As microbiome science advances rapidly, the number of books on microbiome-related topics is growing—yet it can be difficult to find reliable, science-based information. The hottest new microbiome book not only contains robust scientific information, but has suggestions on how to apply the findings throughout the lifespan: The Whole-Body Microbiome, written by Microbiome Insights co-founder Dr. Brett Finlay, along with his daughter Dr. Jessica Finlay, an environmental gerontologist.
The new book is a practical take on how to use the latest knowledge about the microbiome for healthy aging, with the father-daughter pair offering perspectives from multiple scientific fields and different points in the lifespan. Jessica Finlay brings to bear her pioneering work in the area of ‘applied clinical geography’, while Brett Finlay (a recent Canadian Medical Hall of Fame inductee) brings decades of insights gained from his scientific work in medical microbiology and immunology.
In this interview, the Drs. Finlay describe how their personal worlds were changed by their knowledge about the human microbiome—and how their book can be put to use, not only by members of the general public, but also by fellow scientists and medical professionals.
What gap did you hope to fill by writing this book?
JF: What to expect when you’re expecting to grow old? While there is an entire industry devoted to preparing expectant parents, scant resources guide us on how to grow old. This is especially true if you’re looking for scientifically-based, accurate information to inform lifestyle, diet, household, and health practices. The major gap we aimed to fill was scientifically-based knowledge on aging and longevity, distilled for a wide audience. The microbiome’s effects on healthy aging has not yet been covered in popular literature.
While there is a lot of hype about the gut microbiome, we in fact know that microbial communities all over our bodies affect how our brain, teeth, skin, heart, gut, bones, immune system, and nearly every other body part functions as we progress through life. Our wellbeing is also intimately to the microbes that surround us – on our cellphones, kitchen sponges, houseplants, pets, and desks. In the book we take a holistic approach to the microbes in and around us (not just in the gut) to explore how they are integral to a healthy and long life.
We focus on aging as a lifelong process in Whole-Body Microbiome. You don’t just suddenly ‘flip the switch’ and become old at, say, 65. We accumulate health risks and liabilities throughout our entire lifetimes. The book offers lifestyle strategies and “quick tips” that we can all take advantage of, whether we’re eighteen or eighty.
BF: Having already written a book for parents on early life microbes—and not getting any younger—we wanted to discuss microbes and healthy aging. It was important to us not just to focus on ‘the elderly’, but on the entire aging process, which includes adults of all ages.
What are a few of the main messages in your book?
BF: We live in harmony (usually) with our microbes, and they play a much larger role in our body’s functions than we once thought. By paying attention to our microbes, we can have significant effects on many aging processes.
JF: Yes, the first main message is to embrace our microbes! They are lifelong partners who are heavily impacted by our lifestyle decisions, and necessary for our health and longevity.
We detail three overarching strategies that intertwine healthy microbes and healthy aging:
(1) Consume a balanced diet filled with fiber (e.g., fruits, nuts, vegetables, whole grains, berries), fermented foods, and limited meat and refined sugars.
(2) Stay active: This doesn’t necessarily mean marathon training, but rather moving around regularly throughout the day, engaging in varied aerobic and strength activities.
(3) Stay engaged with others: Regular social contact with family, friends, and extended networks is important for our wellbeing – and our microbes as well! We deposit, swap, and share microbes every time we shake hands, hug, play cards, eat communally, and share spaces.
As scientists, how has the microbiome changed the way you think?
BF: I now see the world through a veneer of microbes! Even though we can’t see them, they are there and can affect many things.
JF: My outlook on the world has also shifted: I now pause to consider my microbes when shopping for groceries, brushing my teeth, sending a text message, washing my hands, talking to my doctor, hugging a family member, going for a run, and gardening.
I also now see microbial connections in my research as an environmental gerontologist: when I consider the level of cleanliness and sanitization in a private home or assisted living facility; microbial exposures in later life through pets, socializing, hospitalizations, and even houseplants; and everyday diet, lifestyle, and health habits that impact older people’s microflora.
How can your professional colleagues make use of this book?
BF: It is based on peer-reviewed science, so scientists will appreciate it. They can use it for their own personal improvement, or if they specialize in one area, they can get a broad overview of the wonderful and amazing invisible world of microbes that live in and on us.
JF: We distill peer-reviewed scientific research and include interviews with leading scientific and medical experts in each chapter. Taking into account the rapid scientific advances and exploding knowledge, we take the current ‘pulse’ of microbiome research as it relates to adult health and longevity.
