Thought LeadersSe Jin Song, Ph.D.Managing DirectorThe Microsetta Initiative

The human microbiome is made up of trillions of microorganisms, including bacteria, viruses, fungi, and other microbes, that live in and on the human body. In recent years, we’ve gained significant insights into these microbial communities, from their role in the gut-brain axis to promising research on how they could influence cancer immunotherapy responses. However, much remains to be discovered, and we are still at the frontier of microbiome research. 

In this interview, we speak with Se Jin Song, Ph.D., Managing Director at The Microsetta Initiative, about the progress in understanding the human microbiome and how both cutting-edge research and public participation are shaping this journey.

Can you start by giving us an overview of The Microsetta Initiative and its primary goals?

The Microsetta Initiative (TMI) is a highly collaborative microbiome research study based out of the Knight Lab and the Center for Microbiome Innovation (CMI) at the University of California San Diego (UC San Diego).

The study’s primary goal is to better understand our microbiomes, like those on our gut or skin, and their connections to diet, lifestyle, age, health, medical history, demographics, and other relevant conditions. Participants submit samples, such as stool, which we then sequence to discover what bacteria and other microbes are present. We pair these data with information participants provide about their personal characteristics and habits.

By analyzing the combination of microbial composition and survey responses, we’re able to tease out novel associations that not only expand our knowledge of human microbiomes but also create new avenues of research to determine how and why these associations exist. Beyond our in-house research and analysis, we also put fully anonymized data into the public domain for anyone to reuse. This way, scientists worldwide can use these data to further our understanding.

The origins of this initiative started with the American Gut (2012) and the British Gut (2014) Projects, which were localized citizen science efforts aimed at collecting microbiome data provided by participants in the US and the UK, respectively.

TMI became the next natural step that provided a framework for generalizing the project’s reach.

The “Microsetta” name is intended to reflect a conceptual relationship to the Rosetta Stone (which helped scholars decipher the code of hieroglyphics).

Along the same lines, we hope that TMI’s output will expand microbiome data from many populations so researchers can ask how results from one population translate to another.

What motivated you to pursue research in the field of microbiomes?

In 2010, I was a graduate student in need of summer funding, and I answered a call put out by Rob Knight, then a professor at the University of Colorado Boulder, for help collecting samples for a study.

The study was about whether a person’s microbiome is shaped by the other people and animals that live with them. At the time, I had a background in genetics and ecology but wasn’t familiar at all with the concept of microbiomes. As I got more involved in the study and learned more about the field, I got hooked. I was fascinated by the idea that we and all other animals on earth are entire ecosystems, home to multitudes of microbial beings and that we still understood so little about them and our relationship with them. I went on to lead that ‘family study’ into my first publication, and this study is why you see questions about who and what animals you live with in TMI’s questionnaire.

What are some of the most significant discoveries or findings that have emerged from The Microsetta Initiative so far?

One of the most impactful discoveries we’ve found is the connection between the variety of plants you eat and the diversity of your gut microbiome. If you’ve seen the recent Netflix documentary, “Hack Your Health: The Secrets of Your Gut,” you’re probably familiar with the 60-plant smoothie, or you may have seen references to the 30-plant challenge. While throwing everything but the kitchen sink into your blender isn’t strictly necessary, the concept is built on findings from our study.

In our 2018 publication, “American Gut: An Open Platform for Citizen Science Microbiome Research,” we found that participants who reported eating 30 or more types of plants per week had more diverse gut microbiomes than participants who reported eating fewer than ten types of plants. This finding was particularly exciting because it wasn’t something we were expecting a priori.

When we dug further, we found that those people also tended to have more of certain compounds and microbes that are thought to play beneficial roles, such as a compound called conjugated linoleic acid (CLA) and microbes putatively identified as Faecalibacterium prausnitzii and Oscillospira. Bacteria like these are important because they can produce short-chain fatty acids (SCFAs), compounds that are beneficial for human health.

Diet and the Gut Microbiome

Another significant finding is that age can be estimated from the microbiome. The skin microbiome is particularly good for this. For this analysis, we combined the TMI data with data from other studies to ensure that this finding was robust to different studies and populations. We are now working on improving these estimations using more advanced methods.

