Dr Rupy: Carl, thanks so much for coming in again. I'm really, really excited to hear more about watercress and also the progress that you've made since the last time we chatted on the pod. Why don't we start off by taking a bit of a step back and just talking a bit about how you got into researching watercress and where we're at at the moment with our understanding of this brassica vegetable and the potential benefits to inflammation and longevity.
Dr Carl Stewart: Yeah, no problem. So I was a junior doctor at Torbay Hospital in 2012 on a ward round and saw a baby who was septic from infected nappy rash. And as you often do, 11 o'clock coffee round comes along and we were talking about what actually causes nappy rash and none of us were very sure. So I went away and did a bit of research and found that nappy rash or incontinence associated dermatitis is a chemical burn from ammonia made by an enzyme that some bacteria have called urease. And it was interesting because it didn't appear that anyone had ever really tried to target urease as a way of preventing the ammonia damage. So ammonia raises the pH in the area which is damaging, it's a direct chemical irritant. It also switches on some of the enzymes in poo to make them more active, like trypsin, and that can then start to digest the barrier of the skin. And fourthly, the ammonia as well can switch on some of the candida species, which is why we often see fungal infections when you've got nappy rash. And obviously those candida species can be damaging as well. So as we were researching this, we found that plants also had a relationship with this urease enzyme. And it turns out that some of the bacteria in soil have urease and they make ammonia. And it appeared to us that plants which either grow very quickly or which grow in quite harsh environments need to try and hold on to the available nitrogen in the soil to make protein. So they don't really want ammonia to be leaching off in the soil and disappearing. They want to keep it as urea that they can make into proteins. So some plants have urease enzyme inhibitors. And pomegranate, camomile and watercress were three of the plants that kept being mentioned in the literature as having urease enzyme inhibitors. So we naturally thought, wouldn't it be neat if you could somehow get these compounds out of one of these plants and could that be a novel treatment or preventative for nappy rash? And that's where our interest started.
Dr Rupy: That's incredible. And is there a precedent in perhaps traditional medicines where they use fast growing plants like you said to treat things like nappy rash or incontinence associated dermatitis?
Dr Carl Stewart: So we're the first group to look at it as far as we know, but in the current environment where people are looking for fast growing plants that can be replenished quickly. So we've got an interest now in wet wipes and a lot of wet wipes and disposable continence products are being made out of bamboo. Bamboo being very, very fast growing. So while there's, we're the first ones to really look at it in terms of the enzyme, I think these fast growing plants have certainly got a role.
Dr Rupy: So you find out that watercress is one of these plants that has this urease enzyme inhibitor in it. What was your next step after that? Because you obviously started the brand Profoundoc, you must have reached out to this professor at Exeter.
Dr Carl Stewart: That's right. So I was introduced to Paul Winyard who is a professor of experimental medicine at the University of Exeter and a biochemist by background and he was quite interested in the project. We were really fortunate that around Torbay we had Torbay Medical Research Fund who are a charity who support health and social care projects on along the south coast and they actually gave us a grant to see if we could extract these interesting compounds from watercress. And that's where we started. So we spent the best part of probably eight years just trying to figure out in a lab-based setting how we could get these urease enzyme inhibitors out of watercress, which we eventually managed to do.
Dr Rupy: It's a brassica vegetable. Are there, what are some of those plants that are anti-inflammatory that have these unique benefits that could be beneficial for longevity and general health purposes?
Dr Carl Stewart: So it was really, it's a really interesting question. So we started out being really interested in watercress because of these urease enzyme inhibitors, thinking we could block the production of ammonia. But watercress is part of the brassica family. So brassica family have things like mustard seed, wasabi, and you know, typically these peppery plants, as well as broccoli, which is in there but isn't peppery. And what's interesting about them is they all have a bit of a defence mechanism where when you crush them, you'll know that when you chew watercress or chew wasabi, you get a really peppery taste. That's a conversion of a group of compounds called glucosinolates, which just sit in one part of the plant. They get mixed with an enzyme called myrosinase and it makes these anti-inflammatory compounds called isothiocyanates. So we quickly discovered alongside getting these urease enzyme inhibitors out of watercress, we could also concentrate the amount of isothiocyanates in watercress by crushing it and maturing the juice. So what we had to do is develop and build and commission our own biorefinery to be able to upregulate watercress's production of these really interesting anti-inflammatory compounds so that our watercress extract not only blocked the ammonia, but potentially was protective to the skin. And we know that there's lots of research going on with isothiocyanates currently. So if you have a look in the literature, they're really promising anti-inflammatory compounds that can be used for a whole range of things from inflammatory bowel disease, skin conditions, there's even been implications in their use in Alzheimer's, reducing oxidative stress in the body, which obviously can lead to damaging consequences down the line. And the other interesting thing is the particular isothiocyanate that watercress makes, which is called PEITC, is really good at mopping up ammonia. So the third benefit to us in having this as a potential treatment for nappy rash is any stale urine which is there, which already has ammonia, will react with the isothiocyanates and effectively detoxify it. And the secondary benefit of that is we get rid of the smell. So we're hopeful that we can continue to develop our extract into something which not only prevents the skin damage, and typically, the population affected by this are often frail, older adults or babies, they're a vulnerable population. This rash can be really uncomfortable. We're not only protecting the skin, but potentially also alleviating that smell, which for adults can be embarrassing and obviously for anyone who's changed a nappy, it's not, that ammonia really gets to the back of your nose and you can smell it. So it's really exciting for us.