In addition to providing relevant information that can inform personal health and diet/lifestyle decisions, we aim to inspire our professional colleagues and fellow scientists to keep pursuing this fascinating and important area of research. This includes figuring out specific microbial genes and mechanisms responsible for particular effects in and on our bodies. We need more studies and data!
What tips do you have about microbiome-related science communication?
BF: Some of us scientists work with microbes and see evidence of what they do every day. But most people have a hard time appreciating microbes because they can’t see them. Convincing people of the invisible is hard. However, we know they have profound effects on both health and disease—and it is these aspects that we can focus on.
JF: There is a lot of hype and misinformation surrounding microbiome-related science: from misleading websites, to health claims (say, for probiotics) not supported by adequate clinical trials. It is important to be clear about what statements are supported by rigorous science, what statements are ‘not quite there yet’ (in terms of extrapolating findings from existing data), and what statements are downright wrong. This was an important task for us when writing the book. Beyond this, we recommend directing audiences to valid sources of information, such as PubMed and other academic search engines, for peer-reviewed articles/reviews, to stay informed.
A growing number of start-up microbiome companies—from new players in the established probiotics industry, to university spin-outs focused on novel microbiome-based therapeutics—are looking for support and funding. In this competitive environment, how can a new company make the cut?
For the past several years Professor Denise Kelly has worked with Seventure Partners, a leading European Investor—which has the first venture fund, Health for Life, dedicated to investing in microbiome-focused start-ups, led by Seventure’s CEO, Isabelle de Cremoux. Kelly has participated in panels at both the Translational Microbiome Conference (Boston, USA) and the Global Engage Microbiome Futures event (New York, USA) and recently gave keynote lectures at the IHMC meeting in Killarney and the NeuroCon-X meeting in Prince Edward Island, Canada. Here, Microbiome Insights hears Prof. Kelly’s summary of what will set up a microbiome-based company for success.
Use strong science—and own it
Kelly says Seventure has looked at more than 400 companies in the microbiome sector. The first question she asks is whether the science behind the product or service is robust—a major factor for the Seventure Life Science team. She notes, “We are really fortunate that a lot of interest comes from tier one academics and the findings are published in high-impact journals”—so the science has been peer-reviewed and often validated by independent research, adding to its credibility.
Moreover, Kelly says the strongest scientific ‘package’ combines wetlab work with human studies that address potential mechanisms of action in humans. And she notes that companies generally need to have more than 16S data on hand: “We know so much about strain level impact; shotgun sequencing gets you a lot more information. But even then, the industry is moving towards a multi-omics approach—for example, including metatranscriptomics and metabolomics, so we know ‘who’ occupies an ecosystem but also what they are doing.”
The next question about the science is whether it’s unique: Do competitors have something similar? Having a strong patent portfolio is crucial as it gives the company a distinct competitive advantage.
Build your revenue stream
Among all the possible life sciences areas in which VCs can invest, microbiome science is still in its early days—meaning they are likely to proceed with caution. Kelly says, “Investing in the ‘discovery’ phase is inherently risky; investors want to see that others have invested in the ideas as well.” She says the solution is to use as many resources as possible to build a company’s revenue space, including building multiple product opportunities and diversifying target disease indications—and importantly, building partnerships and licensing opportunities. Very competitive companies are also winning sizeable non-dilutive grants.
Get your regulatory ducks in a row
The science may look exciting now, but what’s the plan for bringing it to market? Many potential therapeutics in the microbiome area—for example, ‘bugs as drugs’—will face unique regulatory challenges. Kelly recommends connecting with regulatory advisors early on so the company can plan for the realities of getting past the hurdles. And even in cases where the regulatory path for a particular indication is relatively well-established, those at the helm of the company need to understand the complexities of the manufacturing process and how regulatory requirements need to be factored in.
Build relationships strategically
Kelly emphasizes that no successful company is built in a bubble: it needs supporters in order to build success. Companies need relationships with key people in academia and elsewhere—and not just a list of names to put up on the web page, but people who really care about what it’s doing and who are willing to jump in with advice and support.
Kelly says it’s especially important to engage with key opinion leaders (KOLs) with knowledge about the specific indication on which the product is focused. A company that demonstrates authentic engagement with these individuals has a better chance of leading the way in the therapeutic space.
