The business of human microbiome
A valuable source for translational outcomes
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Microbiome – Opening new avenues for diagnosis and therapy
The human body constitutes approximately 30 trillion cells. Contrast that with more than 38 trillion microorganisms estimated to be thriving in miniature ecosystems inside a human. The constitutional paradox emerging out of this quantitative skew is much relevant – are we harboring the microbes or is it otherwise? Accounting for only the human population, the number of microorganisms on earth stand to exceed the number of stars known in the entire observable universe. This microcosmos of countless microorganisms on earth present complex implications for the planet as well as human health (µ = 10-6, or one millionth represents the typical scale for microorganisms namely, micrometer).
Metagenomics—the study of the entire pool of microbes and their genomic content in an environment—is a sought-after research and operational capability for pharma, energy, consumer health, and food and beverage industries, among others. Advancements in the DNA sequencing technology leading to development of cost-effective and portable sequencers have paved the way for quick and continuous tracing of the microbiome. This is further empowered by the availability of the cloud infrastructure, state-of-the-art and affordable compute power, enabling the intersection of metagenomics with data science. From health and pharma perspectives, human microbiome signatures hold immense clinical importance. These can aid diagnosis (Dx) and therapy (Tx) of diseases beyond the scope of conventional Dx and Tx regimen.
The crosstalk of drugs with microbes and whether microbes can act as drugs, are new dimensions in drug discovery. Further, the evidence that microbes can regulate the host gene expression and even serve as endpoints in tracing the outcomes of cell or gene therapies are furthering interest in this new modality, to holistically approach human health. Figure 1 highlights this changing paradigm. The number of clinical trials exploring the effect of drugs on the host microbiome or application of microbes as live biotherapeutics (microbial drugs) are continually increasing. This interest testifies how microbiome is emerging as an essential modality; it has immense biological and regulatory implications for the drug lifecycle, as shown in Figure 1. Microbiome matters to the industry and to the consumers.
It is now being appreciated that microbiome, like an organ system, represents a critical, hitherto largely unknown ecosystem in and on the human body. It is reasonable to check the effect of drugs, diet, existing and new therapeutic regimes on this system as well. The rise in registration of trials around human microbiome is an encouraging evidence that the industry and research community is appreciating its significance.
The trend was obtained by counting the number of trials observed for each year on clinicaltrials.gov using a combinatorial keyword query, such as microbiome or microbiota or Metagenomic or Metagenomics or 16S or Shotgun or metagenome. Details of the highlights were obtained from associated press releases by the organisations
Acknowledging the microbiome modality
Microbiome and the human immune system are closely related, and they shape each other. The intricate mechanistic details of the host-microbe crosstalk continue to emerge. However, multiple studies across different animal models, involving ‘microbiota depletion strategies’ have indicated the importance of the microbiome like an organ, without which homeostasis (state of physiological balance) cannot prevail. Moreover, the observation of perturbed microbial community signatures (a signature is a peculiar pattern or profile of the microbiota) in the state of disease or disorder seeks exploration and development of cause or consequence models of microbial association. This is particularly true for asymptomatic and silently aggravating disorders of the gastrointestinal tract, skin, nervous system, respiratory tract, hepatic system, as well as hormonal and cardiometabolic diseases.
To lay the premise for the application of the microbiome as a valuable source, an endpoint or drug for translational outcomes, particularly in diagnosis and therapy of implicated diseases or states of health, it is important to find answers to questions such as these. Does microbial dysbiosis lead to disease pathogenesis? If not, is dysbiosis a mere consequence of the disease? How do existing and new therapeutic interventions, like diet and lifestyle affect the host-microbiome? How does the host-microbiome interfere or cooperate with the interventions?
Acknowledging the microbiome modality is critical for the pharma industry in the existing market scenario and changing healthcare needs. With increasing affordability and miniaturization of DNA sequencing infrastructure, the world is moving toward continuous and personalized tracing of human microbiome. We are not far from a world where handheld devices and wellness apps would sequence and quantify personalized microbial profile. The massive data so generated will need preparedness – agile infrastructure, artificial intelligence (AI), and machine learning (ML) algorithms that can train on such continuous data streams and provide dynamic and reliable insights into the health of the host driven by its omnipresent microbiome. This acknowledgement is important as the pharma industry aims to adopt groundbreaking drug technologies, diversify the product portfolio, and open new growth avenues for new solutions.
As per various recent estimates, the human microbiome ‘alone’ is expected to grow into a multi-billion-dollar market (USD 3-10 billion by 2026-2028). We emphasize on ’alone’ as this does not take into account the increasing market of microbiome solutions in the space of animal health, agriculture (plant and soil health), energy, sustainability (bioremediation, carbon sequestration), and the like. The previous decade (2010-2020) of research and development has contributed immensely in evolving the now well-founded significance of microbiome, as public and private organizations across the world invested billions of dollars to further the R&D in this space (Figure 2 and Figure 3). In the past decade, Europe invested more than EUR 498 million (up to USD 556 million) in 216 projects under the 7th Framework Programme for Research and Innovation (and Horizon 2020).
