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Skin Anarchy
The Truth About Regenerative Science in Skincare with Dr. Saranya Wyles of Mayo Clinic
00:33:46
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- [00:00]
A
Hey, guys, welcome back to Skin Anarchy. This is a very special episode, and I am truly honored to host our guest today. She is a trailblazer in the regenerative medicine space, a true expert, and I am really, really excited because as many of you know, I've been wanting to bring this to you guys for so many years at this point where we can get a real understanding of what does regenerative medicine mean in the context of skin care and aesthetics, and how should we be thinking about it, you know, from obviously the consumer standpoint, but also for those of you who want to dive deeper into the sc, you know, how to kind of frame your mindsets around it. Without further ado, please welcome Dr. Saranya Wiles, who is leading the charge at Mayo clinic. So welcome, Dr. Wiles. I'm so honored to host you.
- [00:44]
B
Thanks, Ekta. It's an honor to be here.
- [00:46]
A
Yeah, I can't wait to dive in. And you have such an amazing, amazing background in medicine. I mean, you're an MD, PhD. You've got one leg in research, the other leg in clinical medicine. I mean, it's such a rare find to come across an expert such as yourself. And so I'd love to kind of start there and walk us down memory lane. Like, what got you into medicine to begin with?
- [01:07]
B
Yeah, so I grew up in a family of physicians and scientists, so it really. I would say it's dinner table conversations. Growing up in India, my dad, who's a pathologist, would have us talk about the cardinal signs of inflammation in Latin. So thinking about signs of my sister, and I would come up with songs like Rhubar Color, Two More Dola, or Punctualasa. So it was a very different, nerdy kind of dinner table conversation. And. But it was fun, you know, my mother was a scientist, and she would take me and my sister to the lab on evenings or weekends. And I grew up pipetting water. And so in a lot of ways, the lab and medical field and pathology was kind of home to me, was familiarity. So as I kind of grew into the fields of science and through science colors in high school and in college and explored the area of neuroscience, I also studied art history because I was very fascinated by the connection of science and art and how they interplay, but also just the beauty within our creative capacity. And during this time, I really thought about regenerative medicine as a sci fi kind of magical specialty. You know, the idea that we can heal from within, that we had stem cells that could repair, rejuvenate, regenerate, and that these just seemed to be like these very magical field of research. When I had graduated college, the field of induced pluripotent stem cells had just taken off. Dr. Shinya Yamanaka in Japan was poised on his way to win the Nobel Prize soon after that. A lot of the science was really magical. The fact that you could take skin fibroblasts and reprogram and turn their clocks back in time and make them into pluripotent ste cells and then get those stem cells to become cardiomyocytes or neurons or even back to skin cells was really fascinating. So to me, it's just, I just kind of followed the magic, I think, and found my way to dermatology.
- [03:18]
A
That's amazing. I love that. I love that you grew up in that environment and like, it really shaped, like, your interest. I feel like I never hear that. You know, I always ask, whenever I'm hosting doctors, I always ask that question of, like, what got you into medicine? Because it's so interesting to learn, right? Like, where did this, like, wanting to discover science, wanting to understand science. And I just. That's fascinating. And I want to go deeper because now I feel like when we think about regenerative medicine, this is what I hear all the time. We talk about stem cells and that's kind of where people stop. And I feel like there needs to be so much clarity. And so I'd love to start there if you could kind of give us an understanding of what is regenerative medicine and what should we be knowing from the get go as like the baseline of this field?
- [04:06]
B
Yeah, absolutely. So regenerative medicine is a field that we've been fascinated with since Greek mythology and even dating back further than that. It's the idea that our bodies can heal from within. It's the idea that if we think about Greek mythology, the stories like Prometheus who stole fire from Zeus and he was banished to punishment, and his punishment was that Zeus's eagle would come and. And peck at his liver, and night after night, that liver would regenerate and regrow and it would happen again. So it's this concept that our bodies could fully recapitulate lost damage, function and structure. So the way I define regenerative medicine is our innate ability, so heal from within, our innate capacity to regenerate, renew, repair, heal, and restore form and function. So it's not just structure, but it's that functional capacity that we're seeking. And this can be really defined broadly. Like, if we were to think about true regenerative medicine, in its nature, it's the idea of scarless healing. So it's the idea that we can replace and renew without fibrosis. We basically have healing back to that native structure and function, which is really hard to achieve outside the in utero environment. Once we escape the womb, there's really fibrosis that we're fighting with injury and a lot of other sequelae. But that's what I think our holy grail, true regeneration still tends to be, and that's a mark that we're striving for. But until that day, what we have right now, I mean, sure it starts within stem cells, but there's a lot of other regenerative tools that we are utilizing, and now more commonly the acellular toolkit within exosomes. But the goal of all these different products remains to try to renew that structure and function.
