Back in October 2023, we spoke to Dr Thomas Dawson, Senior Principal Investigator leading the Skin and Hair Health department in the Skin Research Institute Singapore/A*STAR Skin Research Labs, a Singapore government translational research institute. A globally respected opinion leader in skin, hair, and microbiome research, Dr Dawson has over 30 years’ experience in end-to-end biotechnology innovation spanning Academic, Commercial, and Governmental expertise, including nine years building two research organizations in Asia. He is committed to leveraging microbiology to improve skin health, with a particular focus on Malassezia, including leading the global consortium on Malassezia phylogeny, physiology, and pathogenesis, termed the “Malassezia Research Consortium”.
Malassezia is a genus of fungi. These lipophilic yeasts form part of the skin microbiome and despite being the most prevalent fungal genus on healthy skin they can also demonstrate pathogenic potential. Most Malassezia species are dependent on exogenous lipids because they lack fatty acid synthase genes, which results in higher accumulation at seborrheic skin areas such as the face and scalp.
We were delighted that Dr Dawson could take the time to discuss with us the current understanding of the role of Malassezia in skin and scalp health, and where he believes research could take us in the future.
Question
Malassezia is known to be associated with various unwanted skin conditions, such as dandruff. However, do you believe that Malassezia is a harmful or helpful bug for human skin and scalp health?
Answer
This is a really important question to me personally because I spent roughly the first 20 years of my career working on killing Malassezia, assuming that it was a generic pathogen, but now I don’t necessarily believe that to be true.
People have been killing Malassezia for decades – half a century or more – and that doesn’t seem to have led to ill effects. However, I think there are opportunities that will present themselves in which Malassezia is shown to be a beneficial microorganism in certain situations.
In atopic dermatitis (AD), certain species of Malassezia are known to be pathogenic. They may not directly cause the disease, but they secrete enzymes that are undoubtedly the cause of problems on skin. Similarly, in dandruff and seborrheic dermatitis, there’s a clear pathogenic role. However, there are other situations in which we see Malassezia as mutualistic – where we humans get some benefit from the Malassezia being on us.
There are now several known examples. Malassezia globosa secretes a protease that disrupts Staphylococcus aureus biofilms in AD. This has the potential to be harnessed as a possible treatment option by providing a mechanism to break down S. aureus biofilms, which are recalcitrant to treatment. I don’t necessarily believe it would be easy, as there’s problems associated with using a protein to treat disease, including allergenicity, but it gives an idea of what is possible.
Research I have worked on previously, and which I think still has potential to be highly beneficial, is identifying metabolites of Malassezia that are present on healthy skin but not on unhealthy skin and synthesizing and utilizing these as postbiotics. For example, I expect we will be able to find Malassezia species and strains that secrete important anti-inflammatory materials and regulate human immunology both positively and negatively in terms of inflammation.
So, in short, while in some instances Malassezia can be pathogenic, I think we are going to find out that there are also some benefits of Malassezia biology that can be leveraged for disease treatment options, to benefit human skin and scalp health.
Question
Leading on from that, do you believe that promoting proliferation of specific Malassezia species under certain conditions could even improve skin/scalp health?
Answer
I think that with regards to treatment options, probiotics and prebiotics, which you are describing, would be difficult to develop due to challenges with delivery and physical conditions. In my opinion, postbiotics would be more straightforward and offer better potential as they would be able to go right to the heart of the issue.
However, although I believe it would be difficult, I think developing prebiotics could be possible. I just don’t think we know enough yet to succeed. For example, we know that different Malassezia species and strains grow preferentially on different substrates. M. restricta likes Tween 40, whereas M. globosa likes Tween 60, and M. furfur grows in minimal media, etc. This indicates their food sources are different, which we might be able to harness, but we do not yet know what those different food sources are.
It will require considerable effort to identify substrates that preferentially support the growth of beneficial Malassezia species over detrimental species, and then to be able to utilize that as a potential treatment. I am not aware of any teams attempting that work today, but with the right resources, including extracts and species, etc. it could be successful.
In summary, I believe that prebiotics, in which you try to feed the good guys and starve the bad guys, or postbiotics, where you figure out what metabolites the beneficial Malassezia are secreting and directly add those, should be possible and even likely in the not-too-distant future.
I do not expect it will be possible to grow up a healthy bug and put it on people’s skin as a probiotic. It is incredibly challenging to successfully deliver live microorganisms to the skin from a product, not to mention the additional hurdles from regulatory, pharmacology and formulation. It’s so much harder developing treatments in that space.
Question
If it was possible to generate a probiotic for skin and scalp care consisting of genetically modified Malassezia, what might you expect this super-bug to look like? Which genes would you try to manipulate?
Answer
Although this is a fun idea, I’m not sure we know enough to really go down that road yet, but I can make some suggestions.
