TAKE a walk in the woods and what do you see? Trees reaching skywards with birds in their branches and, at their roots, mushrooms pushing through the leaf litter. These, and all the organisms you can see with the naked eye, have one fundamental similarity. Like us, they are constructed from the same kind of cell. Under the microscope, the differences between plants, animals and fungi fall away to reveal a common internal structure.
The biosphere would be unimaginably different had this “eukaryotic” cell never evolved, making its origin one of the most critical events in the development of life on Earth. Almost everybody agrees that the complex eukaryotic cell evolved from a simple ancestor. The question is how.
Inside the eukaryotic cell is an intricate meshwork of membranes called the endoplasmic reticulum (ER), interspersed with other structures such as the energy-generating mitochondria. At the core is the nucleus, a large compartment with a double membrane, within which lies the cell’s genetic material. Take away this type of cellular organisation and the only thing left on the planet would be simple cells known as prokaryotes – bacteria, for example – which under a microscope appear as little more than tiny gel-filled sacs.
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Biologists have always assumed that the eukaryotic cell evolved when a prokaryote folded parts of its outer membrane inwards, pinching off portions to generate internal compartments (see diagram). Some membranes, it is imagined, wrapped around the DNA to make the membrane of the nucleus, while others morphed into the ER. And at some time during this process, free-living bacteria are thought to have been engulfed by the rest of the cell in a process akin to swallowing, called phagocytosis. These bacteria went on to become mitochondria. While lots of variants of this model have been developed over the years, all make the implicit assumption that eukaryotes evolved from the outside in – by pulling pieces of external membrane and mitochondria into the cell.
We think this is the wrong way round. In a recent paper, we propose instead that eukaryotic cells evolved from the inside out – that a prokaryote extruded blebs of outer membrane through its cell wall, and these fused to form the peripheral parts of the eukaryotic cell that contain the ER and mitochondria (). Like the famous , when the eukaryotic cell is viewed afresh from this perspective, many things look different. Now the outer membrane of the eukaryotic cell is an evolutionary novelty, while the nuclear envelope corresponds to the boundary of the original prokaryotic ancestor – the opposite of what is assumed by traditional hypotheses.
Although our inside-out model was published last year, the idea was born some 30 years ago when David was studying botany at the University of Oxford. Looking at an image of a large eukaryotic cell next to a much smaller prokaryotic cell, David wondered why it was always assumed that the boundaries of the two types of cell were equivalent, when it was easy enough to imagine that the prokaryote cell corresponded to the nucleus of the eukaryote. His essay on the topic, written in 1984, described this basic idea. While it got a respectable mark, it did not seem very compelling at the time. For a start, no prokaryote was then known to extrude membrane outwards. David sat on the idea, always thinking that somebody else would come forward with the concept, and his research turned in other directions.
Thirty years later, when David started to think again about the origin and early evolution of life, he was surprised to see that, in the interim, nobody had suggested that complex cells arose in this way. Perhaps it required the naiveté of an undergraduate to question dogma? So David dusted off his inside-out model and wrote up a short piece to explain how it might work and why it ought to be considered as an alternative explanation for the origin of eukaryotes. And it was much more compelling now it is known that the prokaryotes most closely related to eukaryotes, the archaea, often produce extracellular protrusions. As well as friends and colleagues, David sent the essay to his cousin, Buzz.
“We think complex cells evolved from the inside out, not the outside in”
As a cell biologist working with yeast, flies and human cells, Buzz had long grown accustomed to staring at the elaborate internal structure of eukaryotes but had never heard a convincing explanation for the origin of this dazzling complexity. Maybe the inside-out model could shed light on this, and on other puzzling features of modern eukaryotes too.
We started exchanging drawings made in snatched moments, on napkins and loose sheets of paper, on buses, planes and trains. Looking at these sketches, answers to some unexplained aspects of eukaryotic cell biology seemed to jump off the page: for instance, the model explained why the ER is directly linked to the bounding membrane of the nucleus, and why they both contain chemicals similar to archaeal cell wall components.
Echoes of the past
The success of this way of thinking got us wondering whether modern cells retain any echoes of their past in the way they work. By thinking about the way cells grew and divided as they evolved into modern eukaryotes, we were able to make some startling predictions for various aspects of cell biology that are currently poorly understood. For instance, the inside-out model suggests a role for the ER in determining the pattern of diffusion of molecules within cells, and predicts functions for several unstudied proteins in archaea.
To test these predictions, Buzz and his students have begun examining the dynamics of diffusion within eukaryotic cells. They will also look at proteins that are shared by eukaryotes and archaea to test their functions and locations within archaeal cells, something that will require overcoming the technical challenge of imaging these cells in sulphuric acid solution at 76 °C, their preferred growth conditions. Meanwhile, David is using computational analysis of various genes to test competing ideas about how the ancestors of mitochondria made a living.
Regardless of whether the inside-out view prevails, testing these ideas will provide a better understanding of how eukaryotes came to be. This may help to explain why eukaryotes evolved just once on Earth and, in so doing, will shape our expectations as to whether other planets might, in addition to microscopic prokaryote-like cells, harbour large and complex organisms such as those that make life on Earth so enchanting.
This article appeared in print under the headline “The world in a cell”