- [06:05]
A
That's very fascinating and it's interesting how you frame that because I don't think that's how it's being portrayed. That's why I asked you. And I think that's important to understand because we have seen so much come out of like wound healing research, for example. Right. And I see this happen so much in various industries where we're taking from regenerative medicine, but then we're not providing a context of like, what that means for entire organs. So like skin is obviously the big clearing example. But even when you look at like other biologics that are being, you know, like supplements, right, that people are using or injectables, people are injecting themselves with peptides, there's no, I feel like there's no baseline understanding of like, what is actual regeneration of the body, you know, like, what does that even mean? And so I think that's very fascinating. And if someone asks you, like, give me like your five top things that come to mind when it comes to true regenerative potential, whatever it is that the body is making, what would those things be that the body utilizes intrinsically to repair itself?
- [07:09]
B
Yeah, great question. So I think we can think about things like starting from surgical repair. So if we even just take a big step back of what's in our toolkit, it's grafting. That's where regenerative medicine started. So we borrowed from Pater to pay Paul this idea that if we needed to replace, place the skin, truly we have to graft from other sites of the body and then use that to transplant that skin into a new area. Like in most micrographic surgery or other facial plastics reconstruction, we're grafting tissues. So that is where we started with that concept that we can use our own tissues that have regenerative potential, like skin and like other organ systems that could be used in a grafting capacity. And then we sort of moved into thinking about wound healing. You can look at matrices or substances that can replace and try to heal that wound. So extracellular matrix scaffolds or keratinocyte sheets were born to try to help patients suffering from wounds and burns. So those types of cellular alternates or extracellular matrix scaffolds really came into the wound care space that I would categorize in that regenerative bucket too. Then we started to move towards more of products that are used in our clinics, like platelet rich plasma, platelet rich fibrin growth factor technology. A lot of them are either human recombinant or human derived. They're from the patient, back to the patient. So those are still being studied in some context or another. And most of what I'm talking about today is in dermatology because that's what we're practicing. And then there's stem cells. So there's lots of different types of stem cells. So mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells. Some of them can be used for clinical trials and therapy. Some of them you cannot. If you have stem cells with that pluripotent capacity, then they also have the risk of teratoma formation. So it's not ideal to use pluripotent stem cells. But multipotent stem cells, like mesenchymal stem cells do have that capacity for regeneration and healing. And then the newer classes of treatment within the regenerative portfolio includes exosomes and peptides. Polynucleotides more or less have some capacity. I also kind of think about gene editing, like CRISPR, Cas9 technology. Anything that can kind of optimize and enhance that structure, function, component could be characterized there. Exosomes are very variable. Very simply put, I talk about them as cell talk. This is how cells communicate with each other. We've known about them for decades, but really disregarded them as cell waste. But now we know that depending on the source, like if it's coming from a platelets or certain types of stem cells, then you can see it having regenerative capacity. So there are a lot of different tools within that regenerative toolkit. But I think how it's being utilized is really variable. If it's autologous or allogeneic sourcing, that's yeah.
- [10:27]
A
And I'm so glad you mentioned that. It was actually going to be. One of my next questions for you is really kind of understanding exosomes, because I've heard so many things, Right. And I think as scientists, we do have to look at and weigh all of the information, all the data. But there is a lot of misinformation from what I've seen going around about exosomes, you know, in both ways. And I think I would love to get some sort of, like, a framework, if you could provide some. Because just a baseline understanding of, like, what can we expect from exosomes when they're being utilized for any kind of regenerative work, whether it's topical use, obviously we can't inject them. Not allowed. The FDA hasn't approved that. But just from understanding the basics, like, what can we really understand? What should we understand about exosomes when they're being used outside of the lab?
