LIFE AS WE KNOW IT 

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The more we learn about life on Earth, the more one thing becomes clear: It's far stranger than we ever imagined. Organisms often behave in ways that clash with the typical rules of biology, sparking mysteries — and lessons — about the true nature of life and death.

DEFINING LIFE

From the tallest tree to the tiniest bacterium, all living things share some common ground. They're all made of cells, they all take in and use energy from their environment, they're all capable of reproducing themselves, and they all grow and evolve.

If something doesn't tick all those boxes, it's not considered a living organism. However, the world is teeming with minuscule things that aren't quite alive, but don't seem to be fully inert either. This microscopic menagerie can make scientists pause — and disagree — over how we even define life in the first place.

Viruses, for instance, are clearly capable of evolving: The COVID-19 pandemic's variant-led waves demon-strate the ever-changing mutability of SARS-CoV-2. But Nobel-winning immunologist Peter Medawar and author Jean Medawar wrote in 1977 that a virus is "simply a piece of bad news wrapped up in protein." While they can evolve, viruses lack other key traits present in even simple life-forms like bacteria, including a cellular makeup and an internal metabolism. "They can mimic life, but they're not alive," says Elodie Ghedin, a virologist with the National Institutes of Health.

Ghedin likens viruses to robots: They can't power themselves, and without an external spark to switch them on, they're inert. To express itself and replicate, a virus must be in the right place at the right time — namely, in contact with a receptive cell.

Once the virus breaches a cell, it harnesses its protein and hijacks the cell's ability to replicate. "Then that activates the whole rest of the process," says Ghedin. "There are virus proteins that get expressed, and those will bind with host proteins, and that triggers this domino effect of replicating a virus." The cell is doing the work, not the virus.

While viruses can't replicate on their own, the same is true for other biological units that are in fact considered life, thus breaking the general rule. Virologist David Bhella at the University of Glasgow in Scotland recalls that as a student, this inconsistency needled him. "This argument that a virus can't be alive because it has to replicate inside another cell really stuck out," Bhella says, "because there are lots of things that can't survive without replicating inside of another cell."

The parasitic bacteria Chlamydia, for instance, has to live inside a host cell. And from a broader view, we humans couldn't survive and reproduce without the many other living things in our environment, such as the plants that provide our food and the oxygen we breathe. Bhella has carried this line of questioning with him throughout his career, and even wrote an editorial in Microbiology Today in 2016 arguing that viruses should be considered living things. "The ability to replicate and evolve is one of the most parsimonious definitions of life," he says, and viruses certainly fit the bill on both fronts.

Anyone who's been infected with one of COVID's many variants can attest to viruses' capacity for evolving into evermore elusive forms. Delta and omicron are much more contagious than the original version of SARS- CoV-2 that began circulating in humans at the end of 2019; these newer variants are the result of errors in the virus's replication process that wound up being beneficial — to the virus, not to us. Within just three years of infecting humans, the collective iterations of SARS-CoV-2 have killed more than 6.8 million people around the world.

Over the past three decades, discoveries of (comparatively) giant viruses, the size of some bacteria and containing DNA and more complex structures than the simple "bad news wrapped in protein" model, have made the distinction between viruses and living things even blurrier. "It's such a fine line with the giant viruses," says Ghedin, "and I think that's why it's been a debate for so long."

Since viruses aren't alive to begin with, they can't really be killed. But heat or chemicals like bleach and the ubiquitous high-alcohol hand sanitizer can destroy their physical structures. "We're smashing them, basically," says Ghedin.

Other not-quite-alive things can't be so easily not-technically-killed. Some of the strangest — and deadliest — are prions. They're far tinier than viruses, but they pack a lot of punch. Prions are misfolded versions of a normal protein found across the mammal family. Simply being folded in the wrong shape causes neighboring proteins to do the same, in a sort of domino effect. These misfolded proteins destroy brain functions, resulting in fatal diseases like bovine spongiform encephalopathy (aka mad cow disease) and its human-infecting form, Creutzfeldt-Jakob.

People can get prion diseases from eating infected meat or from contamination during brain surgery or blood transfusion. These proteins can even be passed hereditarily, with rare diseases like fatal familial insomnia causing the inability to sleep and deadly dementia. Scariest of all, they remain stable in the environment for decades, waiting for an unsuspecting organism to infect.

"Prions are not alive, by any stretch of the definition," says Mark Zabel, a prion researcher at Colorado State University. But they push the limits of how scientists understand the transmission of biological instructions. Amid all this blurriness, prions and viruses help illustrate one thing that is clear: Nature abhors a hard and fast rule.