There is research ongoing to better understand some anti-inflammatory cytokines that are secreted by Malassezia. If we were able to genetically engineer Malassezia to produce those cytokines, you could make a more anti-inflammatory microbe. I don’t know the genes for that yet.
Another possibility could be to engineer Malassezia to secrete metabolites that kill other bugs. Malassezia are very good at occupying their niche, such that where Malassezia are present on the skin you don’t see a much other microbiology – they are really good at creating their home and kicking off the other guys. Therefore, with a relatively subtle genetic change, for example, knocking in an S. aureus-specific antimicrobial peptide, or a gene that makes an antibacterial compound against a known pathogen, you could create a potential therapeutic.
Most of my knowledge and experience is of pathogenic genes that would need to be knocked out, such as lipase or secreted aspartyl protease. However, that would be unlikely to succeed because the wild type would still be present, which would therefore still secrete those compounds.
I would suggest it would be better to try to engineer a positive benefit into the Malassezia, to enable them to secrete an anti-inflammatory cytokine, or a protease that activates human antimicrobial peptides, or a specific antimicrobial against another bug that is a known pathogen, or some anti-inflammatory lipid mediators. Some of this research is underway but we haven’t figured it out yet.
Question
Looking back at the last 20 years of research on Malassezia, where do you think the ongoing work in the field will lead us in the future?
Answer
This is an interesting question because there’s been so much change over the past 20 years in microbiology. I think the big thing, especially with regards to Malassezia, is that scientists in general, but particularly in the West, tend to assume that one cause will have one effect. However, it is turning out, especially with Malassezia, that that’s probably not the case. In reality it is much more complicated. There appears to be a complex interplay, with the many different Malassezia species and strains acting differently from each other and also being highly responsive to the environment, other microbes, and the skin.
I believe research over the next few years will show that we need to look more holistically at what’s going on, accepting that a single cause does not have a single effect. We need to look at the whole system to understand it. From a scientific standpoint I expect this will involve using transcriptomics and chemistry to study the metabolites present on the skin and applying all the tools at our disposal to look at it as a compositional model. Expecting there to be a single species that does a single thing and generates a single effect is not going to work.
In Asia it is more common to look at whole systems in a more holistic way, and that is what I believe is needed here. You work with and test interventions that are not molecularly specific but that alter the whole community and skin environment and look at the overall impact they have.
Of course, in real life the system is incredibly complex. There are numerous intrinsic and extrinsic factors such as your genetics, nutrition, UV, or pollution, that all impact how microbes might interact with your skin. Developing a model system that captured all of that would be a challenge, and it is unlikely that in the near future we are going to understand every piece of it. However, that doesn’t mean we won’t be able to model facets of the system in a way that we can develop paradigms. I anticipate that we will move to more and more complex models and, while we may never get a model that recapitulates the entire system in vitro or ex vivo, we will be able to figure out how to intervene.
I have seen first-hand from previous lipase and protease work that it is possible to isolate important vectors in vitro and design interventions. However, I believe it is necessary that research moves more quickly into human skin – that needs to be the model. When you test on human skin you capture the whole complexity of the system. You will see the true impact of your intervention. It’s not a model, it’s the real thing.
Research work should be progressed more quickly into clinic, and clinical work and research in humans needs to be more extensive to allow us to better understand what’s going on in human skin. If necessary, I believe this could be at the expense of complicated animal models. However, these could be used to investigate pathways, materials, and metabolites, to look at their impact on individual cultures of skin-relevant Malassezia and thereby develop hypotheses that can be tested in human skin.
Question
In the West, products claiming to be microbiome-friendly, i.e. to minimally impact the microbial compositions on skin, are gaining popularity. Given your many years of experience in the skin and scalp care industry in the US and Southeast Asia, do you see similar or diverging trends between these two regions?
Answer
At the moment what I am seeing is that in the West products focus on not impacting the microbiome, whereas in India there are already products that make claims about promoting a more beneficial skin microbiome.
I anticipate products that impact and improve the microbiome are more likely to be successfully developed and be accepted in Asia. One of the reasons I chose to work here is that I felt there was a more holistic attitude about nature and naturals and an enthusiasm that they can be successfully used in products and will work.
This relates to my answer to the previous question; to my belief that because human health is dependent on a complex ecosystem, in which a whole bunch of stuff that we don’t understand is going on, you cannot expect a single intervention against one bug to give you one benefit. I therefore think that in Asia, where it is more common to look at whole systems in a more holistic way, we will be in a better position to make discoveries and to become more aware and more educated about skin microbiology and skin health.
Having said that, consumers do not really care about skin microbiology. They care about skin health. Is my skin healthy and smooth or is it inflamed and itchy? However, I think that a mechanism that is supported by microbiology and is able to deliver healthy skin as assessed via holistic approaches is more likely to be researched and to ultimately gain regulatory approval and be accepted by the public in Asia.