- [11:14]
B
Yeah. And I think with the space of exosomes, especially in esthetics, what has happened is we've put the cart in front of the horse a little bit. It's really gotten to be that the marketing has advanced so much farther. If we could redo the playbook, what I think we should do is to reclassify exosomes and into the word extracellular vesicles. Most marketed exosomes are extracellular vesicles, and I would say that's true for about 90% of the products out there. To be a true exosomes, there are very specific characterization that you need to hit and satisfy. Exosomes have surface markers called tetraspanins, and those need to be shown as present. Exosomes have very specific size, but there could be some variability there. So it's not necessarily size only dependent. There's other ways that you can detect exosomes. So there's considerable variability. But before we even talk about that, I want to just share how much details that go into exosome production, and that will kind of clarify why there's so much variability. The first step is the source. There's so many different types of sources. So there's platelets, stem cells, plant, some are claiming cancer, inflammation. So there's a lot of different cells that make exosomes. In some ways, exosomes are just messages. Right. And so you can have spam or bad messages that you can get, and you can have good messages or positive signals. In fact, I think the way to do this is to reframe exosomes into therapeutics and diagnostics. So you can actually measure exosomes in your blood and do cancer staging. So certain types of cancer cells and metastasis can release exosomes too. And I say this because there's variability in the source level. Number one second is there's variability in isolation. So say you do decide to pick your favorite regenerative source and then you decide to produce exosomes from that source. You have to think about how the how is very different. So you can just like you would think about making coffee, you know, there's pour over, there's filtered, there's espresso, there's a lat, there's very different cold brew. There's a lot of different ways to make coffee. Right? So just like that, there's a lot of different ways to make an isolate that exosome. So some of them is like comparing apples to oranges. It's really hard to compare between the different sourced products because there's also differences in production. And then the third layer of variability is differences in detection. So not only is it how you make them, it's how you test it once you have it. So looking for tetraspanins, mark versus one, you can do things like nanoparticle tracking. There's also ELISA and Western blot. So all these different ways to identify the protein is there, the exosomes there. And so we're actually working on a global consensus survey right now on topical exosome products. And we're trying to get survey from over 100 different experts from around the world so that we can try to get on the same page as what we agree and disagree on for where this exosome category should be classified as. And like I said in the beginning, the key term would be extracellular vesicles. If we can go back and reclassify, it's really a lot of different signals that these cells communicate. So to get a pure population of exosomes, it's quite hard.
- [14:53]
A
Yeah, thank you so much for diving into that. That's incredibly, incredibly enlightening. And what really came to mind was like people often micep from 2018, then 2023, and one of the things you brought up were the tetraspanins. But then no One talks about MICICEP. Also says you need to look at the cytoplasmic markers and then also look at Golgi and, you know, certain organella markers. And like, we have to understand if they're there. I mean, these are just topics that I never see come up. But then we, like you said, we put the cart before the horse and we now it almost feels like we don't know how to backtrack. That's what I see a lot of with brands. Right. So with that in mind, I mean for consumers that are buying these, is there, do you think there's some sort of a risk associated with buying exosomes? I mean like what, what is your, just your opinion around that? Like exosome products right now, like topical
- [15:44]
B
ones, it's really variable, you know, so it's hard to decipher risk when the products can have other actives or other formulations within them that could either be driving benefits or driving adverse effects. So exosomes in and of itself could either be active or not active. And certain types of exosomes maybe if it's from sourced incorrectly, can be more inflammatory. So you just need to be very diligent on that sourcing. There's also considerable variability from sources. So if you have even the same source, let's say you are looking at adipose mesenchymal stem cells. Yeah, that's coming from one donor usually. So if you have a 35 year old male who has donated their adipose to make mesenchymal stem cell exosome line, it's kind of like this sourdough starter analogy where you have it like this base and then you're making X amount of sourdough bread or X amount of mesenchymal stem cell exosome from that one specific donor. But after you run out then you have to go find another donor and then now maybe you're at a 45 year old female going through perimenopause and there are changes that are coming through that source that was different from the previous source. So you're going to see batch to batch variability in some of these exosome products that we have right now. So that's important to keep in mind.
- [17:12]
A
That makes sense. That makes a lot of sense and it's very insightful to know that. You know, and I want to actually shift. I think you had brought this up a little earlier where things like growth factors, for example, growth factors in peptides, I know they also get classified in that regenerative skin care category and people are making products with growth factors in them or growth factor mimetic. Right. Sequences. So what do we need to know about growth factors? Like do they actually go and help with signaling between cells when used topically? I mean, what are your thoughts around them?