The bacteria Chlamydia, illustrated here as red and green balls, relies on a host cell in order to L replicate.

Prions, which are smaller than viruses, can cause mad cow disease and other fatal brain disorders.

3 LIFE-DEFYING ORGANISMS

Shark Bay, in Western — Australia, is home to impressive marine life, including this 4,500-year-old seagrass meadow.

THE WORLD'S BIGGEST PLANT IS A CLONE

1 At first glance, the seagrass in Western Australia's Shark Bay appears to be thousands of separate patches and meadows. But research published just last year revealed the Shark Bay seagrass, stretching over an area the size of Cincinnati, is just one individual plant — connected in many places by stems under the sand called rhizomes, and in other spots by genetic code alone.

"It's pretty mind-blowing," says Elizabeth Sinclair, a biologist at the University of Western Australia. When Sinclair and her colleagues analyzed the DNA of seagrass samples from different meadows across the bay, they found nearly identical genetic coding. They realized that the seagrass has been cloning itself for the past 4,500 years, resulting in the largest plant — in the world, based on surface area.

Grasses spread by sending out shoots called runners, Sinclair explains. "You can't always see them because they might be buried," she says, but "they just keep expanding, and they put down new roots, and a new shoot grows up." This creates a dizzyingly complex network. Even if the runners get severed, the two sections are still genetically identical, like when you take a cutting of a plant.

The disconnected sections of the Shark Bay seagrass continue cloning themselves, resulting in a sort of thought puzzle: Even if the seagrass meadows lose their physical connection, does their genetic identity mean they still count as one biological individual? And if the clonal seagrass counts as one organism, then does the same logic hold for all clones? For now, science offers more musings than answers.

HOW TARDIGRADES CHEAT DEATH

2 Of all the weird, tiny organisms out there, tardigrades might be the cutest. "Under a microscope, what you would see is this little critter that kind of looks like either an eight-legged Gummi bear, or an eight- legged manatee," says Thomas Boothby, a molecular biologist at the University of Wyoming. To top it off, these lovable micro-animals are known colloquially as water bears or moss piglets.

Despite their cuddly appearances, tardigrades are tough. "They can survive just about any sort of environmental stress that you could throw at them," says Boothby. That includes the crushing pressure of the ocean floor, the DNA-shredding powers of radiation, the vacuum of space and even temperatures just 1 degree above absolute zero (the temperature at which molecular motion ceases).

Scientists like Boothby are attempting to get to the bottom of tardigrades' death-defying hardiness. Boothby's lab focuses on how tardigrades can survive the evaporation of all the water in their cells by curling up and suspending their metabolic processes, essentially just hitting the "pause" button on life until they're reunited with water. One of the secrets that Boothby and his colleagues have found involves a special, flexible protein in tardigrades that doesn't break when damaged, perhaps via freezing or drying out. What's more, when the genes to create this protein are put into another organism like a yeast or bacteria, that organism takes on the tardigrade's drying-resistant superpowers.

Boothby says that tardigrade cells' ability to survive desiccation could be the key to stabilizing vaccines and pharmaceuticals so that they can be stored at room temperature, instead of relying on fridges and freezers. With any luck, tardigrades' legendary durability will make it a little easier for humans to survive, too.

The water bear is one of the most resilient creatures known on Earth (and in space).

THE SECRETS OF IMMORTAL JELLYFISH

3 At first, the tiny Turritopsis dohrnii jellyfish progresses through its life cycle predictably: It matures from a free-swimming larva to a polyp stuck to the seafloor of its Mediterranean home, awaiting the next stage of its life. Eventually, it transforms into an adult medusa, trailing delicate tentacles from its bell, still only the size of a lentil. But once it's done being an adult, instead of dying, it does something extraordinary: It reverts back into a polyp. From there, it switches back and forth from polyp to medusa ad infinitum. This immunity to old age has earned T. dohrnii the nickname "immortal jellyfish." (Though they still can die from infections or, say, getting slurped up by fishes.)

In 2022, researchers published a comparison of the genes of immortal and mortal jellyfish to see what makes the immortal ones so special. They found that the immortal jellyfish had extra copies of some genes associated with the aging process, including ones relating to DNA repair. The modifications and backup copies suggest that these genes are crucial to the jellyfish's ability to rejuvenate.

Maria Pascual Torner, a scientist at the Universidad de Oviedo in Spain and the study's lead author, cautions that these jellyfish aren't our ticket to immortality. However, they could give us "a better understanding of healthy aging and pathologies associated with aging such as cancer or neurodegenerative disease." In the meantime, they complicate our picture of what it means to live and die — and, as Pascual Torner notes, "the understanding of life, like the understanding of nature, is always complex."

