Drs. Heidi Kong and Ian Myles — Derm Germs: The Human Skin Microbiome

Thursday, October 22, 2020

In nature, strategic alliances can mean the difference between life and death. For humans, such vital partnerships exist between us and the trillions of microbes we unwittingly host in and on our bodies - together called the microbiome. Dr. Heidi Kong uses genomics to uncover the microbe-host interactions taking place all over our skin. Building on her work and a growing understanding of the skin microbiome, Dr. Ian Myles has developed a bacterial spray that improves eczema, an inflammatory skin disease.

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Transcript

>> Diego (narration): In nature, a strategic alliance can mean the difference between life and death. Take sea anemones and clownfish for example. Clownfish help scare off potential threats and also donate their waste as a source of nutrients for sea anemones. In return, anemones give the clownfish a comfy place to shelter and hide from their own predators. Without anemones there might not even be a Nemo to find.

Mutually beneficial partnerships like these aren’t hard to find. In fact, you don’t even have to look outside yourself to see how different species help each other survive.

There are trillions of microscopic organisms living, crawling and essentially colonizing our bodily surfaces. These microorganisms, like bacteria, viruses, and fungi, together make up what scientists call the microbiome. Now, your gut reaction might not be to keep these guys around, since we often associate microbes with sickness and disease, but your gut wouldn’t work at all if it weren’t for these stealthy little symbiotic companions.

In exchange for the perfect conditions to grow and reproduce, gut microbes break down food that humans can’t digest by themselves and in doing so produce essential vitamins and enzymes we need.

Research into the gut microbiome has exploded in recent history. And scientist have discovered all sorts of biological connections between our silent partners and us. Imbalances in the delicate ecosystem of our gut, have been linked to obesity and diabetes. And it’s not just our digestive system that seems to be affected—there’s evidence to suggest that some good microbes help educate our immunes system to respond to bad invades. Other unsung heroes are said to communicate with our nervous system and help regulate our mood.

The bulk of microbiome research has focused on the gut, with probiotics and fecal transplants often grabbing the headlines. But some scientists have set their sights on unlocking the secrets of another microbiome. One that’s not so much in but on our bodies—I’m talking about the microbial communities on our skin.

>> Dr. Kong: These are microbes that are on healthy people, everybody, all over the skin, in and on the body.

>> Diego (narration): Dr. Heidi Kong is a dermatologist and head of the Cutaneous Microbiome and Inflammation Section at the National Institute of Arthritis and Musculoskeletal and Skin Disease. She is interested in the microbe-host interactions that lead to inflammatory skin diseases. But to understand what happens when these interactions go awry, she is first getting a sense of what’s there to begin with.

>> Dr. Kong: We need to understand: What is the baseline? What is “normal?” What is healthy? So that's why many of our initial studies looked at health volunteers and studied what are the microbes that were there.

>> Diego (narration): Together with her collaborator Dr. Julie Segre, Dr. Kong uses genomics to determine the types of germs we unwittingly carry on our largest organ. But the mix of critters changes from person to person. The microbes that have set up shop on my skin could very well be different from those that call your skin home.

Each person has a distinct biology and life experience that culminates in a unique microbiome. Not even identical twins are colonized by the same microbial life. Because the special blend of viruses, bacteria and the like is so unique to each person, it is often likened to a fingerprint.

And just like our fingerprints differ from one finger to the next, it turns out that our skin microbiome is not the same throughout our bodies.

>> Diego (narration): Dr.  Kong explained these differences to me when we spoke. 

>> Dr. Kong: There are certain patterns of bacteria that we commonly find on healthy individuals. It can range depending on where you are on the skin's surface. You might see certain bacteria predominate or certain fungi predominate in certain body areas. And so what we've done is systematically looked at this in multiple body sites in healthy people.

>> Diego (interview): I found it really interesting that the feet are more populated by fungi than bacteria.

>> Dr. Kong: So, if we look at all of the different body sites, all of the body sites tend to be predominantly bacteria. It's just that on the feet, the small population of microbes that are fungi, they tend to be much more diverse. So many different types of fungi will be found in a single swab on feet versus what we might find on other parts of the body, which tend to be much more Malassezia-rich. So if we're looking only at the fungi on most of the skin's surface, we will find usually something called Malassezia.

>> Diego (interview): Do you have any inkling as to why we have more species or varieties of fungi on the feet?

>> Dr. Kong: Some of it is likely, we anticipate to be physiological.