- [17:43]
B
Yeah, I mean growth factors certainly do have a lot of benefit. Like physiologically we see during wound healing, certain growth factors are upregulated, and then with even scar formation or other types of healing, other growth factors are downregulated or upregulated. So certainly physiologically growth factors make sense, but they do in the context of human healing, where it's controlled release. Where I get concerned with exogenously applied growth factors is it's a pretty powerful signal, first of all. So continuous application of a growth factor signal topically, you could be over activating proliferation pathways. So there is concern of people when they talk about pre cancers and skin cancer overactivation. If you are overactivating certain pathways through certain types of growth factors, that is going to be a consideration. But second, and probably more important is the actual delivery of the growth factor. So are some of the growth factors way too large and they just kind of sit on top of your skin and the stability of the growth factors. Do you need to microneedle the skin to allow the growth factor to be better delivered, as we know and do in prp, for instance? So with acne scarring, for a lot of our patients, we are microneedling, and then we apply topical prp, which contains a rich cocktail of growth factors that's endogenously produced. So I just worry with exogenous growth factors about the timing of it, the duration of it, and the stability of it.
- [19:14]
A
Makes sense. Yeah, that's. That's really fascinating. And you know, I always wonder, because also there's like, not a lot of transparency, I feel like, in the growth factor products, like, you know, they don't really tell you what growth factors. You know, they might be like, oh, this is a growth factor mix. And I'm like, I don't know what that means. It's a little scary. But on the same topic, you know, just to dive in deeper, like things that when I think of regenerative medicine also, like, it also bleeds into, I think, what we're now calling longevity, which is like, you know, maintenance. Right. Of our, of our skin health. I'd love to get your perspective on this. I know that you, before the call, had mentioned vitamin D, and I think vitamin D is an amazing topic and I'd love to have you kind of tell us about that and just what skin longevity means. Right. In this context of like, overall everything that we're doing and what we should be thinking about.
- [20:03]
B
Absolutely. So let's break down regenerative medicine from longevity science. And I think that's the first line of distinction. A lot of people talk about it in parallel, but it's really important to know that they are synergistic, but they're, they're different. Right. So when you think about regenerative medicine, this is what we started off talking about. This is more of ways that a body heals. It's a repair, regenerate, renew. Think about regenerative medicine as a build process versus longevity science is a prevent process. So longevity science is a defense driven mechanism. And I always say the number one skin longevity product that we have is sunscreen. So it's a protective factor that if applied regularly, broad spectrum, you know, reapplied, you're going to see an amazing result in your skin because it confers resilience. So longevity is this idea of building skin resilience because you're adding protection versus regenerative medicine gives you reparative tools and building tools. It's not necessarily one in the same, but there is an overlap. You know, I think that if you're kind of thinking through the circadian biology of the skin, where the skin naturally, during the daytime can help protect and prevent damage, and it's kind of going through that defense mode in the daytime, and then at nighttime, the skin circadian switch to offense or rebuild, repair, protection, and it kind of switches to that build mode. So that's where you can kind of think about regenerative actives being more stronger at night versus longevity products and sunscreen being stronger during the daytime. So that's one way to kind of distinguish where these two can play within our skincare regimen, but also where their synergy and maybe applying together makes makes sense too.
- [22:02]
A
That makes sense. Yeah. And talking about vitamin D, I mean, you brought up sunscreen. I know a lot of people worry about, well, if I use sunscreen too much, I'm not going to have enough vitamin D. And I'd love for you to kind of debunk that myth or, or tell us a little bit more about that, you know, because I see that a lot people are concerned about that.