Rather than deteriorate and die, this tiny jellyfish reverts back to its infant stage as it ages.

Q+A

WITH MERLIN SHELDRAKE

Sheldrake's debut book, Entangled Life (Random House, 2020), investigates how fungi shape the living world around us — and even within our own bodies.

Merlin Sheldrake eyes his book-turned- fungi-garden.

Author and biologist Merlin Sheldrake knows fungi inside and out — he even used a copy of his book Entangled Life as a breeding ground for oyster mushrooms, which he cooked up and ate. In that 2020 bestselling work, Sheldrake explores the nature of fungi, from their underground, interconnected mycelial webs to their mushrooms, which can range from psychedelic to deadly. Fungi, which occupy a kingdom of life separate from plants and animals, tend to break a lot of rules about how we think about individual organisms, evolution and even life itself. Here are some of Sheldrake's thoughts, both biological and philosophical, on what that means for our understanding of the world.

Q ln your book, you explore how fungi and lichens [which are made up of fungi living in symbiosis with organisms like algae that can perform photosynthesis] thrive on interconnectedness. But we're often taught that evolution is more of a dog-eat-dog world. How do these organisms challenge or reframe the concept of evolutionary competition?

MS: Traditionally, evolution was seen as unmitigated conflict or competition, which mirrored views of human social progress within an industrial capitalist system. But I think of life as collaboration, and collaboration is a blend of cooperation and competition. That view has arisen partly through the study of fungi and lichens, which coaxed modern scientists into thinking more about how organisms cooperate with one another.

Q All that interconnected- ness and cooperation begs the question, how do fungi push the limits on how we think about one individual organism?

MS: The way that we've come to think about life as made up of autonomous individuals marching about according to their needs and definable purposes is a pretty old-school, out-of-date model. It doesn't pay enough attention to the relationships between organisms. Fungi play games with individuality on so many levels. You can take a fragment of a mycelial network, it will regenerate into a whole new network, and that network will fuse with the original network again. The nuclei within fungal networks can move around the network; they don't have such bounded cells as we do. They stretch the limits of what we, in our human-centered view, tend to think of as life.

Q Fungi are associated with decomposition; they occupy a liminal space on the border of life and death, surviving because they eat dead things. Of course, so do we, but they're on the front lines. What do fungi reveal about the connection between life and death?

MS: They make it very clear that life can only be life with death. We think about life and death as two distinct things, but they're coupled in a kind of cycle. If the composers [that is, all living plants and animals] didn't decompose, then the composers wouldn't have anything to compose with.

Q Humans seem to be in a constant battle for individual resources; meanwhile, so many species are going extinct and a climate crisis is unfolding before our eyes. What lessons from fungi might help us out?

MS: They're fundamentally interconnected organisms and make very vivid the dense networks of interaction and connection that make life happen. They teach us about indeterminacy and open-endedness, that organisms aren't things, they're processes unfolding in time. Mycelial networks are always growing in this open-ended, unpredictable way. They teach about the limits of rigid categorization — their taxonomy is in constant flux, and they're confusing, and they confuse the scientists who try to order them. And one more thing I think is very important: They teach about the importance of what lies beneath, what's hidden. These organisms are experiencing their lives in ways that we can't see with our naked eyes, but nonetheless which shape the whole planet.

Q You famously (and literally) ate your words, cultivating and then cooking oyster mushrooms grown from a copy of your book. How'd they taste?

MS: Perfectly fine! Maybe they didn't taste as rich and meaty as they might have done if they'd grown on a log, but I was pleasantly surprised.

This interview has been edited for length and clarity.

Oyster mushrooms are just one of many fungi species with edible fruiting bodies.

LIFE CYCLE OF A COMMON MUSHROOM

Formation of vertical hyphae that will form new mushrooms

Fusion of the two cells of different mycelia

Two hyphae of mycelium get in touch

Mycelium: a rootlike set of fungus hyphae

INTERCONNECTED

THE TRICKY BOUNDARIES BETWEEN ONE LIVING THING AND ANOTHER

In 1674, Anton van Leeuwenhoek became the first person to set eyes on living cells, and revealed that there's an entire microscopic world right under our noses — sometimes literally. In 1683, when examining plaque from people's teeth, he reported finding "with great wonder, that in the said matter there were many very little living animalcules, very prettily a-moving." Unwittingly, he had become one of the first people in the world to document the human microbiome: millions of microbial organisms living on and in our bodies.

In more recent years, scientists have discovered just how much of our bodies are made up of microbes. There are about 30 trillion human cells in your body, and about 39 trillion microbial cells. By pure numbers, we're more microbe than not.

