Virus

• 1. Organisms At The Edge Of Life

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  Fewer than 100 particles of norovirus are enough to make a person sick. That is the infectious dose of one common virus, an agent so small it sits at one-hundredth the size of most bacteria. A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. It infects all life forms, from animals and plants to bacteria and archaea, and it is the most numerous type of biological entity on Earth. Yet despite that abundance, scientists still argue over whether a virus is even alive. Viruses carry genetic material, they reproduce, and they evolve through natural selection. They also lack cell structure, the feature generally considered necessary to define life. For this reason, some biologists have called them organisms at the edge of life, and others have called them simply replicators. This documentary asks what a virus actually is, where it came from, how it hijacks a cell to copy itself thousands of times, and how it shaped both human disease and the chemistry of the oceans. The answers reach back to a diseased tobacco plant and forward to viruses engineered to kill cancer.

• 2. A Filter And A Poison

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  In 1892, Dmitri Ivanovsky pushed sap from a diseased tobacco plant through a filter with pores small enough to trap bacteria. The filtered sap still infected healthy tobacco plants. Something smaller than any known bacterium was at work. In 1898, Martinus Beijerinck called this filtered, infectious substance a virus, and that moment is treated as the beginning of virology. The word itself was far older. It comes from the Latin term for poison and other noxious liquids, sharing an Indo-European root with the Sanskrit visa and the Ancient Greek ios, both meaning poison. The first attested use in English appeared in 1398, in John Trevisa's translation of a work by Bartholomeus Anglicus. The meaning of an agent that causes infectious disease was first recorded in 1728, long before anyone could see what such an agent was. Discovery accelerated quickly. Frederick Twort and Felix d'Herelle characterized bacteriophages, viruses that infect bacteria. In 1926, Thomas Milton Rivers defined viruses as obligate parasites. Wendell Meredith Stanley showed they were particles rather than a fluid, and the electron microscope, invented in 1931, finally let researchers see their structures. The adjective viral dates only to 1948, and the term virion, for a single released particle, dates to 1959.

• 3. Anatomy Of A Particle

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  Most studied viruses are spherical with a diameter between 20 and 300 nanometres, and more than a thousand bacteriophages would fit inside a single Escherichia coli cell. A complete virus particle, the virion, is genetic material wrapped in a protein coat called the capsid, built from subunits called capsomeres. Some viruses add an outer envelope of lipids taken from the host cell membrane. The shapes fall into a handful of types, and each tells a story about how the virus works. Helical viruses stack a single kind of capsomere around a central axis, producing rigid rods or flexible filaments; the well-studied tobacco mosaic virus is one. Icosahedral viruses, the form of most animal viruses, build a near-spherical shell, with curved pentons at the twelve vertices and flatter hexons across the faces. Bacteriophage T4 shows the complex type, an icosahedral head bound to a helical tail with a base plate and protruding fibres. That tail acts like a molecular syringe, attaching to a bacterium and injecting the viral genome while the capsid stays outside. The giants stretch the definition of small. Mimivirus has a capsid 400 nanometres across with protein filaments projecting 100 nanometres from its surface. In 2011, researchers found an even larger virus in water from the ocean floor off Las Cruces, Chile, and named it Megavirus chilensis; it can be seen under a basic optical microscope. In 2013 the Pandoravirus genus turned up in Chile and Australia, with genomes about twice the size of Megavirus and Mimivirus.

• 4. Hijacking The Cell

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  When a virus infects a cell, the host is forced to rapidly produce thousands of copies of the original virus. Viral populations do not grow by cell division, because they are acellular; they borrow the machinery and metabolism of the host and self-assemble inside it. The life cycle runs through six basic stages: attachment, penetration, uncoating, replication, assembly, and release. Attachment is a precise lock-and-key event. HIV infects only a narrow range of human leucocytes because its surface protein, gp120, binds the CD4 molecule found mostly on CD4+ T-cells. This specificity is what sets a virus's host range. Penetration follows, and the route depends on the host. Plant cells have rigid cellulose walls, so most viruses can enter only through a wound, though tobacco mosaic virus can also travel cell to cell through pores called plasmodesmata. Release can be violent or quiet. Lysis bursts the cell open, a feature of many bacterial and some animal viruses. Enveloped viruses such as HIV instead bud from the cell, wrapping themselves in a piece of the host's membrane on the way out. Some viruses choose patience. In the lysogenic cycle, the viral genome is stitched into a specific place in the host's chromosome, where it is called a provirus, or a prophage in bacteriophages. It sits mostly silent, copied every time the host divides, until some signal wakes it and it turns active again. The genomes driving all of this are astonishingly varied. As a group, viruses contain more structural genomic diversity than plants, animals, archaea, or bacteria combined.