>> Diego (interview): Uh-huh.

>> Dr. Kong: Or even just where we put our feet.

>> Diego (interview):  Right.

>> Dr. Kong: It could be related to what our feet are exposed to, you know, they're in shoes, they may be walking on different surfaces, but also it may be physiological in that, for example, the feet don't have as many sebaceous glands, which are the oil glands. We'll see that more in the head and upper trunk region which is why we see much more Cutibacterium acne in those regions. And also, Malassezia is a lipid-loving fungus, and so that also is probably why see much more Malassezia on upper parts of our body versus our feet. So, it may be based on what are the nutrients there for the microbes to actually survive on.

>> Diego (interview): Well, all in all, it seems like the microbiome is kind of in a very delicate balance, whether it's the feet or the, you know, the neck, the upper torso like you said. All the populations are kind of kept in check. So, what happens if or when the scales tip too far either one way or another?

 >> Dr. Kong: Some of the patients we study have primary immunodeficiency syndromes and we’re looking at these patients because these patients tend to have infections that are potentially life-threatening or at least cause serious disease for them. So what we do is look at these patients and we compare that to what we see in the healthy individuals, and that is helping us to better understand how certain problems and defined issues with the problems with the immune system might actually change what microbes we see in and on the body.

>> Diego (interview):  Uh-huh.

>> Dr. Kong: We have also studies patient with a form of eczema called atopic dermatitis.

>> Diego (narration): For anyone who’s not familiar…

>> Dr. Myles: Eczema is an inflammatory skin disorder.

>> Diego (narration): That’s Dr. Ian Myles a clinician and head of the Epithelial Therapeutics Unit in the National Institute of Allergy and Infectious Disease. Like Dr. Kong, Dr. Myles is focused on the skin microbiome and how it plays into the development of eczema, which affects more than 30 million people in the US—a large part of them being children under seven. During an eczema flare-up a person can experience very dry sensitive skin with areas of swelling and irresistible itching.

>> Dr. Myles:  It's an incredibly itchy skin disorder. That itch often keeps people from being able to sleep. It keeps their children—if their children are affected, then their whole house is incapable of sleeping. And then there's a predominant visible rash for most patients and then there's an increased risk of eventually developing allergic disorders.

>> Diego (narration): …disorders like asthma, hay fever and food allergies.

>> Dr. Kong: This is called the Atopic March where patients that have eczema, a proportion of them may go on to then develop hay fever and asthma. And so, there is this question of whether or not, can we stop that march towards more respiratory diseases. That would be really interesting if one could alter their course of developing eczema, would that mean that this patient then would not go on to develop asthma or hay fever.

>> Diego (narration): But what causes eczema in the first place it not yet clear.

>> Dr. Myles: I’m sure it’s going to be a combination of environment and genetics and so forth. But there are forms of eczema or atopic derm that are monogenic where a single gene mutation almost assures that you'll have the disorder. But that's not the problem for most patients. There has been a pretty substantive explosion in the rates of atopic derm since about 1980 or so, that really speaks to industrialization. There is a very big in difference in the risk between how likely it is your child will develop atopic dermatitis if you live in an urban environment versus a rural environment is quite stark, particularly for developing nations. So, there's a very strong environmental component. What exactly all those environmental factors are, is a debate and part of what we're working on.

>> Diego (narration): Although the mystery behind eczema remains unraveled, there is one possible accomplice.  

>> Dr. Kong: In the patients we've studied with atopic dermatitis, when their disease flares, they often have an increase in the bacteria called staphylococcus aureus.

>> Diego (narration): And that’s who Dr. Myles is after in his lab.

Like an invasive species that barges in and spreads—wreaking havoc on ecosystem—staph aureus seems to grow freely on inflamed skin. Scientists don’t know whether it causes the inflammation or just takes advantage of it to reproduce, but Dr. Myles thought the bacteria might only be able to run amuck, because there’s nothing keeping it in check.

Think back to the clownfish and sea anemones. If clownfish aren’t there to stand guard, other less helpful species could come along and the anemones might not fare so well.

>> Dr. Myles: We thought well maybe there's something in the environment that has caused us to lose a beneficial microorganism. Maybe there's a bacteria out there that is protective that kids with atopic dermatitis have lost. And so that's when we started to look to the gram-negative organisms based on that genetic work from Dr. Segrey and Dr. Kong, where they kind of mapped out the microbiome on the skin. When you look at where you tend to find atopic derm, that’s where on the skin you tend to find gram-negative organisms, so in like the inside of the elbows or like the back of the knees, what you call the flexor surfaces. You knew the gram-negatives were there because they're genetic material was there, and so we went out trying to culture gram-negatives from healthy to see what we could find.