Know when to keep your cards close
As a company is building, it’s important to strategize about how much to reveal—at what times, and to whom. She says, “Approach investors, such as Seventure, when you have a clear vision of your commercial opportunity. Although we invest in early stage start-ups, we appreciate companies that have a strong science package as well as a robust business plan that clearly sells the path to clinic and ultimately, to the marketplace.”
Having all these pieces in place won’t guarantee success—but Kelly says they will certainly make investors take a closer look. “The microbiome industry is moving very fast and the number of new start-ups continues to grow exponentially. At Seventure, we continue to build our portfolio and very recently our CEO, Isabelle de Cremoux, announced the first close of a new AVF fund with Adisseo, dedicated to innovation in Animal Health and Nutrition.”
Without a doubt, the microbiome industry as a whole is truly disruptive and represents a complete paradigm shift in human and animal healthcare. Says Kelly: “We are confronted with numerous modalities, ranging from nutritional products through to microbiome-based drug therapies which can modulate microbiome community function and structure, significantly impacting health status but also disease risk and disease progression. Personalized approaches to medical care are also envisaged, as predictive microbiome biomarkers are being sought—and these could provide more accurate diagnostic and prognostic patient read-outs, leading to more predictable and enhanced drug efficacy. The next five years will be very exciting for many, many reasons. Our knowledge base will continue to grow, but most importantly, we also start to see completion of phase II/III human clinical trials.”
Microbiome Insights was a proud founding partner of the Microbiome Skin Health and Dermatology conference, a part of the Hanson Wade Microbiome Movement Series—held September 10th to 12th, 2018. The aim of this event was to explore ways of understanding the mechanisms underlying microbial interactions with skin health, and to discuss standardization of metagenomics research and how to develop effective products. Over 100 leaders in the skin microbiome field were on site at this exciting event.
We’re pleased to present a summary of the highlights from both the pre-conference workshop and the two-day main event.
The September 10th workshop, called “Harnessing the gut-skin-brain axis in health and disease”, was led by Lionel Breton, L’Oreal Advanced Research, Scientific Director. Breton spoke about what we know today regarding the connections between the skin microbiota, gut microbiota, and neurological disorders. Scientists are puzzling through these links, on the path to developing commercially viable therapeutics for skin health and brain health.
Day 1 summary
The first day of the conference began with opening remarks by Larry Weiss of Persona Biome: he acknowledged that the skin microbiome represents an exciting therapeutic frontier in dermatology, but encouraged the audience to be cautious and exercise humility—because after all, “we still don’t know what we don’t know”.
Richard Gallo of UCSD then spoke about “Targeted Design of Microbial Biotherapy for Skin Disease”. Gallo began with an overview of how microbes relate to human health in general: he argued that researchers need to look at the ‘hologenome’, as it takes into account that human functions are based on genes that are expressed via microbes and the environment.
Gallo turned specifically to the microbial life surrounding hair follicles on the skin. He noted that human follicles greatly increase the surface area of the skin; when the microbes in follicles were analyzed using 16S DNA sequencing, it appeared that most of the microbial DNA did not exist on the surface, but rather, it existed deep down in the follicle. A very small percentage of the microbes were further down, penetrating the fat and tissues under the follicle. The composition of the microbes in the fat was similar to that found on the surface.
Gallo emphasized the capacity for systemic interactions linked to the skin microbiome, as the blood vessels on the skin can have extensive communication with, and impact on, the rest of the body. He gave the example of atopic dermatitis: not only do people with this condition have a higher abundance of Gram-positive bacteria (S. aureus) than other people, but Gallo’s work showed that they also have an immune abnormality that inhibited the development of antimicrobial peptides to fight the disease. The presence of S. aureus drives a Th2 immune response, which further decreases the antimicrobial peptides and amplifies the disease. So what appears to be a skin disease is actually a complex condition with systemic influences.
Next up was a talk by Curtis Huttenhower of the Harvard TH Chan School of Public Health, a member of the Microbiome Insights Scientific Advisory Board. He presented on “Structure, Function and Diversity of the Healthy Human Microbiome”. Huttenhower began by explaining the phases of the Human Microbiome Project (HMP): while HMP 1 had the goal of identifying the baseline microbiota of a healthy cohort of individuals, HMP 2 included more multi-omics analyses, and had a longitudinal focus, aiming to uncover interactions in disease. HMP1-II was a recent follow-up on the HMP 2 data; it involved 300 people (half men, half women). Huttenhower noted that the field has seen great advancements since the kick-off of HMP 1, and argued that we are getting to the point where scientists can do meta-analyses to see which methods are more reproducible and reliable.