Dr Rupy: And if we just sit with the brassica vegetable sort of array for a moment. So we know that it has these isothiocyanates, this collection of anti-inflammatory compounds. Are there any ways in which we can benefit from those foods simply by eating them? And what kind of doses are we talking about when it comes to just eating them in their raw or mildly cooked form?
Dr Carl Stewart: Yeah, absolutely. So when we were talking before about watercress and you crush it up and then you get that peppery taste, you're only going to get that with the raw plant. So if you were to cook or steam watercress, same as if you were to steam wasabi or any of the other brassicas, you knock out that myrosinase enzyme. So while those precursor glucosinolates have some benefit, you're not really getting the full benefit of those isothiocyanates which are produced by the plants as a stress response. So this comes back to this idea that actually, if you overcook vegetables, you take a lot of the nutrition out. This is perhaps one of those examples where that's the case, where just eating it in its native raw form means you're activating lots of different plant pathways which the plant uses as a protective mechanism, but which actually also benefit us internally as well. We know that a cupful of watercress, which is about a third of a bag, has huge benefits when you ingest it. And it's the same for the other brassicas as well. These leafy greens are superbly good for you internally. And the worry is we get too used to just cooking everything. And really, I think we should get back to trying to have raw fruit and veg, activating these internal pathways and getting the maximum benefit from our food.
Dr Rupy: And you're sort of setting a precedent here for the preparation of watercress in this manner, like these topical preparations, but I can imagine there's the potential for doing similar things with other members of the brassica family, whether it's cabbage or broccoli or broccoli sprouts, for example.
Dr Carl Stewart: Well, absolutely. So as I mentioned, the isothiocyanate that watercress produces is called PEITC. It happens to be really good at being an anti-inflammatory agent, has some antibacterial properties. And one of the things it's being looked at now is its role in regulating skin cancers. So one of the groups we've been working with have shown it can act as what's called an epigenetic regulator. So it can switch on the death genes of melanoma skin cancer cells and switch off their survival genes. So while your DNA stays the same through your life, you can switch genes on and off, which is a really interesting area of science. It's a bit like the DNA of a caterpillar is the same as a butterfly, but you look at them and they're completely different. You need to switch off the caterpillar, switch on the butterfly genes to obviously make the butterfly. And you know, so for watercress, you have that with PEITC. But if you look at wasabi, the particular isothiocyanate it makes, allyl isothiocyanate, seems to be good at breaking down barriers. So barriers that bacteria make. So in the bladder, you can have these horrible mucus barriers that bacteria make, really difficult to get antibiotics to penetrate, but the allyl isothiocyanate in wasabi has been shown to be able to break down that barrier. So it may well be, and what we're interested in, is could we take lots of combinations of brassicas with all their different isothiocyanates which have a slightly different function and make unique blends which can target certain conditions within the body. And because they're single compounds, it may be that we can synthesise them. It may be that we can try and mimic what watercress does in terms of activating it with myrosinase, we might be able to do that synthetically, which opens up a whole range of opportunities for targeting different medical conditions based on the chemistry of eating a plant. And and I think this poses huge opportunities for farmers as well. So the watercress that we get, for example, from the watercress company is their excess crop. So they have to overproduce by 10 or 20% every day in case there is a sudden surge in demand. So if someone makes a watercress salad on a Tuesday evening, everyone goes out on the Wednesday, wants to buy watercress, it has to already be pre-cut. That means there is going to be a waste. And the shelf life is about nine days refrigerated. Well, we can take that watercress, and when we're doing a production run, we take 300 kilos of it, and then we can turn it into 200 litres of our sterile extract. So what we're doing is making something with value from effectively farmer wastage or farmer excess crop. And our two byproducts are a fibre and a protein we've got plans for in the future. So we're hoping to be zero waste from an excess crop. And if you look at some of the value that we think there could be in mustard seed, in wasabi, in broccoli, we think the same thing could be applied to those. They all have to be produced in excess, they all have really interesting compounds in, it may be possible to refine them for use in skincare, for use in a range of different things.
Dr Rupy: We've had Dr William Li on the podcast a couple of times and he's in a position where he sees a lot of companies that are trying to do similar things with extracts from pretty diverse ingredients like oats, for example, and other fruits and vegetables, mainly fruits actually that he's come across. He runs the Angiogenesis Foundation. And I'm just thinking about all the the the products that are commonly wasted in the UK. I remember watching a program about leeks that they don't use most of the leek. When you go to the supermarket, you've seen them like very nicely trimmed, the outer leaves have been stripped and they're cut pretty much in half and you're left with this beautifully presented, often wrapped in plastic unfortunately, leek that you just pick up from the supermarket. But there's a huge amount of waste there and I just think, you know, within each class of ingredient, the allium vegetables, umbelliferous vegetables, brassica vegetables, there's probably a universe of compounds that have benefits to humans when concentrated in the way that you've done with your biotech company.
Dr Carl Stewart: Well, absolutely. You know, I mean, we use a similar example with turnips. They're always top and tailed in the shops. Where do the tops and the tails go? You know, that thick fibrous material could be recycled into something. And I'm sure there are companies out there that are doing that, but we also know there's still an awful lot of wastage of this fresh produce. And I think, you know, this idea of almost upcycling the waste raw material into new ingredients, into new healthcare products, I think it's a completely under-utilised resource.
Dr Rupy: Yeah, yeah, yeah. You mentioned this property, the urease enzyme inhibition. Are there any other properties that you're using your watercress extracts for?
