The molecular building blocks that make up the cells of humans, animals and plants so sophisticated appear to be older than scientists previously assumed. They were already present in our single-celled ancestor that lived 2.5 billion years ago. That is the conclusion of Wageningen and American researchers in two studies published in Nature and Nature Microbiology.
Our single-celled ancestor lived in a world without plants, animals or oxygen-rich oceans. Yet, this seemingly simple microorganism took the first steps towards complex life. From this ancestor emerged all multicellular (complex) life as we know it today: from yeast to blue wales, collectively known as eukaryotes. These organisms are built from cells containing specialised structures, such as a nucleus and other specialised structures, each performing distinct functions. For a long time, scientists assumed that the unicellular ancestor itself was relatively simple: a bacterium-like primitive cell, far removed from the sophistication of human cells. The new research paints a different picture. Our microbial ancestor may already have possessed a surprisingly extensive molecular toolkit.
Distant cousins
Because no one can travel back to the moment when our microbial ancestor lived, the researchers had to take a different approach. Thijs Ettema, Professor of Microbiology at Wageningen University & Research and co-author of both publications, explains: "We study the two groups of organisms that descend from the same common ancestor." On one side are the eukaryotes, including humans, animals and fungi. On the other are the Asgard archaea: single-celled micro-organisms discovered only a decade ago in deep-sea sediments. Since both lineages share a common ancestry, Asgard archaea and humans can be considered distant evolutionary cousins. Shared genetic information we therefore, most likely, inherited from our single-celled common ancestor.
The researchers collected genetic material from over four hundred different Asgard archaea from the Bohai Sea in China and the Gulf of California and read their genetic information. Based on DNA sequences alone, the similarity with eukaryotes appeared limited. This is not surprising: both groups have undergone roughly two billion years of evolution, during which their DNA gradually changed. The researchers therefore shifted their focus from DNA to proteins, the molecular machines encoded by DNA that carry out the work inside cells. "Specifically, we focussed on protein structure", says Ettema.
"Our microbial ancestor possessed a more extensive eukaryotic toolkit than we previously assumed"
- Thijs Ettema
- Professor of Microbiology
Comparing protein structures
Each protein folds into a specific three-dimensional structure; that shape determines its function. Such protein structures tend to change far more slowly during evolution than DNA sequences. Using artificial intelligence tools such as AlphaFold, the researchers predicted the 3D structures of more than 35 thousand Asgard archaeal proteins and compared them with proteins found in eukaryotes. The result? Asgard archaea contain around 1,300 proteins previously thought to exist exclusively in eukaryotes. These are proteins involved in processes such as intracellular transport and storage, and in forming cellular compartments - hallmarks of complex cells in humans and other eukaryotes. Because these proteins occur in both evolutionary lineages, they were most likely inherited from their shared ancestor. "This means that our microbial ancestor possessed a more extensive eukaryotic toolkit than we previously assumed," says Ettema.
This is now cautiously supported by observations under the microscope. Cultivating Asgard archaea in the laboratory remains challenging, Ettema explains: they naturally inhabit oxygen-poor environments, grow extremely slowly and sometimes take weeks to divide just once. Nevertheless, researchers are increasingly succeeding in growing them in controlled conditions. Microscopy studies reveal that some species display unexpected structural features, including tentacle-like protrusions used for movement, as well as internal vesicles and membranes reminiscent of the compartments found in eukaryotic cells.
Adapting to oxygen
The picture is also shifting in another respect. Until recently, Asgard archaea had only been found in oxygen-free environments such as deep-sea sediments. In the new Nature study, however, researchers identified Asgard archaea living in oxygen-rich environments, with genes in their DNA involved in oxygen processing. "These microbes have adapted to cope with oxygen," says Ettema. For the earliest organisms on Earth, oxygen was toxic. "Some Asgard archaea may even be able to respire oxygen to generate energy."
It remains unclear, however, whether this capability was inherited from their shared ancestor or acquired independently over the past two billion years. Eukaryotes use a different mechanism to produce energy with oxygen: mitochondria. These 'powerhouses' of the cell originated from once free-living bacteria and contain their own DNA, including genes involved in respiration.
A technological revolution
Shortly after Ettema and his colleagues discovered the Asgard archaea, ten years ago, they already noticed similarities with eukaryotes. However, at the time evidence was limited. "We had genetic information from only a single Asgard archaeon," says Ettema. "We identified genes that somewhat resembled those of more complex life forms such as humans, animals and plants, but the similarity was not extremely convincing." Simply put: there was a great deal of uncertainty. Rapid technological advances in DNA sequencing and AI-driven protein structure prediction over the past decade have now enabled far more comprehensive analyses. Ettema and his collaborators seized this opportunity, confirming the intuition they had a decade earlier.
Exactly what our single-celled ancestor looked like and whether the ancient proteins performed the same function in our single-celled ancestor as they do in eukaryotes remains an open question for now. But there seems to be no denying that this distant ancestor already had the potential to develop into the complex cells that make up our bodies.