Specifically related to the skin microbiome, Huttenhower said we have a long way to go—not only in characterizing the ‘healthy’ skin microbiome, but also in defining its biochemistry. Novel functionality is associated with certain strains. Ongoing work is looking at how the skin microbiome may be acquired in the first place, by examining mother-infant pairs. Initial analyses indicate the strains of most bugs on the infant do not originate from the mother.
Julia Oh of The Jackson Laboratory spoke next, on “The Human Skin Microbiome: From Metagenomes to Therapeutics”. Oh emphasized the differences in composition of the skin microbiome, depending on body site: oily sites, for example, are very different from dry sites.
She advised that when looking at therapeutics, skin microbiome researchers should consider factors like site specificity, diversity of the microbiome, and stability of the community. For instance, in those with atopic dermatitis, the skin microbiome looks different depending on whether you measure it at baseline, during a disease flare (when relative abundance of S. aureus increases), and post-flare.
Oh offered some general criteria for what organisms to focus on in the development of new skin therapeutics:
- An organism that grows well on the skin—that is, on a graph of time versus growth, an organism that has a U-shaped trajectory (rather than flat).
- An organism that is beneficial to the immune system. Their group looked at T cells and measured the rate of MAIT activation with 4000 different species.
- An organism that is innate. Most skin sites are stable over time, so the challenge is integrating a foreign species into a community. Previous experiments show it’s difficult to get something to colonize on the skin.
The set of talks was rounded out by Microbiome Insights CEO Malcolm Kendall, on the topic: “From Swab to Data: Considerations for Designing Skin Microbiome Studies.” He emphasized looking at skin microbiome studies from many angles: study design (including the power), collection, stabilization, transport, sequencing, and analysis.
He noted the in-house work of Microbiome Insights that investigated the total DNA as well as the microbial content while using swabs versus tape for a skin microbiome sample. Results showed little difference in total DNA content across systems, but higher microbial content (less host content) on premoistened swabs. Of course, this approach is useful for skin surface microbiome but may not be the best method to look at the follicle microbiome.
Kendall says he has noticed a lot of debate surrounding the variable region that will provide the most fruitful information for skin microbiome analysis using 16S. Microbiome Insights has done some internal R&D work to address this issue: the outcome of which is a new ‘V4_skin’ primer that provides better species-level identification of skin taxa while maintaining low error.
An intriguing panel discussion was held later that morning: “Where will the Skin Microbiome Need Standardization to Advance Science & Future Products?” It was led by Huttenhower, joined by Amanda Nelson of PennState.
Participants emphasized the problem of contamination, since skin microbiome samples have a low microbial biomass; researchers need to include positive and negative controls for ‘human’ and body site. The panelists covered the relative advantages of different collection techniques, sequencing techniques, and culture libraries. For bacteria and skin fungi, libraries are improving, but viruses change so quickly that they won’t be covered in reference libraries. Integrating different data (using multi-omics analyses) will lead to better insights.
In the afternoon of day one, participants heard from Huiying Li of UCLA, on “The Human Skin Microbiome in Health and Disease”. Li spoke about acne in particular: they found individuals with acne and those with healthy skin had significant differences in the facial microbiome at the strain level; there are genes that are differentially expressed.
Later, Pieter Dorrestein of UCSD moved the topic to metabolomics—he spoke about “Microbial Metabolites of the Skin Microbiome – Identifying Skin Chemistry to Search for Function.” He described how his group is taking several hundred swabs from the bodies of two individuals and translating the mass spectrometry data onto a 3D model—with the ultimate aim being to find the origin of the molecules. A combined metabolomics and 16S analysis showed no changes when the face and arms were treated with certain personal care products; however, there appeared to be a deodorant-dependent change in the armpit skin. In general, it appears that the profile is resilient, but that certain lifestyle factors can indeed impact the skin.
Day 2 summary
The second day of the Skin Health & Dermatology meeting featured another great lineup of speakers addressing different aspects of the skin microbiome. Amitabha Majumdar, Senior Research Scientist at Unilever, presented on “Commercializing Microbiome-based Beauty & Personal Care Products”.
Majumdar spoke about some of the major challenges in microbiome-focused product development:
- Finding the right target: In looking for the cause of malodour, the company found certain microbes, molecules, and pathways that were responsible; when they had the right target, they developed products (like Dove deodorant) to address the problem.