Dr Carl Stewart: So it's interesting. When we were interested in the urease enzyme inhibition, we also then found that the urea which is in urine, which is what this urease enzyme uses, is also present in sweat. And actually we started to look at sweat rash. And sweat rash is effectively nappy rash just in other sweatier areas of the body. So often in the groin, in the armpits. And that's why we thought actually a general skincare group of products, creams and lotions may benefit the general public who maybe have some of these irritated skin conditions. So that's why we launched our Profoundoc skincare range, A, because we wanted to try and generate some funds to go into the research, but also just to test and see whether our extract was amenable to going into a cream or a lotion. Because just because we made the extract, of course, there's no guarantee we can preserve it, can we make it sterile, is it stable, does it go into creams? And we were quite fortunate that it was able to. So we launched our products and since January when they've when they've launched, we've had phenomenal feedback. So we've had a lot of people saying it's been beneficial in particularly dry, irritable skin conditions. So eczema has been referenced an awful lot. And we always have to caveat and say we won't and we can't make medical claims because we're a plant extract, we're well aware of the MHRA rules, we don't want to step outside of those. But with me with my CEO of a kind of biotech company hat on, we have found something really exciting for these skin conditions and we're going to continue developing our extracts. And if it means that we have to synthesise compounds that we identify or replicate synthetically chemical pathways from watercress to make new medicines, that's a route we'll go down. But certainly people with sweat rash and eczema are reporting really good outcomes. Now, we're also aware that the urease enzymes involved in lots of other conditions as well. So the stinging and burning that typically ladies will get who've got urinary tract infections, the majority of the time that is urease from proteus or klebsiella or a similar bacteria making ammonia and it's effectively like a nappy rash process but in the bladder. That's why you get the pain in your pelvis, that's why you get the burning, the stinging, the bladder gets irritable so you go to have a wee all the time. And we strongly believe that the best way of treating these sorts of urinary tract infections in the future is not throwing antibiotics at people, which then decimate your microbiome in your skin, in your gut, can often then lead to people getting secondary infections like thrush, but just target the urease enzyme. So we're now doing a program of work looking at how we can get our specific combination of urease inhibitors to be excreted by the kidneys, get them past the gut, get them into the kidneys to see whether we can then rain back in those symptoms. Because if we can do that as a mechanism to prevent the symptoms, we also don't provide an evolutionary stressor for bugs to have antimicrobial resistance. And we know that the urease enzyme, the structure of it is really well preserved across nature. So if you look at it in bacteria in the soil or in the bladder or on the skin, it's very, very similar, which suggests that there's only certain confirmations that will actually work for bacteria. So if you manage to inhibit it, it can't really evolve a change to that enzyme if that makes sense. Otherwise, we would see lots and lots and lots of different types. So we think potentially for urinary tract infections, this could be a really neat antibiotic alternative to rain in the bugs that are producing ammonia as an alternative to antibiotic therapy. And it's a completely different way of looking at treating infections. It's more about re-establishing a microbiome. We know that in most women over 60, for example, they have bugs that sit in their bladder. And they just sit there, they feed off some of the sugars, they feed off some of the amino acids and they don't cause any problems. For whatever reason, at some point, that microbiome becomes altered and the bugs start competing and some of them make ammonia and then you get urinary tract infections. The bugs that have urease use the ammonia to colonise areas and out compete. So if you knock out the urease, you can actually just re-establish the microbiome, then you've protected your gut. Then you've protected your skin, then you're not going to get secondary infections. And it means when you do have a really severe infection in the future, you've not been exposed to half a dozen antibiotics. So you may have better sensitivity to that. So we're really excited by that. That's a that's a program of work that we're probably going to be looking at over the next five or 10 years. We've got really good knowledge now about how we can knock out this urease enzyme. And I mentioned urinary tract infections, it's the same thing with kidney stones. So the same bugs that make ammonia raise the pH in the urine, calcium, phosphate, they come out of solution, they form crystals, that's where you get struvite kidney stones from. Some of the consequences of liver cirrhosis where people turn yellow and get jaundice and and they get a syndrome called hepatic encephalopathy. A lot of that is driven by ammonia. And a lot of that ammonia in the gut is from urease. So by inhibiting the urease enzyme, we can potentially help in a range of conditions. And our key piece of work at the minute is a bug in the stomach called Helicobacter pylori. So that buries itself in the stomach wall and it produces ammonia on its cell surface through the urease enzyme. And the ammonia damages the stomach wall and with all that chronic inflammation, at some point, one of the cells of your stomach makes a mistake and the majority of gastric cancers are therefore due to Helicobacter pylori. We can we can knock out the urease. So we've shown in a in a broth of sort of stomach acid resembling broth, you put our watercress extract in, it can't make ammonia, the acid therefore kills the cells. So for us, you know, we're really excited that this idea of starting with nappy rash is just going to open the door to all these other urease driven conditions. And with Helicobacter pylori, if we can effectively inhibit it, it's responsible currently for 85 million cases of gastric cancer every year. So we could have huge, huge effects in the future. And that's just around urease. You take the separate story of the isothiocyanates, their anti-inflammatory function and the literature which is coming out, we think we're kind of at the tip of the iceberg of new medicine, new antibiotic alternative discoveries which you know, could be revolutionary. I mean, that's what we're striving for. And it does sound a little bit far-fetched and we recognise it does, but we have come a long way in the last few years and actually, you look where most antibiotics and most medicines came from, plants.