• 5. Pandemics And Disease

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  The 1918 flu pandemic, which lasted into 1919, struck down healthy young adults rather than the usual juvenile, elderly, or weakened patients. Older estimates put its toll at 40-50 million people, while more recent research suggests as many as 100 million, around 5 percent of the world's population in 1918. It was a category 5 influenza pandemic driven by an unusually severe influenza A virus. During the 20th century, influenza caused four pandemics, with those of 1918, 1957, and 1968 the severe ones. HIV tells a slower story. It evolved from viruses found in monkeys and chimpanzees and has been pandemic since at least the 1980s, with most researchers placing its origin in sub-Saharan Africa during the 20th century. The Joint United Nations Programme on HIV/AIDS and the World Health Organization estimate AIDS has killed more than 25 million people since it was first recognised on the 5th of June 1981. An estimated 37.9 million people were living with the disease, and there were about 770,000 deaths from AIDS in 2018. Other viruses kill fast and frighten. The filoviruses, filament-like agents that cause viral hemorrhagic fever, include the ebolaviruses and marburgviruses. Marburg virus, first discovered in 1967, drew widespread press attention in April 2005 for an outbreak in Angola. Ebola virus disease has caused intermittent outbreaks with high mortality since it was first identified in 1976, the worst being the 2013-2016 West Africa epidemic. Coronaviruses brought the most recent shock. SARS had caused around 8,000 cases and 800 deaths by July 2003. A related virus, SARS-CoV-2, thought to have originated in bats, emerged in Wuhan, China in November 2019 and spread worldwide, causing the COVID-19 pandemic that began in 2020. Some viruses turn disease into cancer. Human papillomaviruses, hepatitis B and C, Epstein-Barr virus, and others are accepted causes of human cancers, and the most recently discovered, Merkel cell polyomavirus, causes most cases of a rare skin cancer called Merkel cell carcinoma.

• 6. The Body Fights Back

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  RNA interference is one of the body's oldest defences, and it begins with a molecular blade. When a virus that uses double-stranded RNA infects a cell, a protein complex called a dicer cuts that RNA into smaller pieces, and the RISC complex then degrades the viral messenger RNA. Rotaviruses dodge this by never fully uncoating, releasing their messenger RNA through pores while keeping their genome protected inside the core. The adaptive immune system answers with antibodies. IgM neutralises viruses powerfully but is made for only a few weeks, while IgG is produced indefinitely; the presence of IgM signals acute infection, and IgG marks an infection sometime in the past. A protein inside cells called TRIM21 can grab antibodies stuck to a virus particle and prime its destruction by the proteasome. Cell-mediated immunity adds a second front, where killer T cells destroy any host cell displaying a suspicious viral fragment. Some viruses slip past all of this. HIV evades the immune system by constantly changing the amino acid sequence of its surface proteins, a trick called escape mutation. When defence fails, medicine steps in. Vaccination is a cheap and effective way to prevent viral infection, and it predates the discovery of viruses themselves. Smallpox infections have been eradicated, and vaccines now exist for over thirteen human viral infections. The yellow fever vaccine, a live-attenuated strain called 17D, is described as probably the safest and most effective vaccine ever generated. Antiviral drugs attack replication directly. Many are nucleoside analogues, fake DNA building blocks that halt the genome's backbone, such as aciclovir for herpes simplex and lamivudine for HIV and hepatitis B. Aciclovir is one of the oldest and most frequently prescribed of these drugs.

• 7. Engines Of The Ocean

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  There are about ten million viruses in a teaspoon of seawater, and in the oceans bacteriophages outnumber bacteria by ten to one, reaching 250 million per millilitre. Most are bacteriophages infecting heterotrophic bacteria and cyanophages infecting cyanobacteria, and they are essential to regulating saltwater and freshwater ecosystems. They are mortality agents of phytoplankton, the base of the aquatic food chain, and one of the most important mechanisms of recycling carbon and cycling nutrients in marine environments. When viruses lyse bacteria, the organic molecules spilled from the dead cells feed fresh bacterial and algal growth, a process known as the viral shunt. Microorganisms make up more than 90 percent of the biomass in the sea, and viruses are estimated to kill roughly 20 percent of that biomass each day. The reach of marine viruses extends into the sky. In January 2018, scientists reported that 800 million viruses, mainly of marine origin, are deposited daily onto every square metre of the planet's surface, carried by an atmospheric stream circulating above the weather but below airline altitude. Viruses also feed and are fed upon. In December 2022, scientists reported the first observation of virovory in pond water containing chlorovirus; when other microbial food was removed, the ciliate Halteria grew in number by actively eating the virus.

• 8. Tools And Origins

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  Talimogene laherparepvec, or T-VEC, is a modified herpes simplex virus engineered to fight cancer. Scientists deleted a gene the virus needs to replicate in healthy cells and replaced it with a human gene, GM-CSF, that stimulates immunity. When T-VEC infects cancer cells it destroys them, and the GM-CSF draws in dendritic cells that present the dead cancer cells to the immune system. After successful clinical trials, the virus gained approval for treating melanoma in late 2015. Viruses reprogrammed this way are called oncolytic viruses. Beyond medicine, a materials scientist can regard a virus as an organic nanoparticle with a precisely defined size, shape, and surface chemistry. At the Naval Research Laboratory in Washington, D.C., researchers used Cowpea mosaic virus particles to amplify signals in DNA microarray sensors and as a nanoscale breadboard for molecular electronics. Where these particles came from remains unsettled. Three classical hypotheses compete. The regressive hypothesis holds that viruses were once small cells that parasitised larger ones and lost the genes they no longer needed, with rickettsia and chlamydia offered as living parallels. The cellular origin hypothesis proposes they escaped as bits of DNA or RNA, perhaps from plasmids or from transposons, the jumping genes that Barbara McClintock discovered in maize in 1950. The co-evolution or virus-first hypothesis suggests viruses arose alongside the first cells. Viruses are now recognised as ancient, with origins predating the split of life into its three domains, and it seems unlikely they all share a single ancestor. They remain one of the largest reservoirs of unexplored genetic diversity on Earth, which is one reason the first synthetic virus, built entirely from scratch, marked such a turn in the science.