In the West, I think there’s a lot of reeducation needed before consumers will accept products that aim to impact the microbiome. The problem is that consumer products companies have spent 50 years teaching people that they need to kill all microorganisms, and that belief has become a part of Western culture. The educational system in North America and Western Europe taught us that microorganisms are bad, and they make you sick, so you need to kill them.
That misunderstanding isn’t as prominent in the East because people have always been more aware that we interact with the environment – that we exist in an ecosystem that includes not just us and our microbiology, but also what we eat, what we put on our skin, how we interact with our surroundings. I expect that the easiest way to appeal to a Western mindset might be explaining that while some microorganisms can be harmful, there are some that can be good and we should try to support those.
Question
An increased bacterial diversity in the gut is associated with health benefits. Do you think that the same is true of skin and scalp health? Do fungal and bacterial diversities have the same implications for the skin and scalp?
Answer
I would argue that, unlike in the gut, increased complexity in the skin microbiome is not associated with health benefits. There is mounting evidence that a healthy skin microbiome is less complicated and populated by healthy microbiology.
A recent paper from my group in collaboration with Zymo shows that a healthy ear requires a stable microbial community that includes Malassezia restricta, Malassezia arunalokei, and P. acnes. When that that microbiome becomes disrupted and gets more complicated, that is associated with ear infections.
We have seen consistent results in recent research comparing the composition of the microbiome in prepubertal children versus adults versus post-menopausal women. Similar research has been conducted at the National Institutes of Health and Heidi Kong, where they looked at individuals pre and during puberty. It appears that, at least in children, a more complicated microbiome results in an increase in skin disease. Once we have been through puberty and developed a more stable lipophilic skin microbiome, which consists mainly of Malassezia and P. acnes, that microbiome tends to have less disease unless it becomes disrupted.
Although significantly more work is required before a firm conclusion can be drawn, it currently appears that in skin a simpler, stable microbiome is desirable and reduces skin disease, which is different from in the gut.
Question
The composition of the skin and scalp microbiome is impacted by different extrinsic and intrinsic factors such as ethnicity and geographic location. If you had some spare money to invest in the development of microbiome-based cosmetic products, would you choose to invest in generic products with broader applicability or highly personalized skin care products?
Answer
This is a tough question. I think my preference would be to go for treatments that are more broadly applicable.
There are a lot of different microbes in existence, and we can split hairs and sequence their genomes, and intergenic transcribed spacer region, and ribosomal 16S region, and we can find differences forever. However, if we start to look more at microbial communities and what they do biologically, and we think about human beings as a species, I think we’re likely to find correlations that are relevant to large populations of people.
I believe there will always be a bell curve distribution in how people respond to treatments. That’s just biology. Normal distributions are the basis of biology and biotechnology. You will always have people that respond two standard deviations away from the mean, but the vast majority of subjects will be in the center. I think therefore that we should be aiming for products that work for the majority of people.
Skin can vary considerably, and many people may argue that you need to have products that are specifically adapted to different cultures. For instance, black skin from people of African origin is different from pale white skin from people from northern Europe, and Asian skin I think is especially different in terms of the pilosebaceous unit, sebum, and water secretion. It might therefore be that one product cannot work for everybody. Perhaps one treatment might be particularly efficacious in North America or Southeast Asia versus different areas. However, the same could be true of many factors, not limited to ethnicity, age, geography, climate, and culture. I think that we could waste a lot of time trying to make personalized products that are different for every individual.
I think it is very important when we look at the microbiome to consider what the real biological drivers are. As scientists we can take two approaches: to group things together or to split things apart. To develop treatments that are broadly applicable, we need to group things together by biological relevance. We need to know whether if you have a microbial community on your skin that consists primarily of Malassezia sympodialis, is that biologically different from one that is primarily Malassezia dermatis or Malassezia nana? Or is the difference between those so small that it’s only genetic and not biological?
One of the first really consequential papers in Malassezia, ‘The genus Malassezia with description of four new species’ by J. Guillot et al., was the first paper to show that there were distinct species of Malassezia. One of the core principles put forth in the publication was that genetics is not enough to define a new species; that it should have a biologically relevant difference. Of the 23 species of Malassezia known today, I wonder how many are truly biologically different. As a result, my group has published a number of papers in which we try to group Malassezia into different biological phenotypes. I think if we can look past the minute differences in genetics to focus on the biological role of the Malassezia community, we will be able to understand what is important and physiologically relevant for human health, and we’ll be able to intervene in it.
This approach links us back to the first question, highlighting again the promise and potential benefits of postbiotics, which focus on biologically active interactions and not the genes that might define the Malassezia. It will rely on technologies that we’re still making headway with, such as transcriptomics, to allow us to investigate what enzymes are present on skin, as well as metabolomics, so these have to be a key focus for the future.
Overall, what is probably needed is a happy medium between your two proposed scenarios, where we don’t have one product for absolutely everybody in the world, but also there’s not a unique product for every person. I think we will be able to understand the human biology and microbiology sufficiently well to make products that work, if not for all, still for big groups of people.