Dr Rupy: Yeah, yeah. Yeah, I know, it's almost like, you know, there's you've got the pharmaceutical world, which is synthetic, but you know, it has the origins in plants and you have the phytopharmaceutical world, which is something that you could probably class this into, right? The like phyto being the chemicals you find in plants. One of the sort of pushbacks I get whenever I talk about this sort of area of future medicines is it's okay if you can replicate that in a model and then pour over an extract that you've isolated from an ingredient or whatever. But how do you deliver that to the point where it's actually going to be useful in the body? So if we use the example of a UTI where you have a bacteria that's sort of attached to the the wall and it's causing all the inflammation, etc. What sort of delivery mechanism would you postulate using watercress extract? Would would manage to get to the the bladder, the area where it could potentially have that effect?
Dr Carl Stewart: Well, that's sort of what we're looking at now and that's where the next step of the puzzle for us really lies. So we know that a lot of compounds are going to be modified or destroyed or changed into other things when you swallow them because of the acidity of the stomach and all the other bacteria that are in there and all the thousands, millions of chemical reactions happening in the gut. So you think, well, how do we get something through the gut, then past the liver, then keep it in the bloodstream, then it has to be excreted by the kidneys and then all of a sudden kind of jump into action. That's the bit which we need to try and understand. But we're fortunate that there are various urease inhibitors in watercress. So there's going to be a little bit of trial and error here around testing things. And there are novel delivery mechanisms that we're looking at. So you can skip parts of the body quite effectively. And it's part of the game. You know, we just have to do it one step at a time. How do we get it absorbed into the bloodstream past the liver? First step. Okay, it's in there. How do we, how do we get it past the kidneys? Then how do we get it past the kidneys in sufficient concentration to have an effect? Will it even have an effect? We don't know. Maybe even the first step is looking at the really extreme cases where you've got some people who have chronic, chronic pain. They've been on multiple antibiotics to treat cystitis or suspected recurrent urinary tract infections. And use a similar delivery mechanism that we use in urology for bladder cancers where it's a catheter that's inserted into the bladder and it's essentially washed out with whatever material you're using, whether that's a chemotherapy or a something like even an antibiotic as well. So it could use that mechanism just to sort of prove the concept that this potentially works.
Dr Carl Stewart: Yeah, and one of the other things which is quick and easy for us to do of course is you get someone to have a wee once an hour, every hour for 24 hours and then on the third or fourth hour you get them to drink a litre of our watercress extract, collect their urine, inoculate it with a urease enzyme and see if it makes ammonia. And you can look at that in terms of colour changes through some clever reactions or you brave it and you just sniff the test tube and say, well, you know, do my eyes water afterwards? Have I made, you know, have I made a difference here? And it sounds, you know, it sounds really daft and I know it does, but something like that proves you have then caused urease inhibiting activity in the urine. That's that's pretty impressive if you can do that. So we're doing a program of work with that at the minute. And it's it's looking promising. That's all I can really say.
Dr Rupy: But before I talk about any other sort of use cases, particularly within beauty, I want to talk a bit about the other sort of byproduct of watercress waste. So you're using it as an extract and then you mentioned two other things, fibre and protein. So what kind of fibres are we talking about within watercress?
Dr Carl Stewart: Yeah, so when we take the watercress, we take about 300 kilos. So we've got international patents pending for the production process, composition and the usage of our final extract. So one of the key things we need to do is activate this myrosinase enzyme. So we have a period where we're macerating up the cells to make these isothiocyanates. And then we are getting all the juice out of watercress. So we're left with a raw, stringy watercress fibre. Now, we're aware from say the apple juice industry that once they've pressed the apples, you're left with, I think it's called the coppice of the apple, and that can be sold as a fibre. Well, when we start developing, when we start generating in bulk, we're going to be able to use that fibre either as a dietary fibre supplement or potentially with the push towards biodegradable wet wipes, it will lend itself to being woven into some of these bamboo and other plant wipes. Okay, yeah, yeah. Which may be where the top and tails of the turnips could potentially end up with biodegradable wipes and you just kind of put all your fibrous waste material in and you can make sanitary products out of them. The other option is bioplastics. So the fibre does lend itself to conversion into bioplastics. So one of our pipe dreams is perhaps the lids of our products can be made by the fibre. And then, you know, the lid could have a oak tree seed in or it's probably too big, but have something in that you can, you know, dispose of and grow something from it. So the fibre is really interesting, really nutritious as well. So we're looking at that as a dietary fibre supplement. And one of the key Eureka moments that we had when we were trying to make an extract is when we take the watercress juice and we heat it, it actually curdles. So we don't know of any other juice which curdles on heating and it's because of the really high protein content in the juice. So it all the protein just kind of comes together as a as a big globby unit and floats on the top. And when we've sent that off to be analysed, it's a fantastic protein source. So the percentage of amino acids, which are the essential amino acids, which you need to take on board so you can't just make them in your gut, are far higher than most other plant protein sources and actually more resemble an animal protein. So for vegans, for example, who don't take in animal or dairy proteins, this could be a complete protein in their diet. The problem we have at the minute is it's about 1% of the starting mass of watercress. So we're going to have to be shifting an awful lot of watercress and doing an awful lot of processing before it becomes viable. But once we start hopefully in the next couple of years selling our extract in bulk or collaborating with wet wipe manufacturers or nappy manufacturers, you know, continence care companies, that sort of thing, we will probably be able to produce that in sufficient volume that it will be available as a watercress protein powder. And our real dream is that we can sell the fibre and sell the protein and we've got the extract and that's about 70% of the starting weight of watercress. And that means we'll be zero waste from an excess crop. And the other nice part of it is, if you look at the watercress company, they have their excess crop, which is in the bag, which looks very nice and we know it from salads. But they've got other non-saleable crops which we might be able to use. So right now we're in the growing period for them, we're having good British watercress. In the winter, some of the production switches over to Spain, purely because the watercress that would grow in the beds in the UK is still edible, but it's a bit thicker, it's a bit more hardy, and it doesn't have the classic watercress appearance, so it gets rejected. Actually, because it grows in harsher environments, we've shown it's higher in urease inhibitors because it hasn't got the protein source, it's a harsher environment. So that winter watercress, which currently just gets scrapped, that could be our nappy rash watercress. And then in the summer, if, you know, we've had a good summer for growing watercress this year, we've had lots of good weather and we've had lots of rain. So some of the watercress is left to flower because the crop isn't needed. Now, the flowering watercress, you can eat, but again, the shops won't take it because there is a picture of what watercress should look like. So what we know now is that the flowers have got more of these glucosinolates in, which are the precursors to those isothiocyanates. So we could come along and take the top four or five inches off that watercress, have all the flowers, and then we have a super isothiocyanate rich extract, which potentially is going to have higher anti-inflammatory properties. So that might be our, let's say, hopefully in the future if we can get a license, eczema product, or should we say, for safety, our dry irritated skin extract. So it may be that there's three or four different stages throughout the year where we can target watercress based on how it inherently changes its chemistry for us to make it for different uses. And all those are currently excess crops as well. So we think there's a really, really nice ecological story around using these not just excess crops, but the sort of non-used streams as well for interesting products.
