A Blog by Ed Yong

Half a Billion Years of Suicide

For us to live, parts of us must die. Every day, billions of our cells shrink, break up into small parcels, and get tidied away by other janitorial cells. This gentle, organised cellular suicide is called apoptosis, and we depend upon it. Our hands start off as solid lumps; it’s apoptosis that sculpts our fingers by killing off the cells in between them. Now and then, our cells threaten to grow out of control; it’s apoptosis that stops them from becoming tumours.

There are many ways of triggering apoptosis, and one route involves two large groups of proteins: the tumour necrosis factors (TNFs), and the receptors that they stick to. When they meet, they set off a chain reaction inside the cell. A large network of proteins is recruited, united, and activated, until the cell eventually dies. Think of TNF as a key twisting in the lock of a door, triggering a Rube-Goldberg machine that ends with the entire room catching fire.

Now, Steven Quistad from San Diego State University has discovered that corals—small tentacle animals that build mighty reefs—have their own TNFs and TNF receptors. Compared to our versions, these coral proteins are made of slightly different building blocks, but they fold into very similar three-dimensional shapes.

In fact, these shapes are so similar that the coral proteins are interchangeable with ours. A coral TNF can persuade our cells to kill themselves by sticking to our receptors. Likewise, human TNFs can kill coral cells by sticking to their receptors. We last shared a common ancestor with corals around 550 million years ago. Our respective lineages have been diverging ever since but our keys fit in their locks, and vice versa.

“[That’s] amazing”, says Marymegan Daly from Ohio State University. “I think this highlights that at some level, animal cells are animal cells. The differences among animals are in the ways that the cells are organized rather than in how they work.”

Quistad made his discovery after analysing the recently sequenced genome of Acropora digitifera, a coral that looks like a mound of miniature Christmas trees. And to his surprise, he didn’t just find TNFs, he found lots of them. We have genes for 18 different TNFs and 29 corresponding receptors, and the coral has a similar number—13 TNFs and 40 receptors. “That’s more receptors than anyone had ever seen in any organism,” says Quistad.

And why is that surprising? Because “they were expected to have just one,” he says.

Two of the animals that biologists have studied most intensely—the fruit fly and the nematode worm—have just one TNF and one TNF receptor each. Based on this, biologists deduced that ancestral animals were similarly poorly stocked. In back-boned animals, this lone pair of proteins diversified into the big families that we humans possess.

But the corals refute this story of simple beginnings. They belong to one of the earliest animal groups—the cnidarians. They’re even more ancient than the last common ancestor of humans, flies and worms. If they have a large number of TNFs and TNF receptors, that must have been the initial status quo. Flies and worms then lost the vast majority of this original diversity. Corals and humans kept and perhaps even expanded upon that old repertoire, but all the while keeping the same lock-and-key interactions. After all, apoptosis is so important for so many aspects of our lives that it is not easily tweaked.

Could corals and humans have evolved our TNF families independently? It’s unlikely, given how compatible the two proteins are. The fact that coral TNFs can kill human cells points to a shared ancestry—and a very deep one to boot.

“This is part of a really cool shift that’s happening in evolutionary biology,” says Quistad. “We’ve learned a lot from flies and worms, but they have led us to these erroneous conclusions about the evolution of all animal life. The assumption has been that older things should be simpler. If we saw something in flies and worms, it should be even simpler in a more ancient organism like a coral. But corals are actually more similar to humans in multiple ways, and flies and worms turn out to be very strange animals.”

Quistad’s work adds to the evidence that the machinery for apoptosis is at least half a billion years old, dating back to the origin of many of the animal groups we know today. “These main players in the immune system were already there, and everything has been tinkered with since that time,” he says.

Thomas Bosch from the University of Kiel notes that other scientists have already found proteins involved in apoptosis in cnidarians. For example, in 1999, Charles David and Angelika Böttger found caspases in a green, tentacled cnidarian called Hydra. If TNFs help to set cells down the road to death, caspases are the executioners that actually carry out the sentence. “Programmed cell death was one of the key inventions in the evolution of animal multicellularity,” says Bosch.

Coral reefs around the world are in decline, and a third of reef-building corals are in danger of extinction. If they vanish, countless species would disappear too, and coastal communities would suffer a huge economic blow. But we’d also lose valuable clues about the origins of the animal kingdom. These ancient and supposedly simple creatures can give us insights about the origins of the animal kingdom, in ways that more familiar workhorses like flies and worms cannot. “Corals have a lot more to teach us about how our own immune systems work and where they came from,” says Quistad.

Reference: Quistad, Stotland, Barott, Smurthwaite, Hilton, Grasis, Wolkowicz & Rohwer. 2014. Evolution of TNF-induced apoptosis reveals 550 My of functional conservation. PNAS http://dx.doi.org/10.1073/pnas.1405912111

More on corals:

6 thoughts on “Half a Billion Years of Suicide

  1. Interesting! But one thing I don’t understand. If this is indeed a case of conserved biology, where the proteins in question have been handed down through the generations for millions of years, shouldn’t there be a lot of other animals whose TNF proteins and receptors work with ours?

  2. Just imagine if this coral can be used in the fight against Cancer, And we are poisoning the environment so bad that they may go extinct! It reminds me of the Sean Connery movie “Medicine Man”. Where he is a doctor working in the rain forest and accidentally discovers the cure for Cancer, But a company building a road through the middle of the rain forest is in such a hurry that they destroy the one single species of Ant that lives in the forest canopy and in doing so they destroy the very cure for Cancer because of their short sightedness.
    Very close to what we are doing to the whole planet unless we start fixing these problems, And very soon!!!
    Keep up the good work guys, And Thank You National Geographic.

  3. Ken, I wouldn’t be surprised if we find that they do, when we test them.

    In fact that would be a reasonable next experimental step in testing the hypothesis.

  4. Ken, I agree with Amphiox one of the the next steps is testing this hypothesis using a broad range of organisms from a variety of phyla. One exciting thing with coral is we only looked at 1 of their TNFs, but they have 13 others that still require elucidation!

  5. Great comment, Dwayne. I’ll check out that movie. Certainly, would that not surprise you if this was the case? We stumble upon cancer’s eradication, but we alone are the ones who prevent its use.

  6. I’m always shocked by how biased some most of my fellow biologists seem to be when it comes to the “basal” animals. Of course modern cnidarians can be genetically complex. The phylum may be around 600 million years old, but the genus is only about 6 million years old. That’s a lot of time for a complex genome to evolve.

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