- Hitting a target better: In terms of acne, Majumdar says they found that lesions were reduced after a particular 3-week treatment that included natural oils. The company then took two natural oils that were part of this treatment and added them to two facial products already on the market.
- ‘Rebalancing’ the microbiota: One of the company’s toothpaste products were studied clinically—and they found that after 14 weeks, some of the bacteria associated with oral health were altered.
Majumdar’s talk was followed by one from Alex Goddard, VP, Research & Development at AOBiome: “Using Ammonia Oxidizing Bacteria to Restore Healthy Skin”. Goddard started with the premise that we are being deprived of certain metabolites because of the nature of our hygiene practices, and this may be altering our overall immune system and general health. He reported that David Whitlock, one of the company founders, noticed animals like horses roll in the soil to relieve an itch on the skin. This led to an investigation of whether the soil somehow had a therapeutic effect—and to the potential of ammonia oxidizing bacteria. These bacteria produce nitric oxide (which is anti-microbial and anti-inflammatory).
The company’s general approach is to discover new environmental bacteria that can be used on the skin. Goddard cited some of the challenges in developing new therapeutics: determining mechanism of action (whether direct or indirect); dosing; and variability in patients (from a physiological and microbial standpoint).
Then, Livia Zaramela, postdoc at UCSD, spoke on “The Role of the active Microbiome in Skin: Emphasis on Atopic Dermatitis”. Zaramela addressed the connection between food allergy and atopic dermatitis, as about one third of children with atopic dermatitis have food allergy. Their group uses a multi-omics approach to identify whether food allergies are intrinsically linked to atopic dermatitis or not.
Zaramela discussed how to overcome the challenges of low biomass samples for metatrascriptomics analysis: they maximize collection, extraction, and mRNA enrichment, and they work to minimize contamination. In terms of contamination, it’s necessary to reduce human content in the samples, but also reagent contamination.
Another speaker in the morning session was Magali Moreau, Associate Principal Scientist, Open Research at L’Oreal. She spoke on “Human Skin Microbiome: Opportunities for Healthy Skin with Aging.”
Moreau described how the company is looking at the skin microbiomes of women of all ages. At four different skin sites across two age groups, the distribution of Staphylococcus appeared to change significantly, while the proportion of Cutibacterium at each site decreased with age. Diversity was higher in the older group, across all sites. Thus, the trend with aging seems to involve a decrease in sebum and an increase in skin microbiome diversity, with some oral bacteria increasing on the skin.
She then addressed how to translate this growing microbiome knowledge into products. Approaches include fostering the growth of beneficial bacteria, controlling the community metabolites to bring back ‘equilibrium’, or perhaps using the virome for precision modulation.
Stephen France, Business Development at SkinBioTherapeutics, was the next speaker, on “Harnessing the Power of the Microbiome for Skin Health.” He focused particularly on some interesting observations on lysates (i.e. fluids containing the contents of lysed cells). They found lysates could inhibit pathogens and change the skin barrier; pretreatment of the skin with lysates protected against S. aureus invasion.
A talk from Greg Hillebrand, Senior Principal Scientist at Amway, capped off the morning sessions: “Changes in the Facial Skin Microbiome: A One-Year Longitudinal Study in Normal Healthy Men and Women.”
Hillebrand began by describing the company’s investigations into the meaning of skin health, with input from 70 individuals. The resulting points were: “it has to perform, but needs to be resilient when stressed; it needs to look even color-toned, and fairly unremarkable (you don’t notice your skin)”.
Hillebrand described the company’s ‘Cinco de mayo’ study, done in collaboration with Microbiome Insights. Skin samples from the forehead and cheek were taken from 150 Amway employees (aged 20 to 60) in 2017, with a repeated measure on 137 of the individuals in 2018. They measured other parameters like elasticity. Microbiome analysis using 16S V4 and V1-V3 revealed overlap in the microbial communities of the forehead and cheek, with some differences. Individuals’ skin microbiomes were relatively stable, and the individuals who had low diversity of their skin microbiome in 2017 also had low diversity the following year.
Barrier function was stronger with a more diverse skin microbiome; as water loss went up, barrier function went down. The other striking finding was that bacteria from the genus Corynebacterium increased with age. Amway is looking to build on these findings, with Microbiome Insights acting as an external R&D arm, to rapidly develop microbiome-focused solutions for skin health.