Dr Rupy: I love the sort of the life cycle story to this as well. And when you were talking about the the ingredient curdling, it sort of reminded me of the the story behind whey protein and a lot of these protein supplement companies because that was, I think, the runoff of cheese making where it was the milk whey that was basically being discarded and somebody had the bright idea of actually supplementing or putting that into a supplemental form after powdering it and you know, selling that into the the protein market. I mean, when I think about vegan protein sources, particularly the supplements available, I think of corn, rice, pea, soy. You know, these are known as some of the best sources. I would have never have put watercress up there, you know?
Dr Carl Stewart: No, well, we wouldn't. And we discovered it by accident. So five or six years ago, we just thought, well, I wonder if we can just make a watercress juice. And if we're going to make a watercress juice, it needs to be sterilised, so we'll heat it. So we actually took it to a drinks manufacturer who heated it and said, I can't use that, it's curdling. And we thought, oh, everything's over, we've ruined, you know, everything's ruined, nothing works. And then some bright spark said, well, hang on a second, doesn't that mean you've taken out the protein? And then when we had a look, that's exactly what had happened. One of the things we're now interested in is whether we can get this protein out in its native form, because it curdles, it might be a good egg alternative in cooking. If you think about scrambled egg, it all comes together and it binds ingredients. If you watch our watercress juice when it's heated, it does exactly the same thing. We end up with bright green scrambled egg. So, you know, it may not have the exact gelling properties, but and we don't quite know how we would get it out in its native form, but if we can, and it's another, again, it's another project for us to look at, it may well be a nice vegan alternative to egg.
Dr Rupy: Does it taste watercressy?
Dr Carl Stewart: It, I'm going to politely say it tastes earthy.
Dr Rupy: Okay, okay, yeah, yeah. I can imagine. That's what I imagine it tasting like to be honest. I wonder if there are other sort of juices made of singular vegetables or ingredients that you could heat up and see if they curdle. Or is there an indication in the profile of watercress even in its raw form that it could be a protein source if you took it through those processing steps?
Dr Carl Stewart: I don't think there was anything that would have suggested this would have happened to watercress. We might be able to discover how we could predict it. But we just had no idea. It was a completely new finding. And when we had a look through, it's actually gone into our patent. It's something that no one had ever seen before. And it was totally unexpected. But it would be interesting to know, are there other juices out there which would curdle so you can get a protein extract and then a non-protein extract which you can go into other things? Possibly.
Dr Rupy: What I tend to see in the market these days is a sort of a natural attraction to plant-based, you know, whether it's a spray that you wipe down your kitchen worktop with or, you know, like shampoos with, you know, different types of plants and that kind of stuff. What separates your company from those? Because I feel, particularly when I look at the ingredients of those products, there's a whole long list of preservatives and, you know, all this extra stuff and very minimal extract, whereas I look at yours and it's like, well, 85, 90% extract. So what's going on there?
Dr Carl Stewart: Yeah, so when you see a lot of the things which says contains essence of something, a lot of the time, there's no evidence that that essence of that plant does anything. But people look at it and go, ooh, that sounds, that sounds nice. Even I do, in full disclosure, I look at something that has like clove in it or like, you know, a little flower, I'm like, oh, natural. Yeah, that'll be great. But typically the inclusions are at 0.5 to 1%. So 99 to 99 and a half percent of it is not that plant. When we were doing our testing of our extract, we found that a dilution down to 10%, so one in 10 dilution, was about 80% as effective on the skin as the whole extract. So this was one of the things that was really exciting for us because then it meant the other 90% could be a carrier. It could be a cream, it could be a barrier cream, it could be a spray. So if you look at our cream, our barrier cream and our spray, that has the extract in at 10%. And we were absolutely adamant that we wanted to keep it in at 10% because that's what the science said worked. 5% could have a good effect, but we had the opportunity to put it in at 10%, so we've really stuck with it. Obviously, people have an expectation when they buy a cream that it looks like a cream, it feels like a cream. So we have had to put in, you know, the classic ingredients of a cream, but we do have a far higher plant-based content than the vast majority of cosmetic products on the market with bioactive activity. Our serum, when you were talking about 85%, so our serum is just our extract with xanthan gum and plant-based glycerin and the preservative. So it's 93% watercress extract. So when you smell it, you get a kind of sweet, appley smell. That's just the watercress. We don't add any fragrances, we don't add any colours. It's going to vary in colour, it's going to vary in fragrance batch to batch. But we wanted to give people the opportunity just to have our extract. It was too runny just to sell on its own, so we had to thicken it up a little bit. But it's the highest plant-based content of anything available on the market as far as we're aware, unless you go and make your own juice. And we had to put a preservative in, you know, like any juice or vegetable matter, you know, it has sugars in, it has amino acids in, it has, you know, things in that bugs like. So we've got as mild a preservative as we can, which is in at 1%. But really, we see the standout of our products in that it's based on science, real professor, real doctor, I'm still a GP, Paul's still a professor. And, you know, the bioactivity is proven, we have the data and we're continuing to do the research to try and refine it and improve it all the time as well.
