Speaker 1 (00:00):
Most of the drugs actually on the market are based on natural products, either natural products themselves, but most are at least inspired by terrestrial natural products.

Speaker 2 (00:12):
How in the world did you decide to go looking in the ocean for new compounds?

Speaker 1 (00:19):
I have to say my day job is really a dream job. I love sports and drug discovery is really a team sport. I have the privilege of interacting, working with chemists, biologists, synthetic biologist and pharmacologist to form a team that has the same vision of developing new therapies from marine environment and bring these compounds, these discoveries really from the beach to bedside.

Speaker 2 (00:48):
I like that beach to bedside. And we were talking off camera, so you are a scuba diver and you’ve trained and been in Hawaii and you’ve been at Scripps Institute in Southern California and now you’re here in Florida. I’ve noticed a pattern that you seem to like warm water and those of us who live in Southern California or California in general, somehow we don’t have warm water. <laugh>

Speaker 1 (01:17):
I know. <laugh> And we didn’t have warm water in, in Germany as well.

Speaker 2 (01:21):
No.

Speaker 1 (01:22):
<laugh> As you know, you can tell by my accent. So I grew up in Germany, landlocked, but I read in the literature about amazing discoveries that were made at the University of Hawaii, which is the birthplace of marine natural products chemistry. So the first pioneers really of the field worked at the University of Hawaii and I had the privilege of working with the first professor who ever looked at marine cyanobacteria, a type of also called blue-green algae as a source of pharmaceuticals. So I saw the amazing structures and the amazing activity and I wanted to be part of that. I thought that’s so fascinating and I applied, got into the university and traveled around the world from Germany to Hawaii to train with the best, to train with the pioneers and had to get scuba certified, right? So that’s where my, you know, adventure started, adventure in the ocean.

(02:17):
And yeah, our starting point, as you mentioned, is, is the water we start with by snorkeling or, or diving. It’s really a treasure hunt in a wetsuit, uh, diving for, for chemical gold.

Speaker 2 (02:31):
Well, I think many people realize that so many medicinal compounds, pharmaceutical agents have their basis in plants and we naturally kind of think of terrestrial plants, but ocean plants predate anything that’s happened here on land and you mentioned cyanobacteria, that’s a fancy word. Most people have heard of spirulina, uh, a blue green algae and that’s a type of that algae that you mentioned.

Speaker 1 (03:05):
That’s correct.

Speaker 2 (03:06):
So take our listeners why get interested in the sea because the sea came first and maybe there’s some pretty cool stuff happening down there.

Speaker 1 (03:16):
As you mentioned, most of the drugs actually on the market are based on natural products, either natural products themselves, but most are at least inspired by terrestrial natural products, products from plants, soil bacteria, fungi. But if you look at our planet, 70% of the planet is covered by ocean. In the three-dimensional space it’s 95% and the greatest biodiversity is in the ocean, not on, not on land. So can you imagine, can you, uh, extrapolate, you know, how many discoveries are just waiting for us to be developed into potential therapies? But then again, there are also so many organisms, which organisms to focus on. Life presumably started in the ocean. So obviously organisms there had long evolution times, but you really wanna work with the best, right? Always. You wanna work with winners. Cyanobacteria, to me, are the winners. They’re the first organisms on the planet, the oldest organisms on the planet.

(04:17):
They had 3.5 billion years of evolution. So they’re now a thing or two about aging well and making it in this environment, planet earth. So we really wanna learn from those cyanobacteria and get inspired by the chemistry they are producing.

Speaker 2 (04:37):
Yeah. Hendrick is very modest. He’s actually made discoveries that have been the blueprint for FDA-approved anti-cancer drugs like doolstatin-10. So what is … I mean, this sky’s impressive, folks. What does that say about, you know, the ability of the ocean to really be a fundamental place to look for drug discovery of pipeline?

Speaker 1 (05:07):
So far there’s over a dozen, 15 or so marine drugs on the market and one-third of them, as you pointed out, are based on dollastatin-10, which is a cyanobacteria compound that we discovered in Florida as well as in the, in the Pacific Ocean. But this is really just the tip of the iceberg. So in every collection that we look at, we find completely new compounds and these new compounds occupy new chemical space that means they probably translates into completely novel pharmacology and we just, you know, looked at less than 1%. Can you imagine if you have the ability to access the remainder of the ocean, how many potential therapies we could find to address unmet clinical need?

