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Human Health, Sustainability

Learning the Language of Cross-Kingdom Communication

Antique color illustration from German fable book for children via ilbusca for iStock

If we can discover how organisms communicate with each other, we might use the specialized language they have developed over billions years for medicines, nutrition, and agriculture.

Billions of years of evolution has led to environmentally specialized organisms across the kingdoms of life: animal, plant, fungi, bacteria, archaea, and protist. To thrive under the inexorable competition for survival, organisms must adapt lest they become extinct. Their adaptations take many forms, including structural or chemical changes that impart unique defensive or offensive tools against predators or prey. But scientists have begun to understand that the fitness of plants and animals is intimately linked to their constant, direct interactions with bacteria, fungi, and archaea.

Microbial organisms can colonize hosts and perform useful or essential functions, and in other cases cause disease and death. Other organisms have learned to productively coexist by providing beneficial services in exchange for resources, protection, or transportation. Whether the interspecies relationship is predatory, commensal, symbiotic, or parasitic, organisms from different kingdoms are in constant communication with one another through physical, chemical, or biological signals that are exchanged. We have already leveraged these evolutionary tools for the benefit of humanity, with examples ranging from potent antimicrobials such as penicillin to advanced therapies such as CRISPR-based gene editing.

However, nature is replete with many less explored examples. For instance, plants are uniquely vulnerable to predators. A plant is unable to outmaneuver attackers, whether the attacker is an herbivorous mammal or a parasitic fungus. In place of flight, plants have developed a variety of elegant tools to repel attacking organisms. Traditionally, plant biologists think of chemicals as the most important plant defense. However, plants have developed cleverer ways of targeting attackers.

One tool they employ is the recently discovered plant extracellular vesicle. Vesicles, originally thought to be artifacts of electron microscopy, are in reality secreted by plants through the nearly impermeable cell wall when the plants are under attack from pathogenic organisms such as fungi. Like mammalian exosomes, they are capable of passing messages from cell to cell. However, in this case the plant preassembles protective biological cargo, such as proteins and nucleic acids, into proteolipid particles that are released across the cell wall toward the invading organism. These particles have unique properties that enable them to protect the delicate biological cargo, target the pathogen, and deliver the anti-infective proteins to the invading organism. In return, fungi have developed their own extracellular vesicles and use them to reduce the ability of the plant to defend itself by packing in small RNAs that silence key plant pathways.

If we could discover how these organisms communicate with each other, we might use the specialized language they have developed over many years to communicate messages that instruct cells to halt pathological processes or initiate protective behaviors.

Although plant defenses may seem to be of little importance to human health, we consume plants and are thereby exposed to a wide range of plant defensive compounds. Because insects and humans have similar nervous-system receptors, plants that try to intoxicate insects with deterrent compounds end up affecting human neurology as well. Classic examples include nicotine, which is a potent insecticide but can produce stimulating effects in humans, and cocaine.

More benign examples include compounds like capsaicin, which is responsible for the spiciness of hot peppers. It deters mammals and fungi by modulating temperature-sensitive receptors to create a burning sensation in the mouth. However, people in many cultures enjoy the taste, and capsaicin can even have beneficial therapeutic effects for conditions such as chronic pain. Although some plant defensive compounds have been identified, many more beneficial molecules have yet to be found.

Humans are no strangers to targeted cross-kingdom communication either. Parasitic protists such as amoebas living inside us have developed an array of tools to evade our defense systems, rendering our bodies more hospitable for invasion. Like plants and fungi, protists have developed specialized extracellular vesicles that are capable of hijacking sentinel cells that look for invaders in our bodies. They are able to turn off cells that should be hunting for them by disrupting key immune regulatory pathways. Analogously, infectious pathogens like SARS-CoV-2 can shield themselves from the immune system by transiently wrapping their pathological cargo in innocuous human membranes like the Trojan Horse of Greek mythology.

In recent decades, scientists have begun to create drugs that modulate the immune system, which will result in new kinds of treatments for autoimmune disorders and many cancers. Perhaps there is an opportunity to leverage the evolutionary tools that these parasites have developed over millennia to expand our capabilities to treat even the most recalcitrant cancers and numerous other diseases.

If we could discover how these organisms communicate with each other, we might use the specialized language they have developed over many years to communicate messages that instruct cells to halt pathological processes or initiate protective behaviors. Fungal pathogens destroy millions of crop plants every year, while consumers and regulators demand less use of synthetic chemicals in food systems. Exploiting the language in which plants and fungi converse could help us develop new ways to protect the environment and protect our food systems.

Inflammatory disorders cause suffering and death for millions of people every year, and rates of such diseases are only increasing. Repurposing the finely honed language that some of our pathogens use to turn off immune sentinels may be a way forward in many difficult-to-treat chronic diseases. To date, we’ve developed numerous solutions that are inspired by intra-kingdom biology, such as monoclonal antibodies and plant growth hormones. However, given the challenges we face with climate change and rising levels of chronic disease, we may need to look outside our own and allied kingdoms to find the next set of solutions for the problems we face.

The complex hidden language that nature has developed to enable cross-kingdom communication may not be easily decodable or interpretable by humans. But at Flagship Pioneering, we are exploring computational, chemical, and biological advances in machine learning, microbiology, and plant biology to learn enough of this language to design products that can solve unmet needs within agriculture, therapeutics, and nutritional health.

Story By

David Kolesky

David Kolesky is an associate at Flagship Pioneering, where he is part of the Flagship Labs creation team that conceives, creates, resources, and builds the next generation of Flagship’s first-in-category companies. As part of this team of…

Hok Hei Tam

Hok Hei joined Flagship Pioneering as an associate after completing the firm's Fellows Program and consulting at the firm on three Flagship Labs companies. At Flagship, Hok Hei conducts explorations to discover unexplored biological mechanisms and…

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