We could harness the power of interspecies molecular connections to improve human health?
A deeper understanding of how the trillions of nonhuman species within our bodies interact with us at a molecular level leads to a new conception of health and disease—and enables the creation of novel medicines and delivery technologies.
Flagship Pioneering originated Senda Biosciences to develop therapeutic applications of intersystems biology, a new research discipline that studies the molecular connections between bacterial, botanical, and human cells and how they define health and disease. Intersystems biology builds on a decade of advances in microbiome science, metagenomics, transcriptomics, metabolomics, and computational biology, and opens a vast and unexplored frontier for the development of novel categories of medicines.
Senda Biosciences evolved from at least four distinct explorations of intersystems biology by the scientist entrepreneurs of Flagship Labs, including Partners David Berry, MD, PhD, and Ignacio Martinez, MBA; Principal John Casey, PhD; Senior Associates David Kolesky, PhD, and Hok Hei Tam, PhD; and Associate Ellen van Rooijen, PhD.
The earliest of these explorations, Kintai Therapeutics, was founded in 2017 to map the molecular interactions of bacteria in the human gastrointestinal system. Kintai built a molecular biogeography platform that invented chemistries for orally administered small molecule drugs that could treat a range of local and systemic diseases. In 2018, Kintai merged with a prototype company inside Flagship Labs, FL51, which had been exploring the gastrointestinal neurology system. Also in 2018, Flagship founded Senda Biosciences, the progenitor of today’s Senda, to harness plant vesicles for the transfer of macromolecules using a third set of molecular systems in the gut. The progenitor company studied the interaction between humans and the fruits and vegetables we eat and demonstrated that certain plant subcellular components were stable and safe and could deliver many therapeutic cargoes. Another prototype company, FL62, was founded in 2019 to exploit a fourth system, using molecular interactions of subcellular components of bacteria to deliver therapeutic cargoes and alter human biology. Kintai, FL51, Senda, and FL62 were collectively an extraordinary investment in using interspecies molecular interactions for drug discovery, development, and delivery—in economic terms, representing more than $88 million in capital commitments. In late 2020, Flagship merged the four companies into a single major venture in intersystems biology.
Although the new Senda Biosciences combines different facets of intersystems biology, its scientists share a core intuition that it will be possible to create revolutionary medicines from nature’s own coevolved molecules. They realize that the systems within us, ranging from the microbes we host to the plants we ingest, are a bidirectional exchange of molecules as important as genetics in determining human health and disease. They also note that the human gastrointestinal tract possesses a rich variety of cells, including immune cells, neural cells, and bacteria, and that different regions of our gut have different interspecies molecular functions, pathways, and connections to the rest of our body.
Senda Biosciences was created to develop novel categories of medicines based on molecular insights into the trillions of interspecies connections within us. The mission demanded charting the first molecular map of intersystems biology and developing unprecedented delivery modalities. The map was drawn by applying cutting-edge analytical chemistry to a comprehensive set of human gastrointestinal samples. The delivery modalities include a chemistry technology for the rational design of potent, precise, orally delivered small molecules; a biological technology for control of therapeutic bacterial activities; and a material technology for producing therapeutic cargo–loaded, highly specific plant-derived vesicles.
Over the last decade, as life scientists advanced their understanding of the complexities of the microbiome, they proposed new therapeutic approaches based on their increased comprehension. Breakthrough medicines based on microbiome science, such as SER-109, from Seres Therapeutics, for the treatment Clostridium difficile, are making their way through clinical trials. But there are wider possibilities for novel medicines based on bacterial and plant systems. A decade of pioneering research and development in microbiome medicine taught Flagship that to realize the potential of the microbiome, scientists will need a more complete view of the molecular connections between species, including species beyond bacteria.
Intersystems biology builds on earlier studies of the taxonomy of microbiota and their associations with health and disease. Now, however, the pharmacological promise for patients can be tested. Senda’s breakthrough is a high-resolution view of interspecies interactions in the human body. The company’s approach combines extensive human sampling of previously uncharted tissues with advanced computational biology. The result is a continually developing, first-of-its-kind map of the molecules and biochemical activities throughout the human gastrointestinal tract. Senda’s drug discovery platform generates geospecific insights into interspecies interactions, mapping millions of genes, metabolites, and pathways to specific parts of the human gastrointestinal tract. The platform can identify, quantify, and locate molecular connections with hundreds of times the diversity of traditional stool-based sampling methods commonly used today—leading to the identification of tens of thousands of novel interspecies interactions. These insights not only suggest interventions for a multitude of diseases but also indicate what type of molecule would need to be where to be effective.
Senda’s geospecific molecular resolution is already creating a pipeline of promising small molecules and new modalities. The Senda discovery platform has uncovered four key interspecies functions with observable impacts on human health and disease: interspecies signaling, or production of commensal metabolites by the microbiota; toxin production, or production of harmful microbial metabolites; drug degradation, or microbial metabolism of therapeutic compounds, diminishing potency; and interspecies transfer, or deployment of medicinal cargoes into human cells using botanical and bacterial mechanisms. Senda’s preclinical programs target these four interspecies functions across a wide range of large therapeutic areas.
Senda harnesses interspecies interactions to create new categories of medicines that will restore systemic or local health by targeting the human and nonhuman processes in our bodies. The medicines will deliver compounds in precise ways, using selectively activated molecules, and for the first time ever will allow patients to take large biomolecules such as peptides and nucleic acids by mouth, instead of receiving injections.
Senda’s strategy is to build a multiproduct platform company: first establishing proof of mechanism across the four interspecies functions, and then advancing six programs toward Investigational New Drug authorization as quickly as possible. Senda’s six preclinical programs across the first three interspecies functions (signaling, toxin production, and drug degradation) leverage its small molecule medicinal chemistry capabilities. In neurology, Senda aims to treat multiple sclerosis and Parkinson’s disease; in oncology, colorectal cancer and cancers that can be eliminated by the immune system; and in metabolic diseases, chronic kidney disease and obesity.
Within the fourth function (interspecies transfer), Senda’s scientists are developing plant and bacterial subcomponents that can transfer macromolecules into our tissues as therapeutics or vaccines. Inspired by the natural evolutionary properties of nonhuman species’ molecular interactions with our tissues, these promising new transfer modalities may pave the way for new categories of medicines such as oral delivery of peptides and mRNA; cancer and infectious disease vaccines; and oral enzyme replacement or anti-cytokine therapies and tolerization.
Senda Biosciences is a first-in-category company in the tradition of other Flagship Pioneering therapeutics companies such as Moderna, Cellarity, and Tessera Therapeutics. It is establishing a new field and developing an unprecedented platform for the creation of novel medicines. Senda can identify, quantify, and locate the molecular connections of Interspecies Biology, revealing ourselves to ourselves, and then get the right molecules to the right places to create novel treatments for disease.