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Human Health

Exoneural Biology

This image of a normal mouse retina in the optic fiber layer was used to demonstrate imaging capabilities of laser scanning microscopes. This layer is responsible for relaying information from the retina to the brain and was fluorescently stained to reveal the distribution of glial cells (green), DNA and RNA in the cell bodies of the retinal ganglion neurons (orange), and their optic nerve fibers (red), and actin in endothelial cells surrounding a prominent branching blood vessel (blue). By studying the microscopic structure of normal and diseased retina and optic nerves, scientists hope to better understand the altered biology of tissues in tumors with the prospects of developing therapeutic interventions. Image credit: National Institute of General Medical Sciences, National Institutes of Health via Creative Commons.

Update: In October 2019, Flagship Pioneering unveiled Cygnal Therapeutics. Founded by Flagship’s innovation foundry, Flagship Labs, Cygnal is advancing the insights and information of exoneural biology to create new medicines. Initially focused on oncology and inflammation, Cygnal is the first company to build a platform to create drugs based on this new domain. Additional disease areas of interest to Cygnal include proliferative diseases, regeneration, metabolism, and neurology. Learn more about the company and their work on exoneural biology at

Advances in technology often lead to unexpected breakthroughs in medicine.

Tools that shine a new light on biological phenomena can expose new opportunities for interventions far afield from the original application (see "Bewitched, Bothered, and Bewildered by Brain Images"). In 2003, Flagship Pioneering founded a company, Helicos Biosciences, that invented single-molecule DNA sequencers that let us see the genome for the first time. That innovation opened the door to the modern era of genomic medicine, but also let us characterize the diversity of the microbiome. We brought to life multiple companies in this new field – Seres, Evelo, and Indigo – that use the microbiome to produce entirely new classes of medicines, health products, and agricultural advances. In 2013, we helped found Editas Medicine to invent and develop CRISPR technologies to precisely edit the genome. It turns out that the ability to write the genome is useful for more than just correcting devastating genetic diseases. Subsequent companies, including KSQ, Rubius, and Inari, leverage gene editing technology to break barriers in genetic drug discovery, precision cellular therapies, and modernized crop engineering.

Neuroscience today is also being revolutionized by new tools.

The brain is no longer a mysterious mash-up of cells that somehow gives rise to consciousness. New tissue processing techniques with funky names like iDISCO and CLARITY let us visualize neurons in multiple colors and three dimensions to see how individual cells are connected to one another. Optogenetics lets us stimulate neurons with precisely-controlled pulses of laser light to fire up cellular circuits, create new memories, and forget fears. High-throughput single-cell RNA sequencing and proteomics expose the subtle differences between myriad neuron types, while neuronal stem cell protocols let us recreate patient genetics and observe how mutations cause disease.

But some things remain in the dark.

Much as a spotlight renders all surrounding features black, the intense focus on the biology of the brain easily blinds us to the nuances of the peripheral nervous system. Often overlooked is that nerves are everywhere within us, innervating all of our tissues, enmeshing our cells in a web of neurites, connecting distant parts of our body to one another. Renaissance physicians described peripheral nerves as passive conduits for the “life fluid” of the body. Although we now have a modern grasp of electrophysiology and action potentials, the peripheral nervous system is still seen as the passive transmission pipelines for information heading to the all-important brain.

What if, instead of being mere conduits of the central nervous system, peripheral nerves are independent biological decision makers?

What if they are not passive bystanders but active biochemical players, communicating with and directing surrounding cells? What if they act independently of the brain? What if they drive disease in non-neuronal tissues? What if we could treat diseases by treating peripheral neurons?

New tools will allow us to answer these questions for the first time. A small team of creative scientists in Flagship Labs, our innovation foundry, has been hard at work adapting modern molecular neuroscience to investigate the peripheral nervous system. We’ve begun the first comprehensive catalogue of peripheral innervation in human tumors. We’ve observed hitherto undescribed interactions between neurons and cancer cells. We’ve triggered neurons using laser light and asked how local stem cells and cancerous tissues respond. We’ve grown neurons in the lab and studied how they interact with immune cells. We’re beginning to understand the molecular basis for physiological changes that medicine saw but could not explain, such as why stress causes inflammatory flares and worsening of cancer. Everywhere we look we’re finding that peripheral neurons are far from passive. More surprisingly, perhaps, we’re discovering that many non-neuronal cells speak the molecular language of neurotransmission. These worlds are not as different as we thought and their interconnectedness runs deep.

Forging a new field of Exoneural Biology.

What is also becoming clear is that the boundaries of existing disciplines are not only inadequate but actively stand in the way of progress. Neuroscientists focused on the unique features of neurons, their synaspes and electrical transmission, have difficulty thinking beyond diseases of the nervous system. Oncologists, immunologists, and other cell biologists trained to study complex multicellular systems don’t encounter neurons in their daily work and are often unfamiliar with the techniques of the field. In diseases like cancer and inflammation, we know peripheral nerves are present, but those who understand nerves don’t know to look, and those trained to look are unable to see.

Even the language we commonly use imposes limits. The portmanteaux of neuroscience are defined already: “Neuro-Oncology” means brain cancer, not the nerves within tumors; “Neuro-Immunology” means inflammation of the brain, not the innervation of lymphoid organs; “Neuro-Regeneration” means spinal cord repair, not the neural control of stem cell niches. Without a new synthesis it will be impossible to perceive these interactions. We’ve had to coin a new term, “Exoneural Biology,” to describe the phenomena we’re discovering: “exo-neural” because it’s neurobiology acting outside the confines of the nervous system.

Therapeutic breakthroughs come from breaking barriers.

Where will Exoneural Biology take us? Perhaps it will turn out that nerves in peripheral tissues control disease processes, and manipulating them will lead to new medicines for cancer. Perhaps neuronal pathways will be useful handles to control the immune system to resolve inflammation and promote wound healing. Perhaps we can mimic the ways nerves regulate tissue development to reverse aging or improve metabolism.

It may sound unreasonable – especially when we lack even the most fundamental language to describe Exoneural Biology – but therapeutic breakthroughs have always come when long-standing barriers between disciplines are dismantled. Today, cancer is treated by blocking oncogenes, stopping angiogenesis, and amplifying the immune response. But before they were the source of therapeutic knowledge, characterizing genetic changes in tumors, observing blood vessels proximal to tumors, and finding infiltrating immune cells in the tumor microenvironment were mere curiosities, siloed in separate disciplines, lacking a language to describe their relevance to cancer.

Similarly, Flagship Pioneering believes Exoneural Biology will be next field that redefines how we treat diseases. Perhaps we will discover that neurons contribute to tumorigenesis, and identify ways to block it. Maybe we will learn that peripheral nerves regulate macrophage state, and find techniques to tip the scale in favor of immune balance. It could be that we learn that enteric neurons can repair broken barriers in the small intestine, and design a therapeutic for patients with IBD and colitis based on this insight. As with any new and fundamental biological insight, we don’t know—and can’t guess—all the breakthroughs that Exoneural biology will deliver to humanity. But Flagship Pioneering is eager to find out.

Story By

Jordi Mata-Fink

Jordi Mata-Fink joined Flagship Pioneering in 2013 after completing the firm's Fellows Program and left the firm in September 2019. At Flagship, Jordi worked as part of a Flagship Labs team, exploring innovative ideas and opportunities, and…

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