Speaker 2 (05:59):
And this is something I’ve been interested, uh, for many years. Why do plants and algae make these compounds in the first place? Are they survivability factors that protect them cells from a harsh environment, or I mean, they don’t just make them for fun?

Speaker 1 (06:19):
Yeah, so I asked them that question <laugh>. Yeah, no it, it’s a, it’s a very good question. Of course, we can now only speculate, but, you know, especially the ocean is a very competitive environment. It’s, it’s a battlefield there, battlefield for nutrients and, and for space, sometimes scarce nutrients, right? And the organisms we are interested in, their sessile, they don’t have teeth to defend themselves, so what do they do? They produce chemical weapons weapons chemistry to defend themselves against predators, competitors, but then also, um, really use these, this chemistry as a language to communicate. So the more communication is going on, that means the more chemistry. And that’s why we really focus on areas of greatest biodiversity like coral reefs, where you have a large number of different organisms because there’s a high level of communication and defense. So we are doing targeted collections in those areas of high biodiversity, which gives us ultimately a rich, uh, arsenal of weapons that we are trying to repurpose essentially for biomedical applications.

Speaker 2 (07:30):
Now, you’ve also done another major cancer drug discovery. Uh, you discovered gatorbulin from cyanobacteria. Uh, now since we’re talking gator bullet, I’ve got to ask, uh, University of Florida Gators, uh, was that a name of coincidence or something you were having fun with? <laugh>

Speaker 1 (07:52):
We’re always having fun. I mean, I think that’s the recipe for success too, that it’s not just a job, right? It’s really passion that happens to be a job and, but I also view it as, you know, an obligation to society to really unlock the therapeutic potential of these natural products, because we are able to do it, we must pursue it. And yes, Getabulin, it’s my favorite name. One of the beautiful aspects of our work is all these compounds are new so we can name these compounds because nobody has ever seen them before and we try to make it catchy and, but also descriptive so that people know where the compound comes from and, and what it potentially does. It targets tubulin, so it incorporates the name Bulin tubulin for the molecular target and the name Gator, of course, really gives credit and tribute to the discovery at the University of Florida, to the team that I led.

(08:49):
And it was a long journey to really characterize this molecule in detail. It started with the cyanobacteria bloom right here nearby, uh, in, in Fort Lauderdale in 2005 and 2006. This was where the original collection happened and we knew there’s something completely novel in there and it took a decade of development, early stage development to understand the chemical makeup to reproduce a compound in our lab and in, at the University of Florida to identify the molecular target and the mechanism of action so that we actually have biomarkers for preclinical studies and hopefully in the future clinical studies. So it’s really a tribute to, to the team at, uh, at UF, the Gators and also, you know, our global collaborators, international collaborators in Europe as well, which we call now the global Gators part of the family.

Speaker 2 (09:48):
But we probably shouldn’t expect to see Gator Bulin in Gatorade anytime soon.

Speaker 1 (09:55):
Not in Gatorade. <laugh> But hopefully eventually on the market in one form or the other.

Speaker 2 (10:00):
Just don’t want people to go to the store looking for that ingredient in Gatorade. So you mentioned this is, this is a very long process. This is like there’s an algae bloom here in Fort Lauderdale and you say, “Oh my gosh, l- look at this. There’s a compound here.” But it took 10 years to get from this algae bloom to actually having something with value for human clinical trials.

Speaker 1 (10:27):
And we are not there yet. The, the, the journey has still just started. And sometimes these discoveries can take a few month o- months only and sometimes it takes 10 years. It, it, it really depends on the novelty, on the novelty of, uh, of the discovery. And the more novel, uh, the harder to predict, you know, the, the path it will take in order to fully understand and characterize a molecule. In this case, we stumbled over, you know, novelty at the level of structure, at the level of chemical synthesis and of how to make it and at the molecular and atomic level, how this compound interacts with molecular targets. So so many elements of novelty delay the process but make it even more rewarding if we are successful at the end.

Speaker 2 (11:17):
So I think a lot of people, a lot of our listeners wonder, okay, so what’s the difference between the drug development pathway that needs FDA approval that you and I know take many years of, of clinical trials versus taking a similar discovery and turning it into a dietary supplement?