>> Diego (interview): What's so special about a gram-negative bacteria?

>> Dr. Myles: So, even when a kid has atopic derm and their disease is under great control, so the skin looks good and they're not having active symptoms, if you look on the skin they have a defect in a certain class of lipids. So, it makes you think all right, well maybe they have a base line failure in some lipid production.

>> Diego (narration): As a quick high school bio refresher, lipids are essentially the skin’s natural fats and oils. They play a major role in maintaining a protective barrier that holds moisture in and keeps dirt and other impurities out.

 >> Dr. Myles: So, then we thought, well what organisms are out there making lipids on the skin? And so gram negative organisms tend to make lipids and the exact lipid profiles aren't really well known, but we thought all right if there's a gram negative that's making lipids and these patients are lacking it, then it would show up as they'd have a baseline defect and lipids and then maybe a baseline defect in the protection.

>> Diego (narration): On the hunt for the right gram-negative bacteria. they found a couple of signs pointing to one, Roseomonas mucosa. This species of bacteria was rare to find on patients with eczema. And, when it was present, there was a stark difference between the roseomonas they collected off of individuals with and without eczema.

>> Dr. Myles: Even just on the culture dish you could look at them and tell that they looked very different. Now by genetics, they were almost identical to each other, so definitely the same species of organism. But in the healthy version they look different and then we started putting them through various models, so throwing them into cell cultures or putting them on the ears of mice and you can see they behaved differently. So the cells in a culture dish will respond differently to a strain of Roseomonas from healthy person than it does from a strain of Roseomonas from a patient with atopic dermatitis.

It ends up being dramatically more complicated than we thought at the beginning. It seems like it's going to be a bit of a puzzle. So, we don't know why yet, one bacteria behaves so improperly so to speak. You can find very consistent, very interesting differences between those organisms, which was part of the reason we thought well maybe we can just replace the Roseomonas from the patients who have disease with the Roseomonas from patients who are healthy and maybe we can help the disease to get better.

>> Diego (narration): And that’s exactly what they set out to do. But not without a few setbacks. To start, they had to figure out how to cultivate the bacteria from healthy volunteers.

>> Dr. Myles: They were listed in the textbooks as non-culturable—that you could not grow gram negative off the skin. So, we tried a few things. One of the more humorous stories I guess was when we started, we thought, well maybe the bacteria need lipids to grow. Because the skin is a very lipid rich organ. So maybe the bacteria need lipids and most bacterial cultures do not have lipids in there. And so, we thought well let's spike lipids into the culture broth and see if we can grow them that way. So, we did a little bit of research and found that the closest commercial oil to human skin on a molecular level is canola oil...

>> Diego (narration): That’s not a skincare tip by the way. Please do not add canola oil to your beauty regimen because you heard it’s similar to the composition of your skin.

>> Dr. Myles: So, we spiked that into the broth. We put in the autoclave and I think it set fire because it just filled the room with smoke, and it burned the cap.

So that approach failed. But then we went and asked who grows organisms we know make lipids. And came across a paper where they grow gram-negatives from tropical fish tanks, apparently tropical fish are extremely sensitive to having any bacterial contamination in their water if you're going to make a tank, right? And so the paper was designed to try to test filtration systems and they use a particular culture method that can get basically any gram-negative out of the water that might be spiked in there. And those bacteria tended to be the exact lipid producers that we were interested in. And so we had to modify their approach just a little bit by basically putting anti-microbial in there that would block the gram- positives and would block the fungus from growing. And then the other key was that we had to take the temperature, so in a normal micro lab, you're culturing things at 37 degrees Celsius. But the bacteria don't really grow that well at that temperature. We needed to drop the incubator down to 32, which the temperature of your skin.

>> Diego (narration): After tinkering and tweaking, they nailed down their protocol and were off to the races

>> Dr. Myles: We started growing all kinds of gram-negatives consistently off of the skin of healthy patients or healthy people and eventually the patients.

>> Diego (narration): With Roseomonas in hand, Dr. Myles and his team eventually launched a clinical trial at the NIH Clinical Center to assess its safety and potential benefit on people with eczema. A total of 10 adults and 20 children between the ages of 3 and 16 joined the study. They were given a freeze-dried mixture of the bacteria with sugar. All they had to do was add water and spray the affected areas twice a week for three months and every other day for an additional month.