Dr Rupy: Forgive my ignorance on the trial side of things, but let's say you wanted to demonstrate watercress extract in a lotion or serum as having anti-eczema or anti-dermatitis properties. How would you actually go about designing a trial to demonstrate just that? And getting it through the next sort of process, which is super important in the UK market of MHRA approval for use as a medicine?
Dr Carl Stewart: So I don't think we're ever going to be able to make medical claims because we have a plant extract. We are really looking forward to having good open, honest discussions with the MHRA about what makes a medicine. And just to clarify, the MHRA that we're referring to is the Medical Health and Regulations Authority. Yeah, Medicines and Healthcare Regulatory Authority. Absolutely. So they set the rules around what claims people can make. And if you make false claims, a little bit like trading standards, they're the ones who'll tell you off. So for them, they will say a plant extract cannot be a medicine. And they say that because there are too many components in a plant extract to know what the mechanism of action is. And they will also say because you can't replicate the extract perfectly every time, so you don't have the purity. My argument would be, if you're looking for medical effect in this day and age, isn't there a broader benefit to society from being able to get that from something like a watercress extract rather than just a synthetic drug when you also happen to then benefit from all the useful things like the vitamin B complexes, vitamin C, all the other things that your body kind of needs, which are in watercress as well.
Dr Rupy: And sorry, just on that point about mechanism of action, I think there's been a lot of discussion, particularly around antidepressants about the actual proposed mechanism of action. We, I don't think people have confidence now in the chemical imbalance theory. I think that's been disproven. But how exactly antidepressants are working, I think it's pretty is unknown. And a lot of people are honest about that now, but that doesn't mean that we take it off the market because we don't understand the mechanism of action. We know it has an effect. So I think that's a bit of a rebuttal.
Dr Carl Stewart: I would agree with you. And I think when these rules were established, which I might be wrong, I think it was around the 70s, there was very little knowledge of the skin microbiome. So, you know, everything was based on the direct interaction with human cells. Well, for anything topical on the skin, you've got millions of bacteria, you've got viruses, you've got fungi that just live on your skin. They are having reactions with whatever you put on your skin. So it's impossible to say what the mechanism of action is because there are so many different species. And my microbiome on my elbow will be different to in the groin. And you know, we, you and I will have different microbiomes ourselves. It's almost like your own individual passport, what your microbiome is. So I think those rules are a little bit archaic, really. So we have to stay on the side of being a cosmetic. So the broadest claims that we hope we're going to be able to substantiate and we're doing a fundraiser at the minute, we're hoping to start this work back end of the year, is to be able to say soothing and helps to reduce irritation and suitable for skin prone to eczema. So there's actually a company we work with, ADS Laboratories in South Devon, they are our responsible officer. So they are a formulation chemistry company for the cosmetic industry. So they can do the trials which will substantiate those claims. So we have them for the extract, we now just need to do them for our individual products, so the barrier cream, the cream, the spray and the serum as well. And for now, that's where we'll probably stop until we get to the point where we've got more evidence that we've got really compelling reason to spend the money to synthesise the compounds and then go after proper drug discovery routes, which of course will be very expensive and we'll have lots of probably other people looking over our shoulders. But we can see a clear pathway to do it. So for now, this is still very much proof of concept and we're hoping to improve the extract all the time, looking at this flowering crop, looking at the overwintered crop, but stay very much within the confines of being a cosmetic. But I still want to be able to talk about the science, which is a very difficult line to tread because I think the science is important. And I think we should be allowed to talk about science and not just go to conferences and hide away and you know, show someone your poster, but then not tell someone in the public what you're doing. So I think it's important we talk about the science.
Dr Rupy: And with your sort of scientist hat on, if you were to hypothesise as to why this might have an effect on dermatitis, let's say, what would be the mechanism of action that you would think is most promising? We've talked about urease inhibition, but...