- [22:18]
B
Absolutely. So the short answer is you can still absorb vitamin D or UVB enough to support vitamin D production at the level of the skin with just 15 minutes of sun exposure with sunscreen on. And I think the reason why people are afraid of sunscreen is because they think it completely blocks out any UV absorption. But you may have noticed that people, even if you wear sunscreen and if you're going outside and if you're diligently reapplying, some people still get a little tan. And that's partly because you're continuously absorbing uvb. Unless you're truly protected and not exposing yourself at all with sun protective clothing, the UVB still penetrates through the skin with sunscreen on at a lower extent. And this is because of a lot of different things. First, maybe not enough application. Typically we need to apply probably three to five times more sunscreen than we think we do. And then improper reapplication so we don't reapply as often as we need to or as much as we should. And then there the SPF factor could be slightly variable or maybe not broad spectrum enough. But even if you're doing all these things and going outside with that SPF 30 or higher on 15 minutes, you can still absorb the vitamin D that you need. In fact, the body has ways to make vitamin D byproducts if it produces too much. So we actually have mechanisms of combating vitamin D toxicity, types of levels. So the minute that your body makes, you know, we basically take UVB light that comes through and then there's this pre molecule 7DH cholesterol, so it's dehydroxycholesterol. And then that gets converted to pre vitamin D and that goes into vitamin D3, which is an active form. So the skin doesn't just make that vitamin D3 active form, it also activates it. It senses, it uses vitamin D receptors to activate it locally. But if it makes too much or if it has too much, it starts making vitamin D reservoirs. So we have Loomis Terrell as an example of a vitamin D reservoir. That's basically a byproduct that just gets made because your skin has enough vitamin D. And it just is almost like a standby product where we don't really have full understanding of its use. It just kind of becomes extra, if you will. So I would be less worried that we're worried about skin cancer risk and things like that and making sure that you are properly applying sunscreen and going outside for just 15 minutes a day or 15 minutes of light exposure to UV light to be able to get that production needed for vitamin D. That's really fascinating.
- [25:09]
A
And you know, one thing that comes to my mind is, you know, we've seen in the last few decades, I think, an increase in people who have a deficiency in vitamin D. I know a lot of internal medicine docs, you know, like they always talk about this, is that we are seeing a spike in people just not having enough. And so I mean, what, in your opinion, what do you think is really contributing to that? Because I think that's really playing into this narrative, right, of people pretending like it's because of sunscreen. But I mean, what are your opinion on that?
- [25:37]
B
There's a couple of reasons. Exactly. There's a couple of reasons for this. And I think partly we have to separate out the vitamin D that is locally made in the skin and then the vitamin D that you do have to take by supplementation and oral dietary needs. So that that is still a very important thing to be doing because you can make vitamin D further downstream. It gets activated in the liver and the kidney. So there are pathways that we need to be supporting for systemic vitamin D. And the blood levels of vitamin D that you're seeing does not correlate to the skin levels of vitamin D. And unfortunately, we don't yet have a good way of measuring vitamin D on the level of the skin, but we can just make inferences from blood. So if you have low levels of vitamin D, it's true, you're probably not getting enough vitamin D exposure. And it could either be going outside and getting sun and even that 15 minutes a day, we're becoming creatures of habit that tend to stay indoors a lot. So a lot of us, you know, unless you're driving a lot or going out in your car, we're no longer outside as much as we should be. So I think part of it is just the movement of the indoor habits and just being indoors a lot more. And then the second it is, if you're darker skin types, you do need to have longer exposure. Maybe instead of 15 minutes, it's 30 minutes to be able to get that absorption of vitamin D because of the melanin content of your skin. So there's a couple of reasons from a skin topical exposure. But the other aspect of this is oral intake, too. You do, you do need to be supplementing vitamin D through foods and diet and even oral supplements to be reaching some of these levels.
- [27:26]
A
That's really. I mean, that's really fascinating. And I think it definitely shines a light, right, in terms of, like, how much misinformation is out there, because we, like, I've seen this time and time again, and I, and I hate seeing sunscreen get blamed for this. You know, that's why I'm glad you dove into this, because, I don't know, I feel like people just come up with a reason to not wear sunscreen at this point. I just think we're. We're constantly in society looking for a reason. But I'm glad you debunked that. It's really, really important to Understand? Yeah.
- [27:54]
B
And I always say the sunscreen to just your point about the sunscreen avoidance, it's not a bad sunscreen, just a sunscreen that you have not yet met, that you like. So sunscreen compatibility is huge. I have patients that if they find the right match, that it doesn't feel heavy and it's tolerated and it feels light and it's not this like sunscreen that's a beach use where you're, where you're kind of feeling more greasy and heavy. It's a very light moisturizer. So there's a lot of great sunscreen formulations and options that are more user friendly and experientially beneficial.