As we move into the next decade, which we opine, is poised to be ‘the decade of the business of microbiome’, investors are taking note of the growing popularity and research. Several biotech startups dedicated to microbiome research have emerged (more than 100 R&D companies) in 2021 to leverage and fast track research in this domain. In the last five years, pharma and consumer health companies have in fact inked potential deals and agreements to the tune of more than USD 3 billion for human microbiome-linked drug discovery in the diagnostic and therapeutic space (Figure 3).
The primary intent of these investments is to translate microbiome research (at scale and pace) into commercial, consumable products, services, and medicines. The focal areas of innovation therefore range from developing state-of-the-art metagenomic and metabolic data analytics platforms (powered by AI, ML, and internet of things) to undertaking clinical research for site-specific therapeutic solution development for gut, skin, brain, lungs, and more.
Developing live biotherapeutic products (LBPs) is the focus of many microbiome-drug-based therapeutic inventions today. LBPs refer to the ‘live-microorganisms whose administration is intended to improve or treat a given medical condition’. LBPs share fundamental similarities with probiotics, often perceived as food or food supplements. However, they carry stronger liabilities, and hence need more regulation, owing to their medical indications.
Traditionally, food companies were looking at microbiome research to develop probiotics and prebiotics. But the emerging insights of how human disease and resident bacteria are interconnected caught the attention of pharma companies, that started seeing microbiome as a tool to develop new drugs. To date, more than 400 microbiome drugs are estimated to be already in various stages of development across the world. In addition, over 300 industry sponsored clinical trials, targeting the measurement of ’microbiome and drug’ as end points, accumulate further evidence toward the significance of the microbiome-modality. It therefore won’t be an overreach to say that this decade is well positioned to be as the ‘decade of the business of microbiome’.
Given the recent advancements, it would be prudent to provide a glimpse of another dimension of microbiome research. In the last two decades, researchers and pharma companies have generated multiple petabytes of microbiome data. The National Center for Biotechnology Information (NCBI) alone hosts more than 32 petabytes of metagenomic data. A single large-scale microbiome research project has the potential to generate terabytes of data. For example, the Human Microbiome Project generated 42 terabytes of data of data. Managing, processing, and analyzing this volume of data, at scale and speed, needs both computational and domain expertise. Governments and organizations across the globe, with stakes in microbiome research, thus continue to focus on and invest in the development of domain-aware digital ecosystems and computational expertise—both for resource management and research.
High performance and quantum computing stand to enable accelerated and accurate discovery process. Additionally, biology-informed algorithms rooted in artificial intelligence, machine learning, and natural language processing, can facilitate a paradigm shift in mining the latent clinical intelligence from complex microbial genomes, reactomes, and metabolic networks. Developing digital twins of microbes and the organ-systems and incorporating host-microbe cross talk, is a promising direction. This can add immense value to the entire pipeline of microbiome-based solution development.
The need for innovative, cost-effective, and non-invasive solutions for diagnosis and personalized therapy continues to rise globally. Additionally, societal awareness of the concept of ‘holistic health’, wherein health is perceived as a multi-modal state of ‘balance’ that needs continuous and personalized care or monitoring, is changing healthcare consumers’ demands and expectations. The microbiome is a crucial piece of the puzzle, which has vast potential to address all of these needs.
When a gentle assessment of a patient’s stool or oral swab indicates the state of health and how the ‘personal microbial fingerprint’ is contributing to the same, it opens avenues for continuous monitoring, greater transparency, and increased patient engagement. The rising number of wellness focused start-ups that offer lifestyle and diet recommendations through personalized assessment of an individual’s microbiome are testimony to the increasing penetration of this concept not only at the business but consumer level as well.
The realization that a vaginal swab from a pregnant woman and a simple observation of its microbial diversity can provide an accurate diagnosis of pre-term birth (as early as first trimester), changes the way microbes need to be perceived. They are not another living cell in or around the human body, but a treasure trove of hidden clinical intelligence and physiological relevance with personalized signatures. Embracing this significance of the human microbiome, the pharma and consumer health industry is taking the steps to add microbiome as a modality to their diverse portfolio.
The world is now ready to transition into the first decade of the business of microbiome. This transition would not have been possible without the tremendous global effort that goes into human microbiome research. An early mover advantage can be the key differentiator for capturing the industry relevant intellectual property (IP) and associated market.
A successful early movement needs an ecosystem approach. One that brings together and nurtures various aspects of scientific inquiry, discovery and clinical research, resource management, and data and computational science. The previous decade of microbiome research created a tremendous knowledgebase, technology stack, and built a well-trained pool of skilled scientists across the globe. This collaboration between consumers, corporate and academia are integral to accelerating microbiome market penetration and future growth.