Speaker 1 (11:41):
Our focus for the most part has been on the discovery of, of therapeutics and that’s where we use these cyanobacteria as a, as a starting point to really address diseases of, you know, with unmet clinical need. It’s a long road to, to begin with. You have to reproduce the molecule in, in the lab, you have to identify the molecular target, uh, and you have to develop a data package that allows you to register the compound with the FDA, uh, and get IND status investigation and new drug status and which then allows you to anti-clinical trials and perform safety studies phase, in phase one, as well as efficacy studies in phase two. So that’s an extremely long process as well as, you know, e- expensive, uh, process. But we are really not starting with a dietary source and that’s why these, you know, uh, studies are, of course, have to be rigorous and are very important.

(12:38):
You really have to start with a dietary source that, uh, is, has proven to be safe already and can be, you know, can be taken in, in a, in a safe, in a safe manner. And for us, it’s important that we show efficacy of these, uh, potentially dietary supplements and our focus in that space has been, has been on seaweed because it’s a proven dietary sauce, um, that has been ingested in, in many particularly Asian countries and has been inversely correlated with the incidence of, of cancers, particularly in Okinawa where the seaweed consumption is the highest and also has been shown that, you know, Okinawans have a lo- long life expectancy and there’s a potential link to, to seaweed consumption. So that’s why we entered the area of, of seaweed.

Speaker 2 (13:37):
Gotcha. Now, if you’ve heard me talk about longevity plus before, this is the origin story behind its headline ingredient, algevity factor. And you were studying a algae, uh, that’s called Uva lactuca, which is sea lettuce for those of us, uh, who have actually seen it or even eaten it. What is it and why, I mean, why look at sea lettuce? Uh, what’s so interesting about that?

Speaker 1 (14:06):
So we did not purposefully only focus on sea lettuce. We are usually use an unbiased data driven approach, right? So we sampled various seaweeds, not from Okinawa where the inspiration come from, came from, but here from the, uh, Florida keys, right, right there. And in an unbiased fashion, sampled numerous seaweeds, 30 plus seaweeds, and looked for its potential to activate a transcription factor called NRF2 that controls the production of glutathione in cells. So consistently and most robustly, we found that ulvalactuca, among all the algae we have tested, produced this effect and that let us focus on ulvalactuca, which as you pointed out is also known as a sea lettuce.

Speaker 2 (14:54):
So you, you mentioned, uh, quickly it rolled off your tongue in RF2 and glutathione. And I think we, we spend a lot of time educating our patients who they feel a lot older than they should. They have low energy, they have brain fog, they have weight issues and when we get down to it, um, glutathione is really one of only two antioxidants that are active in mitochondria that are producing energy in the first place. So where does NRF2 come into getting the glutathione pathway activated?

Speaker 1 (15:38):
So NRF2 is a so- called transcription factor and it binds to elements on the DNA and then induces the transcription of biosynthetic genes that are involved in the production of glutathione. So that means this transcription factor controls the intracellular production of glutathione and not just glutathione, it also activates a battery of other antioxidant enzyme. So it’s a complex mix of target genes that are antio- have antioxidant properties and also detoxification prophecies and it also controls the production of glutathione. So it’s an indirect way of, uh, of producing antioxidants without actually supplementing with antioxidant.

Speaker 2 (16:28):
So the naysayer in me says, “Well, why can’t I just swallow glutathione capsules and I’ll be fine?” <laugh>

Speaker 1 (16:35):
The more effective way would be, uh, uh, to activate the transcription factor and really, uh, induce a robust response. So yes, you can take antioxidants and that quickly take care perhaps of immediate oxidative stress, but you wanna have a pronounced robust long-term effect and by activating the endogenous machinery that controls the biosynthesis of glutathione, you get this long-term pronounced effect.

Speaker 2 (17:06):
Right. Working from the inside out rather than the outside in. Right.

Speaker 1 (17:10):
And you don’t even know if you get things from the outside to the inside, which is another hurdle.

Speaker 2 (17:15):
Which is another hurdle.

Speaker 1 (17:16):
And we don’t have, we don’t have that problem.