Could you elaborate on the methodologies and technologies employed in The Microsetta Initiative to analyze and understand microbiomes?

Our lab uses metagenomic DNA sequencing, also known as shotgun metagenomic sequencing, to determine the microbes in a sample. This method involves taking random snippets from all of the DNA found in a sample and sequencing them. We then match those DNA sequences to sequences from known microbial genomes to estimate the types and relative amounts of microorganisms present.

For the 2018 publication, we used a then widely used approach called 16S amplicon sequencing, which sequenced just one part of one gene present in all microbes. While that method was already very effective, metagenomic sequencing provides a more detailed picture of microbiome samples by allowing us to cover more parts of the genomes, which gives us insight into not just which microbes are there but also what they can do.

How does microbiome research fundamentally change our understanding of human biology, and what potential does it hold for revolutionizing medical treatments and public health strategies?

Microbiome research has opened our eyes to the immense complexity and variability of the microorganisms that live around, on, and within us and how much we rely on them. Each of us has a unique assemblage of microbes shaped by everything from our genetics and the way we were born to the foods we eat and where we live.

While we have more questions than answers at this stage, research has found that microbes are heavily associated with human health and biology in ways that we didn’t fully appreciate just a couple of decades ago. Not only do they train our immune systems, but we’re finding that they also play a part in metabolic health, how we respond to drugs and immunotherapies, and even mental health.

A key public health issue we face is the ongoing loss of microbial diversity due to activities associated with westernization, urbanization, and environmental change. Many human studies have shown that Westernized and urban populations have much lower microbial diversity than populations that have maintained more traditional lifestyles. Environmental change is also likely to deplete plant, animal, and soil microbial communities in irreversible ways.

Researchers are still grappling with the precise effects of these losses. Still, we’ve observed on a larger scale that when species of animals or plants are lost to extinction, it generally has a negative impact on the ecosystems and communities of which they were a part. Human microbiomes are likely subject to similar risks, as researchers believe that decreases in microbial diversity are linked to the increased prevalence of chronic diseases and reduce our collective resilience against pathogens.

With diversity loss, we’re additionally losing opportunities to discover microbiota as sources of novel drugs, therapeutics, or supplements. The Microbiota Vault is an international consortium working to preserve existing diversity in much the same way as the Svalbard Seed Vault safegaurds plant diversity. TMI is honored to be a member of the coalition.

From the perspective of medical treatments informed by or derived from microbiome research, the ultimate goal is highly personalized, precision medicine. However, the fact that the microbiome can be so variable from one individual to the next means that getting to this kind of application will likely rely on enormous amounts of data and new technologies like AI to help decipher that information. Large population studies that are both rich and diverse, like the one we are building with The Microsetta Initiative, will be important to these types of approaches.

The Microsetta Initiative involves collaboration with various institutions and researchers. How do these collaborations enhance the scope and impact of your research?

Every collaboration is unique and rewarding in its own way, but one of the overarching themes is that it connects us with specific subsets of the population who might be under-represented in our existing dataset. And in many cases, the study is clinically focused or designed to understand or address a real-world issue. Other collaborations help us reach foreign populations by bridging the logistical and cultural gaps involved.

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For example, through a study funded by Danone and collaboration with local institutions, we were recently able to study cohorts in the United Kingdom, Mexico, Spain, and Japan and compare those data to what we collected from American participants. In all cases, the data are collected and generated under a common protocol, which means that with each added study, the overall dataset becomes that much more powerful for detecting complex associations. It also becomes a richer resource for the research community to be able to pick and choose from a variety of criteria to meet their research needs.

Image Credit: Edge Creative/Shutterstock.com

Public participation is a key element of The Microsetta Initiative. How do you engage with the public, and what role do citizen scientists play in your research?

Given the crowdsourced beginnings and nature of The Microsetta Initiative, public participation isn’t just a key element—it’s foundational to our work. While we do recruit targeted cohorts from time to time and run focused studies with collaborators, it would be nearly impossible for us to reach wide-scale participation without people discovering our project and proactively contributing.

