality in the US. It's basically obesity that's causing this.

I thought, if I want to make an impact in this field, I can see patients one by one, and I can probably do some good and people would appreciate that. Or I could take a longer, potentially rockier path that's maybe not as remunerative but potentially affect millions of patients by developing something that can address obesity, assuming it gets to the market. That's what drove me at the beginning.

Sal Daher: Wow. This is so similar to Peter Attia, who's been mentioning those. You're familiar with him? He's a physician who has a longevity practice in Austin, Texas. He has a podcast, and he has a book called  Outlive. I'm one of these followers of Peter Attia. He has this image of this malefactor throwing these eggs from a-- This is a dream he used to have in residency, and you have to catch the eggs as they're falling. This is trying to keep the patients from dying.

He decided that he wanted to stop that malefactor, that bad guy, the villain throwing the eggs over the side of the building instead of just catching them in the bottom, which is what you're doing as a neurologist. You're trying to help people recover from their stroke. Instead, you decided to go after the villain up there that's causing these people to have strokes.

Brian Freeman: Yes, I think that's a great analogy.

Sal Daher: I think that that is very compelling. Gosh, young people do such foolish things, but if it weren't for that, we wouldn't have any advancements in humanity if they wouldn't take these risks.

Brian Freeman: [chuckles] Right.

Sal Daher: No, no, but you have made tremendous progress with just being able to identify a molecule that has had this result and is well-tolerated in human beings. This is really promising.

Brian Freeman: Yes, we're getting there.

Sal Daher: Great. Any other thoughts that you want to get out to people before we wrap up our conversation?

"... What if you could magically make everybody in America lean overnight, think of what that would do to healthcare costs. It would be reduced by at least two-thirds..."

Brian Freeman: I don't think so. It's just that obesity has made real significant strides, and there are more to come. I think we can get to the bottom of this. It's been an intractable problem for a long time, but things are changing very, very rapidly now. I think the next decade is going to be really a wondrous time. Just to put it into perspective, think about the healthcare system. What if you could magically make everybody in America lean overnight, think of what that would do to healthcare costs. It would be reduced by at least two-thirds.

Sal Daher: Yes.

Brian Freeman: This is a real revolution in medicine that we're in the middle of right now, more at the beginning than the end I think. It's a very exciting time.

Sal Daher: See, the problem that we're having right now in this technologically advanced society is a problem that we are able to do things that we could never do before. A hundred years ago, consuming enough calories was an iffy proposition for a lot of people. Today, there are still pockets of famine in the world. It's usually associated with war. I can attest to you that, in Nigeria, there is an obesity problem. In Brazil, there's an obesity problem.

Getting enough calories is no longer a pervasive human problem, it's quite the opposite. It's how to deal with abundance, but it's not just abundance of food, it's also abundance of entertainment. People are engaged with social media. People are engaged passive consumption of all kinds of content. I think that we need to develop this attitude of very selective consumption of these wonderful things that technology have brought us. We have to become people who sip, not guzzle.

Brian Freeman: Right. Moderation.

Sal Daher: Yes, moderation. [laughs] We're getting back to the wisdom of the ancients, but the problem is they couldn't imagine. It was a problem that Roman emperors had. I don't know if it's where Robert Graves'  I, Claudius, in one of those books, Claudius is advised by his physician to leave the dining table before you are full.

Brian Freeman: Yes. [chuckles]

Sal Daher: Don't eat too much. That was a problem for a Roman emperor and maybe for a few senators.

Brian Freeman: Now, we're all Roman emperors. That's the problem.

Sal Daher: We're all Roman emperors, but nobody's leaving the dining table. I think there's a vast amount of work that has to be done on the behavioral side, a vast amount of work that has to be done with exercise, with behavior around food, food choices, and so forth. I think there's also a lot to be done on the pharmacological side because, look, for me, the GLP-1 receptor agonists are not a thing, not useful, because I can control my weight without it.

If you can't control your weight without it, that's a life vest for you. Don't pass up the life vest. Don't pass up the lifesaver because you're going to drown. You're going to end up with calcification of your arteries, and you're going to have a very, very sad later half of your life, incapacitated, unable to do things. On the other hand, if you seize the moment and you do something about obesity, you will have a splendid old age.

Brian Freeman: You're right. A hundred years ago, this wasn't a problem at all. Obesity, it's now recently surpassed smoking as the largest cause of preventable death in the world, not just in the US where we are leaders, but in the rest of the world as well. I think we're getting there, which is why this is going to transform healthcare in the next decade or two.

Sal Daher: I remember my dad, in the early '60s, he used to be a smoker. This is in Brazil. When he read it-- he used to read  Time Magazine, and that's how he taught himself English.  Voice of America, Time Magazine, and he taught himself English. He was a polymath. He's a mathematician and so on. When he heard that cigarettes cause cancer, he stopped smoking immediately. He had unbelievable self-control. Incredible self-control.

Brian Freeman: That explains the 100-pound weight loss.

Sal Daher: No, no, no. If I had three quarters of my dad's self-control, I wouldn't have gained the weight to begin with. Of course, he did not have the genetic propensity to gain weight. My mother did. My father did not. My brother would pass up the chocolates. Well, I'll have it later. My sister and I were like, "Oh, chocolate." No, but the serious point here is that both my sister and I have a weight problem.

My brothers didn't because they have the genes of my father, the set of genes that have a lot to do with weight. Genetic traits' involved, but the environment is tremendously-- because when I was a kid, I was a little chunky, but I wasn't as fat as I got because I wasn't living in modern day America.

Brian Freeman: Right, right.

Sal Daher: Anyway, I'm very grateful that you made time to be on the podcast.

Brian Freeman: Well, my pleasure.

Sal Daher: Brian Freeman, MD, co-founder with Olivier Boss and Jean-Paul Giacobino of Energesis, which has a platform for discovering compounds that activate the precursor cells to brown fat in the body. Oh, man, this is so promising. Thanks for being on the  Angel Invest Boston Podcast.

Brian Freeman: Oh, thank you so much for having me. It's a pleasure to talk to someone who's so well-informed about this area.

Sal Daher: I'm Sal Daher. Thanks for listening.

[music]

Sal Daher: I'm glad you were able to join us. Our engineer is Raul Rosa. Our theme was composed by John McKusick. Our graphic design is by Katharine Woodman-Maynard. Our host is coached by Grace Daher.