Speaker 2 (17:18):
Gotcha. So when you, when you’re starting to work with Uva, what did you see there? You said, “Oh my gosh, we’re onto something

Speaker 1 (17:29):
Here.” I mean, first of all, as I mentioned, it was the, you know, the seaweed that showed the most robust response in cells, but going from cells to in vivo system to mouse models is, is another big step and we found that, uh, the extract and an enriched fraction of oval lactuca also had pronounced the fact, uh, in vivo, not just in cells, but also in vivo, meaning in a, in a, in a mouse model. And then we knew this, we all do something, as you, as you mentioned, right?

Speaker 2 (18:03):
Yeah. I often tell anyone who will listen that in vitro, I, I say what happens in a test tube or what happens in a Petri dish, unfortunately for those of us in research, doesn’t always transfer to an animal model to in vivo. And we see so many companies say, “Oh, you know, th- this, this happens at the cellular level and we tested it on a, on a cell culture and it never translates to actual clinical mouse.” So congratulations on doing that. And that’s why, you know, I was so excited to learn about you and your work and to meet you. So how do you then say, “Okay, there’s this amazing compound in sea lettuce that you named algevity factor. How do you take that and then bring it into productions so it can be one of the prime ingredients in longevity plus?” Tell me about Indonesia

Speaker 1 (19:05):
Indonesia’s beautiful country- <laugh> … Consists of 17,000 islands and many places to dive and to snorkel. But really, so when,

(19:16):
When we made the discovery that it works in vitro and, and in vivo, the next step was how can we possibly scale the production scaling as an issue, can we get this activity in a reproducible manner and we have to ensure, uh, that, you know, the purity and lack of contamination and that we are not harvesting it from potentially polluted water. So these are the issues that we had in mind when we were looking for potential sources. So now I, as you know, I, I really literally traveled the world. I’ve seen many countries and, you know, and was really impressed with some of the pristine waters, especially in Southeast Asia and Philippines and particularly in Indonesia we found, you know, the, the place where that hits checks or the boxes, including the expertise of a local team that we are working with to ensure the highest quality at all stages of production from harvesting down to, uh, enrichment of, uh, the active ingredients.

Speaker 2 (20:29):
So you’re not taking seaweed here in Florida that washes up on the shore and rinsing it off and mincing it up and throwing it into, uh, longevity plus.

Speaker 1 (20:43):
As I mentioned, I want to make sure that, that the quality is really, uh, uh, up to, up to standards and I have a trusted team in, in Indonesia, in, including, uh, one of the PhDs who, who worked with me before in Florida so I know I can have confidence in the team over there that, uh, we can provide ingredients that are of absolute purity.

Speaker 2 (21:10):
So this is your team.

Speaker 1 (21:12):
Yeah. <laugh> In a, in a way, right? I mean, that’s what, what we do, right? If you’re in, in our business that we, we train the next generation of scientists- Right. … and that’s really a, you know, part of a legacy and it’s, it’s great to see a former trainees, you know, take things to the, to the next level.

Speaker 2 (21:30):
Yeah. No, I know what you mean. I’ve trained many heart surgeons who went on to head departments and, yeah, you’re, you’re right. It’s, uh, it’s great to see our, our trainees thrive and so you have a trainee who’s heading this project.

Speaker 1 (21:44):
Yeah. And other, other trainees are professors at, you know, universities all over the world, and it’s …

Speaker 2 (21:51):
So are there next steps that you wanna see that, you know, that led up to algevity factor and more broadly, what’s the exciting direction you see in terms of healthy aging and longevity research that you think sea plants, sea vegetables can bring us?

Speaker 1 (22:09):
So far we only focus on one, really on one seaweed and, you know, I, I’m sure there, there are other seaweeds that remain unexplored that we could pursue with, uh, our current discoveries, it’s important to have more clinical studies, uh, as, as next steps. And, you know, well, ultimately, I, I, the most exciting avenues would be an area of immune health, immune health and mitochondrial support and yeah, combating inflammation in general. A- as you know, I mean, with this cytoprotective mechanism that, uh, is driven by NF2, we also, we combat inflammation, right? And inflammation is really the precursor or driver of so many diseases. So if we can, you know, stop inflammation at an early stage, this is the goal of preventing diseases.

Speaker 2 (23:07):
Yeah, absolutely.