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Human Health

Intersystems Biology

Hand drawing of oral bacteria by royaltystockphoto.

Biology and ecology are moving beyond the idea that individual plants and animals are autonomous organisms. What would it look like if medicine did the same?

Every kingdom of life is present in the human ecosystem: bacteria, fungi, protista, archaea, plants, even animalia. Every cell in your body contains symbiont organelles with their own genomes. Eight percent of the DNA in your nuclei was placed there by retroviruses. There are more microbiota on your skin, in your gut, and in the crannies of your body than human cells, and these microbes carry hundreds of times more information than your own cells.

We coevolved with these myriad other species, and our bodies are an unending storm of interspecies molecular interactions. As systems, we are commensal holobionts: communities of human cells and complementary microorganisms. We metabolize carbohydrates and proteins from other living things, and we depend on plants and animals for essential minerals that we cannot make ourselves.

Why are humans so dependent on other species? Evolution is parsimonious. In every ecosystem, including the human body, life enforces both a division of labor between species and unceasing war. Organisms work together and against each other to maximize resource utilization. Biologically, this manifests as a continuous bidirectional exchange of molecules: joint metabolism, coordinated signaling, pathogenic toxins, and antibiotic exchange.

At Flagship Pioneering, we call this emergent network behavior intersystems biology, and we have created several companies, including Senda Biosciences, to explore and exploit its potential to create life-changing medicines.

We coevolved with these myriad other species, and our bodies are an unending storm of interspecies molecular interactions.

Intersystems biology builds on a decade of research in microbiome science, metagenomics, transcriptomics, metabolomics, and computational biology, and advances beyond taxonomic descriptions of microbiota to open a vast and unexplored frontier for the creation of novel medicines and drug delivery solutions.

Examples of intersystems biology are everywhere once you know where and how to look, and their impact on human health and disease is startling. When humans eat meat, the bacteria in our guts harvest the energy in their own ways, turning protein into indole metabolites like tryptophan derivatives. These molecules can act as agonists or antagonists of the aryl hydrocarbon receptor, a transcription factor for gene expression, for both good and ill. Francisco Quintana, at the Department of Neurology at Harvard Medical School, has found an axis between the gut and central nervous system in multiple sclerosis, and described how microbiota affect T cells and glial cells, controlling inflammation and neurodegeneration.

Or consider serotonin, a critical neurotransmitter. Most of it, perhaps as much as 90 percent, is found not in the central nervous system but in our guts, made by human enterochromaffin cells in response to bacterial metabolism. We depend on this gut-derived serotonin to regulate our blood glucose and appetite. If the microbiome doesn’t induce enough serotonin production, or produces too much, our health is affected in serious ways. People with low blood sugar are fatigued, weak, and sometimes confused. Hyperglycemia causes obesity and is associated with heart disease, strokes, kidney disease, glaucoma, and nerve problems.

Many people understand that plants produce anti-inflammatory and antioxidant compounds. What’s less known is that they also secrete vesicles to shepherd molecules into human cells, and that these vesicles themselves are important for human biology. For instance, essential fatty acids are part of every human cell membrane, especially in brain cells, but they can’t be made by human cells. Instead, they come from plant lipid membranes, like those that make up secreted plant vesicles. The lipids from these vesicles from fruits and vegetables are fundamental building blocks for our human cells.

Intersystems biology crosstalk can even amplify or mute the effects of nonnatural molecules like drugs. Bacteria transform drugs into more absorbable or bioactive forms, as bacterial azoreductase enzymes do to the anti-inflammatory drug sulfasalazine. Or they can break them down before they reach their intended target, as H. pylori does to levodopa, a treatment for psychosis and Parkinson’s disease. Other bacteria inactivate gemcitabine, a chemotherapeutic for pancreatic cancers. Most dangerously, bacteria can increase the toxicity of drugs, as Clostridium difficile does by producing p-cresol, which reduces the liver’s ability to metabolize acetaminophen.

Molecules often cross interspecies borders with little resistance, like goods or people crossing the borders of European countries.

The great lesson of intersystems biology is that there are no boundaries between species. Within the human body, there are long chains of metabolism and signaling, representing every kingdom of life. Molecules often cross interspecies borders with little resistance, like goods or people crossing the borders of European countries. Even when molecules seem constrained by a biochemical trade or travel ban, they usually find a way to get around.

Improvements in the versatility and quality of tools that measure how the trillions of nonhuman species within our bodies interact with us at a molecular level will lead to a new conception of health and disease and to novel medicines and delivery solutions.

By creating comprehensive higher-resolution maps of molecular interactions between human cells and all the buzzing life within us, we may soon be able to identify targets for rationally designed molecules that block drug degradation, reduce toxin production, modify immune signaling—and more.

If our bodies are just big, lumbering survival machines for their genes, as Richard Dawkins argued, then these machines depend on components from the species with whom we coevolved. From the point of view of intersystems biology, we will only optimize our own health when we understand our connection to the wider environment.

John Casey, PhD, is a principal at Flagship Pioneering and a cofounder of Senda Biosciences, Kintai Therapeutics (a progenitor of Senda), and Inari Agriculture.

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John Casey

John Casey joined Flagship Pioneering in 2015 after completing the summer Fellows Program. At Flagship, he works as part of a venture creation team, exploring innovative ideas and opportunities, and developing critical scientific and business…

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