After the four months, most of the people enrolled, experienced substantial improvements in their symptoms. Upon a closer look, the researchers found that the microbial diversity on patients’ skin had increased as well as the levels of those skin-sealing lipids produced by Roseomonas. And as for the pesky staph aureus, it looked like the numbers had dwindled significantly.

>> Dr. Myles: On average we got about 65-75% improvement in their rash, in their itch and that was despite them being able to come off of their topical steroids. So, they were able to stop their background medication and just use our bacterial spray. And what has been interesting is that –they’re not cured, I mean they still have some disease and they'll still get flares, and if they were allergic to foods before, they're still allergic to those foods now, it's not a miracle cure—but they get substantially better and then they stay that way.

We follow people now up to eight months, but kind of unofficial through emails and so forth, we’re now looking at about a year and that improvement is sustained and it's potentially because we've colonized them with the healthy bacteria that we were using in the treatment.

>> Diego (narration): Dr. Myles spray could be a break-through therapy for the millions of people dealing with eczema today. It offers relief not just from the irritating symptoms of eczema, but also from the financial burden of current available treatment options that are often costly and require multiple applications a day.

It’s simple yet elegant solution. One that avoids the use of strong antibiotics or other harsh medications. Instead, it capitalizes on a growing understanding of the microbiome to restore balance the delicate symbiosis of our skin. 

Despite their relatively small size, there is mounting evidence to suggest that the trillions of microorganisms we carry are an inextricable part of our health. Experiments that raised mice in a completely sterile environment have shown impairments in the immune system, endocrine function and even learning and memory. If that’s any indication of the influence microbes have on humans, it seems that whether we like it or not, we’re bound to them much as they are to us.

As scientist like Dr. Kong and Dr. Myles continue to uncover the invisible world of microbes, it’s tempting to think of all the possibilities that could come from their work. How one day we might be well-acquainted with most, if not all, the critters wriggling around on our skin and in our gut. And how we could possibly even improve our health by boosting certain types of bacteria or curbing others. Many companies are already touting products that claim to enhance health and beauty by targeting the microbiome. However, it’s worth noting that we still have a long way to go. While it’s good to be optimistic, Dr. Kong and Dr. Myles both emphasize that it’s important to remain cautious.

>> Dr. Kong: So if there is a product marketed to say, "Oh, make your skin a healthy microbiome,” the question is what is a healthy microbiome. And that is likely, fairly individual. Because if everybody has a different physiological, immunological make-up, then it’s possible that there is one person promoting a certain particular bacterium is helpful, but actually it may be harmful to somebody else. And so that’s where I think it’s important to be a bit skeptical and cautious when there are these claims of what is healthy microbiome.

>> Dr. Myles: There'll be a lot of low-hanging fruit, where just certain organisms make for good medications. But then when not everybody responds that's when things are going to get very complicated as you try to match up the exact organism for the exact person in the exact disease state. And so, when you see a study—particularly this is a problem around probiotic studies or at the grocery store—if you go it's going to say lactobacillus on it. But that doesn't mean anything. That could be one of 1,000 organisms and you don't know whether or not that's the one that's actually been proven to be beneficial or not.

>> Diego (narration): And so now, these types of conversations are pivoting to really focus on the different strains of the same microbial species.

>> Dr. Myles: Finding something in one isolate of a species doesn't necessarily guarantee that that same isolate will provide any benefit. Like if I say staph aureus, that could be 300 different isolates. You know we think of it as a class, right? You think of staph aureus as like one thing, one microorganism, but it's a group of microorganisms that are similar enough to share that designation but could be very different from each other. And so, I think the part that complicates that’s going to make it much more muddy before it gets clear in terms of the microbiome field, is that the conversations are now going to be very narrow in terms of we could only really talk about the results of a study in the context of the exact strain or collection of strains that they used as treatment, whether that's gut or skin or anywhere else.

>> Diego (narration): As these conversations continue to evolve, so will the way most of us think about microbes. Since the days of Louis Pasteur and the first vaccines, microbes have been feared as causes of illness. Humans have been largely concerned with eliminating germs, so much so that we may have over sanitized and over prescribed ourselves into a predicament of antibiotic-resistance. But the more light scientists shed on the microbiome, the more we see  that not all the actors are agents of disease. That in fact, if we reframe our perspective, we may very well come to know the majority as benefactors of health.