We’re especially grateful for our most ardent supporters, who not only participate in the project themselves but also evangelize the project to their friends and families. As much as the day-to-day mechanics of microbiome research can sometimes feel like a slog, it’s refreshing and rewarding to see that there are people who are genuinely excited about the work we do.

For us, public engagement is built on principles of education, scientific rigor, and continuous improvement:

• Education – We’re committed to sharing our findings both with other researchers and the general public. But critically, we strive to make information approachable and accessible for as many audiences as possible.
• Scientific rigor – Emerging fields of research are often fertile ground for exciting claims. And while we hope that our work leads to impactful discoveries for human health, we ensure that everything we share with participants is well-supported by scientific evidence.
• Continuous improvement – Microbiome research is a rapidly evolving field, and our communication with participants reflects that.

Whenever we develop new analyses or improve our microbiome sample report, we share those changes with past participants and apply the new features to their data, even if they contributed their sample several years ago.

What are some of the main challenges you face in conducting research within The Microsetta Initiative, and how do you address them?

Managing participants’ expectations is a frequent challenge. Over the past several years, microbiomes and their relationships with health have gone from a research niche to a commonly discussed concept. However, like many emerging scientific fields that enter the public consciousness, microbiomes’ popularity has given rise to both misunderstandings and misinformation.

One of the most prevalent issues is that people think that measuring the microbial composition of a given sample can infer actionable advice. In many cases, this comes from a place of hope for which we have great empathy. People contact us because they have long-standing gut health issues or conditions their doctors have been unable to resolve, and they hope to discover a microbial silver bullet, whether it’s eliminating some bacteria from their gut or encouraging another to grow.

Unfortunately, for most conditions, that sort of approach isn’t currently backed by scientific research. Human microbiomes are incredibly complex ecosystems whose constituents are rarely outright “good” or “bad.” A given microbe can be beneficial in some contexts but harmful in others.

While we hope to one day reach a point where microbiome-based precision medicine is a realistic avenue, we’re not there yet. We try to temper expectations by being transparent about what they will learn about their microbiomes and not over-promising the results or overreaching what they may mean.

While this sometimes leads to an initial sense of disappointment, most participants are still excited to learn more about their microbiomes and to know that they are helping to push the field forward. The opportunity to provide education and outreach while carrying out our study provides a sort of symbiotic enrichment for both participants and researchers.

What future directions or expansions do you foresee for The Microsetta Initiative in the coming years?

We’re excited about continuing to expand our platform to broaden support for microbiome research. The latest research program powered by our platform is the Skin Biome Initiative, which aims to build a large public repository of skin microbiome data. The pilot study, funded by L’Oréal Research & Innovation, will recruit over 2350 participants over the next three years, but the Initiative also plans to open for general participation.

Looking further into the future, we’d like to open our study to residents of other countries. Microbiome datasets are known to be heavily biased towards European and North American populations, yet large portions of microbiome diversity are contained within other populations.

Collecting microbiome data from diverse populations is one of the foundational goals of the Microsetta Initiative, and expanding internationally is a key component of that. While there are logistical challenges to consider, the study and its supporting technologies have all been built with internationalization in mind.

We’re continuously seeking new collaborators to help diversify the project and expand its reach. We encourage organizations to reach out and explore mutually beneficial ways we can work together. Companies bring resources that help us overcome logistical challenges while they benefit from leveraging our expertise and infrastructure to accelerate research.

At the same time, we frequently work with academic investigators on highly targeted studies. Our platform allows any group to conduct efficient and impactful cohort studies, and these collaborations are integral to the project’s growth.

What aspects of leading The Microsetta Initiative do you find most rewarding, and how has it influenced your perspective on microbiome research?

The most rewarding part of leading this project is working with people who are clearly passionate about the science and the work being done. This includes everyone from the outreach and communications team to the sample processing team and the data analysts, and this has allowed this project to advance and improve while continuing to be grounded in good science—and mind you, this has been without the kind of resources that private companies have.

On the other hand, I love hearing from supporters who are excited about the research and often have insightful questions. This project is a constant reminder to me of how important it is to not only do quality research but also translate the research findings responsibly and in accessible ways.