- [28:29]
A
Yeah, no, I agree. And I think with also like the rise of K beauty, one thing I'm happy about is people started looking at how sunscreen can feel comfortable, you know, like you don't always have to have that greasy, like kind of heavy feel to it. So, yeah, I mean, I'm hoping we can move past that, you know, as society and get to a point where it's just fundamental. We do it automatically. But I want to actually kind of, you know, pick your brain about, I guess, future directions. Right. Because I think we're right now, I mean, this is just my opinion. We're at a place right now where I see skincare, for example. It's really kind of bridging gaps for a lot of consumers because I'm sure, as you know, like there are so many parts of just the United States where people don't get dermatological care, they don't have access to it, they're not able to see someone. And so oftentimes skin care plays that role for them. And I'd love to get your insight on this for those listeners. Right. And those individuals that are using skincare. Like, what in your mind is something that's apart from sunscreen is something that can be fundamental in someone's routine that could truly provide benefits. I mean, obviously anti aging is the goal for a lot of consumers, but really just skin health, like, do you really believe in like some tried and true ingredients or products that you think could be very beneficial for pretty much everybody?
- [29:50]
B
Absolutely. So I always say there's two ingredients that are so key. If you just make it habitual, you're going to have healthier skin. I mean, everybody's routines could look different. You may, you may have like a three to five step in the morning and like three to five step or however you feel you can tolerate or what you want to do as A wind down experience at the end of the day, in the evening, but that's your routine. But fundamentally you really just need two key actives, one being sunscreen that we've talked about already and the second one is a really good moisturizer. And now I'm kind of moving away from face and sun exposed areas and I'm going into the body. People often forget that the skin is the largest organ that wraps our entire bodies, right? So the back skin is neglected, the legs are neglected, the abdominal trunk area is neglected, the elbows. So there's the. So much of our skin that is the 90% of the neck below, if you will, that needs to be cared for. And the key there is a good moisturizer. There's a lot of great actives within moisturizers like humectants. Glycerin is one of them that basically pulls water in. But I'm a big fan of colloidal oatmeal too. Colloidal oatmeal has been really shown, we've known this about this for thousands of years. It's really been shown to help with inflammatory skin burden, reducing that local skin inflammation if it is present. And it's really a body lotion with colloidal oatmeal I think is a true key ingredient that's going to help with skin health, as you mentioned, because it's helping with factors like itch and dry skin that permeate beyond the sun exposed sites.
- [31:33]
A
That's very interesting. And speaking of oatmeal, I love that you brought that up because inflammation is always, I feel like on my mind and especially now think certain words were thrown around, you know, there for a while like inflamma, aging and the inflammasome and you know, all of these things that have to do with understanding what inflammation actually means. Even if you don't see the redness, you don't see the itching. And I'd love to get your, your thoughts on that, you know.
- [31:57]
B
Yeah, absolutely. So inflammation is this idea that low levels of inflammation can really accelerate different types of cytokines and pathways or communication signals in the body that degrade that extracellular matrix or the scaffold of our skin. So you want to be mindful of the things that can over inflame your skin. We talked about what the skin is exposed to, collectively known as the exposome, like pollutants, humidity changes, smoke in the environment, UV exposure, et cetera. So all of these exposome factors are certainly influencing the skin from the outside in. But you want to be also thinking through how you can influence the inside out factors too. So what are the things that you're instigating the fibroblast to do? If you're using a product like a Retin, a prescription strength and you're over peeling your skin and you're getting a lot more skin turnover and you think that that should be the the end goal? Well, it's not. If you're over peeling your skin, then you're kind of having a mini chemical peel consistently and it actually kind of propagates that inflammaging and low levels of inflammation. So there are people who can't tolerate a Retin, a prescription strength that I either say try a over the counter retinol or don't use a retinol at all and we can find another active that your skin's going to receive in a different or better way. So that's really important to consider that how are we overstimulating the skin? Is it an exposure factor or is it a topical active factor that's causing our skin to be irritated?
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A
That makes sense. Well, Dr. Walls, thank you so much. This has been phenomenal and I would love to have you back if you ever have the time in your schedule. But thank you so much for all of the insights. It's been amazing.
- [33:43]
B
It's been a pleasure. Thank you, Dr. Ekta. Thank you.