Dr Carl Stewart: So if you take some forms of eczema, so eczema, you know, is a bit of an umbrella term. There's various mechanisms of dysfunction at play. But we know that these isothiocyanates, so again, it all comes back to these peppery compounds, they react with toll-like receptors and something called the NRF2 pathway, which is involved in the regulation of itch. And Paul, my co-founder, his sub-specialty is inflammation. So actually, he's well aware of the how these isothiocyanates can kind of be involved in the cascade of reactions that cause the redness and the itch. And then, you know, for a lot of people who get flexural eczema, there is a thought that some of that may well be due to urease-driven ammonia, the same way as you get the sweat rash. So not only can we stop that ammonia, but you then preserve urea. Urea itself is what we call hygroscopic, so it absorbs water, which is why we often see 5% urea creams being used as moisturisers. Urea is really good at retaining water. So by having a urease inhibitor, it kind of makes sense that you can hold on to more urea and therefore hydrate your skin. Plus the fact, you know, with our barrier cream, we've worked hard to make a non-petroleum based jelly barrier using waxes and butters to again, trap in that moisture. And we've got absolutely no doubt there will be other mechanisms that we haven't understood yet. The isothiocyanate mechanism and the urea preservation mechanism are two really plausible ones. We're sure there's going to be more and we just haven't discovered them yet. So again, part of our work going forward is to do more in-depth chemical analysis of our extract and of extracts in flowering watercress, winter watercress, watercress in Spain, and just see how that composition changes and just see if we get any clues as to some of these other mechanisms which may be responsible for the benefit we're having in skin.
Dr Rupy: What I tend to see in the market these days is a sort of a natural attraction to plant-based, you know, whether it's a spray that you wipe down your kitchen worktop with or, you know, like shampoos with, you know, different types of plants and that kind of stuff. What separates your company from those? Because I feel, particularly when I look at the ingredients of those products, there's a whole long list of preservatives and, you know, all this extra stuff and very minimal extract, whereas I look at yours and it's like, well, 85, 90% extract. So what's going on there?
Dr Carl Stewart: Yeah, so when you see a lot of the things which says contains essence of something, a lot of the time, there's no evidence that that essence of that plant does anything. But people look at it and go, ooh, that sounds, that sounds nice. Even I do, in full disclosure, I look at something that has like clove in it or like, you know, a little flower, I'm like, oh, natural. Yeah, that'll be great. But typically the inclusions are at 0.5 to 1%. So 99 to 99 and a half percent of it is not that plant. When we were doing our testing of our extract, we found that a dilution down to 10%, so one in 10 dilution, was about 80% as effective on the skin as the whole extract. So this was one of the things that was really exciting for us because then it meant the other 90% could be a carrier. It could be a cream, it could be a barrier cream, it could be a spray. So if you look at our cream, our barrier cream and our spray, that has the extract in at 10%. And we were absolutely adamant that we wanted to keep it in at 10% because that's what the science said worked. 5% could have a good effect, but we had the opportunity to put it in at 10%, so we've really stuck with it. Obviously, people have an expectation when they buy a cream that it looks like a cream, it feels like a cream. So we have had to put in, you know, the classic ingredients of a cream, but we do have a far higher plant-based content than the vast majority of cosmetic products on the market with bioactive activity. Our serum, when you were talking about 85%, so our serum is just our extract with xanthan gum and plant-based glycerin and the preservative. So it's 93% watercress extract. So when you smell it, you get a kind of sweet, appley smell. That's just the watercress. We don't add any fragrances, we don't add any colours. It's going to vary in colour, it's going to vary in fragrance batch to batch. But we wanted to give people the opportunity just to have our extract. It was too runny just to sell on its own, so we had to thicken it up a little bit. But it's the highest plant-based content of anything available on the market as far as we're aware, unless you go and make your own juice. And we had to put a preservative in, you know, like any juice or vegetable matter, you know, it has sugars in, it has amino acids in, it has, you know, things in that bugs like. So we've got as mild a preservative as we can, which is in at 1%. But really, we see the standout of our products in that it's based on science, real professor, real doctor, I'm still a GP, Paul's still a professor. And, you know, the bioactivity is proven, we have the data and we're continuing to do the research to try and refine it and improve it all the time as well.
Dr Rupy: I'm always, I'm interested in this area now because I'm turning 40 next year. I'm in the business of trying to maintain my youthfulness as much as possible both on the inside and the outside. And whenever I look at these claims that the big names always make on big posters with, you know, celebrities and all the rest of it, it's like collagen boosting, anti-ageing, all this kind of stuff. And as far as I'm aware, there are only three main things or three products that have been proven to have these anti-ageing benefits. That's topical vitamin C, your retinol, certain retinols, I think it's like 0.5% or 1% depending on your skin condition. And standard sun cream. So, you know, just making sure that you're doing those preventative things, making sure that you're not getting overexposed. I am interested in sort of the mechanism behind why a topical component, a topical product could have those improvements in appearance subjectively, but also the skin wrinkle depth that you just talked about. Because I don't think a lot of companies do what you're talking about in terms of the rigorous science, so you can actually make those claims.
Dr Carl Stewart: And that's what we're, and it sort of comes back. I mean, the point you made about vitamin C, one of the highest plant-based sources of vitamin C is watercress. You know, and that's why we're interested in doing lots of different chemical analysis to make sure that the vitamin C carries through and isn't lost in one of the processes. But we're pretty sure we're going to have a load of vitamin C in watercress. So there's one mechanism. And of course, you know, when you talk about sun damage, a lot of that is inflammation, which then damages the skin. And obviously, you've got these isothiocyanates, known anti-inflammatory compounds. So the mechanisms that you're describing, you know, along with, you mentioned the retinols, you know, watercress has got polyphenols and these flavonoids and all sorts of other known antioxidant species. It ticks all three boxes that you've mentioned. So that's how we believe that there is an effect. And again, we're absolutely convinced there are mechanisms of action at play that we have not discovered yet. So we've got plausibility in those three with watercress, but there's more to be discovered. We're absolutely sure of it. And that's why, you know, we're hoping to generate revenue from Profoundoc to really allow us to do that deep dive into the full composition of watercress, understand what happens when you apply it on the skin, what are the key biochemical pathways that it's interfering with or regulating, which are having benefit. And really, you know, can we isolate them? Because if it's having an effect on the skin, where else in the body can it have an effect in? And that's why this whole idea of medicines development and drug development for us is so exciting. There are things at play we don't understand, but we're learning all the time.
