When German pathologist Robert Koch discovered the bacterium behind tuberculosis in 1882, he included a short guide for linking microorganisms to the diseases they cause. It was a windfall for germ theory, the modern understanding that pathogens can make us sick. But it didn’t only shake up the field of medicine: Botanists took note, too.

When a blight of mosaic disease threatened European tobacco crops in the mid-1800s, plant pathologists set out to identify its root cause. For decades, only one forward-thinking botanist, Martinus Beijerinck, realized the source was neither a bacterial nor a fungal infection, but something completely different: a virus.

Today, we know that viruses can be found nearly anywhere in the air, oceans and soil. A tiny percentage of these are dangerous pathogens that cause disease, such as the current coronavirus called SARS-CoV-2 causing a worldwide pandemic. Yet the study of viruses started not in medical science, but in botany, the study of plants. Viruses are so small—and so strange—that it would take decades for scientific consensus to agree that they exist at all.

Agents of Disease

The idea that microorganisms could cause plant disease wasn’t entirely new even in the late 19th century. In the 1840s, Reverend Miles Berkeley, also a botanist, identified the fungus behind Ireland’s potato blight, despite the clergy’s notion that the devil was to blame.

In 1857, farmers in the Netherlands reported a disease threatening another economically vital crop: tobacco. The leaves began turning a mottled dark green, yellow, and grey, causing farmers to lose up to 80 percent of crops in affected fields. Massive fields of tobacco that had been planted with the same crop repeatedly were especially susceptible. Once the disease reached a farmer’s field, it spread rapidly.

“It's very easy for it to move around,” says plant virologist Karen-Beth Scholthof of Texas A&M University. “If you're in a greenhouse or your garden and you're watering with a hose and the hose touches an affected plant, you can end up damaging a plant next to it.”

In the Netherlands, plant pathologist Adolf Mayer began researching the disease in 1879 and named it the “mosaic disease of tobacco.” He tried to use Koch’s guidelines, which call for a series of germ isolations and re-infections, to find its cause. But Mayer ran into trouble. Although he showed that the sap from a sick tobacco leaf could pass the disease to a healthy leaf, he couldn’t produce a pure culture of the pathogen and couldn’t spot the culprit under a microscope.

“The tools did not exist to see a virus,” says biological anthropologist Sabrina Sholts, curator of the Smithsonian National Museum of Natural History’s Outbreak exhibit. “It was just this invisible contagion.”

When botanist Dmitri Ivanovski researched tobacco mosaic disease in Crimea beginning in 1887, he took a different approach. He strained the sap through fine filters made of unglazed porcelain, a material with pores that were too small for bacteria to squeeze through. But when Ivanovski put the filtered sap on a healthy tobacco leaf, it turned mottled yellow with disease. Ivanovski could barely believe his data, which he published in 1892. He concluded that the disease was caused by a toxin that fit through the filter or that some bacteria had slipped through a crack.

Dutch microbiologist Beijerinck independently conducted almost the same experiments as Ivanovski, but he came to a much different conclusion. The early pathologist added to the porcelain filter experiments with a second kind of filtration system that used a gelatin called agar to prove that no microorganisms survived the first filtration. Bacteria get stuck on top of the gelatin, but the mysterious mosaic-causing pathogen diffused through it.

Beijerinck also provided evidence that the disease agent relies on growing leaves to multiply. By re-filtering the pathogen from an infected leaf and using it to cause mosaic disease on another plant, he showed that the agent could spread without diluting its disease-causing power. He proved the pathogen was growing in the leaves, but strangely, it couldn’t reproduce without them.

When he published his findings in 1898, Beijerinck called the infectious, filtered substance contagium vivum fluidum—a contagious, living fluid. As a shorthand, he reintroduced the word “virus” from the Latin for a liquid poison to refer specifically to this new kind of pathogen.

“I don't think Ivanovski really understood his results,” Scholthof says. “Beijerinck set up the experiments and trusted what he saw… The way we use ‘virus’ today, he was the first one to bring that term to us in a modern context, and I would give him credit for the beginning of virology.”

A Bold Hypothesis

Although Beijerinck incorrectly thought viruses were liquid (they are particles) his results were close to the mark. Yet his idea didn’t catch on. His suggestion of a pathogen without a cell conflicted with early germ theory and was radical for the time.

Ivanovski continued to search for a bacterial cause of tobacco mosaic disease, claiming “that the entire problem will be solved without such a bold hypothesis” as Beijerinck’s. In the meantime, researchers grappled with the evidence at hand. In 1898, the same year as Beijerinck’s work was published, foot-and-mouth disease in cattle became the first animal illness linked to a filterable agent, or a microbe small enough to pass through a porcelain filter. In 1901, American researchers studying yellow fever in Cuba concluded that the disease carried by mosquitoes was caused by something small enough to be filterable, too.

At the time, the researchers didn’t consider their discoveries to be viruses like Beijerinck’s. The prevailing theory was that there were simply bacterial that could fit through the filter. Early review articles of invisible contagions sometimes grouped barely visible bacteria with Beijerinck’s viruses.

“In the early days, there was a lot of confusion because you couldn’t see them,” Scholthof says. Questions about whether these tiny germs were small bacteria, molecules secreted by bacteria, or something else remained unanswered into the 1920s. “Some people would probably say [the questions went on] until they could be seen with an electron microscope,” she says.

A Model Virus

In 1929, biologist Francis Holmes used the tobacco mosaic virus to develop a method proving that viruses are discrete particles mixed in the filtered sap and that they have stronger effects at higher concentrations. In 1935, chemist Wendell M. Stanley created a crystallized sample of the virus that could be visualized with X-rays, earning him a share of the 1946 Nobel Prize. (The clearest X-ray diffraction image of tobacco mosaic virus came from Rosalind Franklin, in 1955, after her contributions to the discovery of DNA’s double helix.) The first clear, direct photographs of tobacco mosaic virus would not come until 1941 with the invention of powerful electron transmission microscopes, which revealed the pathogen’s skinny, sticklike shape.

This was a turning point in the scientific understanding of viruses because visual proof dispelled any doubt of their existence. The images showed that viruses are simple structures made of genetic material wrapped in a solid coat of protein molecules—a far cry from squishy, cellular bacteria. But Beijerinck didn’t live to see his theory validated, as he died in 1931.

“In a way, we were lucky that it was this was a disease found on tobacco,” Scholthof says. “It was an economic problem. It was easy to work with and purify. The virus itself only in it encodes five genes.” Because the virus has been a research subject for so long, it was used to develop fundamental ideas in virology. It remains a tool in plant virology today.

Mayer, Ivanovski and Beijerinck’s work didn’t stop the spread of tobacco mosaic during their lifetime; tobacco production halted entirely in the Netherlands. But their pioneering work on tobacco mosaic virus opened the door to a century of research that has revealed a diverse range of viral structures and strategies for survival.

While tobacco mosaic virus is rod-shaped and made up only of genes and protein, others, like the COVID-19 coronavirus, are round and wrapped in a fatty envelope that makes them especially susceptible to soap when you wash your hands. Advancements in the understanding of how viruses spread allowed for the eradication of smallpox and the invention of several life-saving vaccinations.

“It's only been in the last century that a lot of these amazing achievements happened, and it's happened so fast and so dramatically that we almost can't relate to what the world was like,” Sholts says. Right now, “there's a lot to be concerned about and take seriously. But I usually find what the scientists are doing to be one of the brightest elements to anything that you might look at.”