These microbes, which are themselves living organisms such as bacteria, aren't just hitching a ride. They're providing key services that we can't perform on our own.

For instance, take the amino-acid- processing microbes in our gut. Amino acids are the building blocks of proteins, and our bodies aren't capable of producing all of them that we need. But bacteria can provide access to essential amino acids. Our microbiome "releases these building blocks that our body can then absorb and use for different purposes," says Holly Lutz, a postdoctoral researcher at Scripps Research in La Jolla, California.

Once jailbroken by our microbiome, these amino acids are able to link together and fold into 3D protein chains that form body tissues and enzymes that carry out biochemical processes we need to survive. The microbes in our gut also contribute to our immune responses and prevent colonization by potentially harmful bacteria. "They're an ecological factor that is most intimately connected to that host, and it's one that we've overlooked in many ways," says Lutz.

Without these trillions of microbes, we would not survive — or at least, we would fail to thrive. As this biological realm comes into view on the microscopic level, it can challenge the traditional notion of life as an individual and independent organism. "It's disorienting to realize that each of us is this motile colony of cells from a lot of different places," says Ellen Clarke, a philosopher who focuses on biology at the University of Leeds in England. "I don't think it undermines our unity. It just means that you've got to be a bit more careful about understanding the basis of that unity."

This more nuanced view of an individual organism as a discrete living unit whose existence is interwoven with other forms of life is known in biology as the holobiont concept. It has been applied not only to organisms and their microbiomes, but also to parasites that can't survive outside their hosts, to colonial organisms like corals, and even to entire ecosystems. To paraphrase the words of English poet John Donne, written half a century before Leeuwenhoek first saw his animalcules: no man, and no microbe, is an island.

The farther you zoom into a human body, the more you encounter a web of living organisms.

ZOMBIE GENES AND RESURRECTED CELLS: THE RESEARCH THAT'S REDEFINING DEATH

The boundary between life and death, for many of us, seems stark. You're either alive, or you're dead, right? Turns out, even when our hearts cease to pump and our brains' electrical signals fizzle out, other elements of our bodies flicker to life.

New research is even finding ways to resurrect cells that have ceased to function.

In 2016, scientists first published an accidental and shocking discovery: Some genes in zebrafish become active after death. What began as a novelty that rattled the scientific community has since been demonstrated in numerous studies with different animals — including humans. In 2022, researchers examining human brain tissues showed that after death, some of the genes in our brains activate.

"A large number of genes were shooting through the roof and growing during this simulated postmortem interval," says Jeffrey Loeb, a neurologist at the University of Illinois Chicago who had expected to see most of the brain's activities shutting down after a few hours.

Loeb and his colleagues found that the brain's anti-inflammatory glial cells were "not only coming alive, but producing these monstrous tentacles." While that might sound like something out of a horror film, Loeb points to a logical explanation. "Basically, what we think they're doing is they're cleaning up," he says. "If you have an injury in your brain, these are the cells that come in" and remove debris. Apparently, they just don't discern between a manageable injury and deadly trauma that shuts down the body's systems.

These "zombie" genes are a quirk of nature, a testament to how life isn't just a switch that gets flipped on or off, with every cell capitulating instantaneously. However, some researchers have found artificial ways to intervene in the process of death. Such scientific pursuits date back to at least the 1880s, when a team got a frog's heart to beat outside of its body, leading to the development of saline solutions that help patients with low blood pressure or dehydration today. In a 2022 study published in Nature, scientists took the field further, restoring some signs of life in dead pigs.

The researchers achieved this by hooking up recently deceased pigs to a machine called the OrganEx, which kept vital organs functioning. They then mixed the animals' blood with a fluid rich in vitamins and amino acids. The combination of OrganEx and the synthetic blood helped restore circulation and even functionality to cells in the pigs' brains, hearts, kidneys and livers. This was an hour after the animals had died.

David Andrijevic, a neuroscientist at the Yale School of Medicine who co-led the study, notes that the language describing what happened is important. "We did not bring pigs back to life, nor did we make zombie pigs. It's just, we restored cellular function," Andrijevic says.

The authors say they aren't aiming to find a cure for death, but to extend the viability of transplant organs. Essentially, their breakthrough could help provide medical treatment for the living by prolonging cell function in donated organs that need to reach faraway recipients. "The implications in transplants would be huge," says Andrijevic.

Scientists first found genes firing post-death in zebrafish. Humans also have these "zombie" genes.

Last year, a team of researchers revived cellular activity in the organs of pigs one hour after death.