Dr Rupy: So watercress is your favourite toy at the moment, right? If I was to come over and I say, look, you can't, watercress is off the table. I'm going to take all these toys away. You're not allowed to play around with watercress or actually anything in the brassica family. What would your sort of next ingredient be that you'd want to do a deep dive in?
Dr Carl Stewart: Oh, that's a good question. I was, I like, see, wasabi's interesting as well, but you've knocked out the brassicas. Um, you know what, I think just to tickle my interest, it would probably be turnips. Oh, really? Because of that hard material, that really fibrous material, I'm, I'm convinced that's amenable to something, whether it's making cloth, whether it's turning it into bioplastics, I think it would be turnips. And I think it would be, you know, and I think if you get it right in something like that, you've then got all sorts of different plant matter that you can potentially be doing something interesting in terms of fibre with. Um, but I'll tell you another one is that I quite like is pine trees.
Dr Rupy: Pine trees?
Dr Carl Stewart: Pine trees. So pine trees, um, the leaves have something called alpha-pinene. Okay. So alpha-pinene is a compound which acts and it's got a bit of a funny name as an acetylcholinesterase inhibitor. Oh, okay. That's what we use. Now you'll recognise that from potentially like Alzheimer's treatments. So galantamine and things like that, rivastigmine, block that enzyme in the brain and it boosts cognitive function. There's been studies in Japan where they've wheeled people with dementia through forests and for the period where they're in pine tree specific forests, cognitive function improves. No way. But if you go through other non-pine, it's not as apparent. Now, is it just the stimulation that they happen to have and it's perked them up and they've had a better cognition? Or are they inhaling alpha-pinene because it's apparently got quite a strong scent, it's the pine tree scent, and it's having the same effect as those anti-Alzheimer's medications. Could you then put that in an air freshener in a care home? There's all sorts of interesting things like that in the literature. That's super interesting. And we've got three or four other ones which, you know, I'm not going to mention. I like, we talked about the, I've talked about the alpha-pinene one before. I think things like that are just sat there waiting, absolutely waiting to be discovered. Yeah. You know, we, I know up in, up in York, they're doing a project where they've discovered galantamine, another one of these anti-Alzheimer's medicines in daffodil bulbs. Really? So they've got tons and tons of daffodil bulbs that aren't being sold. Instead of wasting them, strip the galantamine out, there's your medicine for Alzheimer's. And then you've got the bulb at the end, which you can probably do something else with. Can you mulch it up? Can you recycle that? But this idea of recycling plants that aren't being used or just stripping out those really interesting little compounds, I think, yeah, I think I'm going to have be doing this for the for the rest of my time, certainly after watercress is finished.
Dr Rupy: Yeah, absolutely. It seems like you're going to have loads more toys to play with when I take those ones off the table. I mean, it's interesting, we talk about like, um, pharmaceuticals and how they have to be distinct synthetic compounds in rigorous quantities without anything else added to them. But there's almost a parallel with CBD and, you know, we had Dr. Danny talk about, um, the different compounds you find in hemp. And it's not just the CBD, it's those entourage compounds that it comes with when you have the the natural form of it. So instead of a synthetic form, you have the natural form with all these other sort of, it's almost like junk DNA, like the sort of like junk that comes with the product that you've distilled. There's those are definitely having impact as well. It's the combination effect.
Dr Carl Stewart: Well, I completely agree. And I think you've got to ask yourself, what's the most important endpoint? And it's to benefit people. And if the rules aren't allowing us to benefit people, then we have to start questioning, questioning the rules. Um, I mean, you know, if we can't, for example, let's say the rules stay as they are, the other thing which is on our side are the huge developments in vertical farming and hydroponics. We may well be able to grow genetic clones of watercress in perfect conditions that we can start getting a pretty pure extract. And if we have good extraction techniques, maybe we can go from the plant down to the compound rather than synthesising the compound, as long as we then have a way of using the rest of the plant or all the other byproducts that come off it. Maybe it is an option. Because, you know, we, and we have, we have started to look at it and it is incredible how quickly and effectively in a confined space you can grow genetic clones. Get the same plant every single time, same fruit, same vegetable, same root structure. Maybe that's a way forward.
Dr Rupy: Mate, this has been fascinating. I just, I love doing pods like this where I get to put a spotlight on just some incredible people. And the fact that, you know, you're a fellow medic and you're on the clinical entrepreneurship program, we know each other for a few years now. Like, it's just great to see the the sort of the trajectory, the growth and what you've been able to achieve with the commercial arm of the company, but still deeply, deeply rooted in the science. It's great to see that passion come through. So I appreciate you coming on. This has been fascinating.
Dr Carl Stewart: No, thank you very much. I mean, you know, the next six months for us are going to be particularly exciting. We've signed two international distribution agreements in the last month. So we've just had some, um, extract being shipped over, sorry, some of the Profoundoc products being shipped over to the Cayman Islands. And we've got some others lined up for Hong Kong and Singapore through another distribution agreement. And we're hopefully not far away from signing a bulk extract export contract for, um, for a continence project as well with a, with a well-known, well-known company. So it's looking bright for us.
Dr Rupy: Yeah, yeah. I'm going to see watercress extract like in everything. Watercress juice. Oh, that's great. That's really good to hear, man. Thank you so much for coming on. I appreciate it.
Dr Carl Stewart: Oh, my pleasure.
