By Kermit Pattison / Harvard Staff Writer
The octopus is a biological oddity. It can use tools, open jars, and its complex nervous system supports as many neurons as a small primate.
Now Harvard biologists have discovered a mysterious distinction in their core biology: some octopuses have an unusual adaptation in the protein-making machinery of their cells that helps ensure accuracy, perhaps an evolutionary byproduct of its acute sensory system.
In a study published July 29 in Current Biology, the researchers report the discovery of a structural aberration in the ribosome—the protein-manufacturing organelles of cells—that appears to be unique in the animal kingdom.
"This shows that the ribosome is actually an important part of the evolution of biological novelty across hundreds of millions of years," said Nicholas Bellono , Professor of Molecular and Cellular Biology (MCB) at Harvard University, one of the senior authors of the new study. "This opens a different way for people to think about the biochemical basis of comparative biology."
The finding began with an accidental observation in the lab. About five years ago, Richard Han, then a Ph.D. student at Harvard Medical School, was conducting some routine control experiments and extracting ribosomal RNA (rRNA) from tissues of the California two-spot octopus, known by the scientific name Octopus bimaculoides, a species native to the Pacific coast. Han worked in the lab of Amy Lee , assistant professor of Cancer Immunology and Virology at Dana-Farber Cancer Institute and assistant professor of Cell Biology at Harvard Medical School, which frequently collaborates with the Bellono team.
Normally, such sequences of rRNA remain uniform even among distantly-related animals. In fact, they are so predictable that lab scientists often use them as a quality controls to check if the material has degraded.
Then Han saw something unexpected. Instead of the normal single band, the octopus rRNA was split into two distinct fragments.
At first, the scientists assumed it was an error. But researchers repeated the experiment numerous times and kept finding the same break in the same spot. They saw the same thing in all octopus tissues at all developmental stages.
Ribosomes contain a common core set of rRNAs and proteins. Some of these elements are among the most evolutionarily-conserved RNA sequences known to biology and variation in the basic architecture of the ribosome is rare.
"The assumption was that this this doesn't change very much," said Lee, who specializes in how genetic code is translated into proteins. "That was the real surprise here."
Intrigued, the scientists continued digging deeper. Ultimately, the study expanded to 10 coauthors and stretched over about five years. They discovered that the shift appears to enhance the accuracy of protein synthesis and reduces errors that cause pathological aggregations of misfolded proteins. Rishav Mitra, a postdoc in the Bellono lab and co-lead author of the new paper, helped decipher the functional consequences of the shift and trace it across the species family tree.
When researchers inserted the same rRNA break into the ribosomes of E. coli, the bacteria produced proteins with twice their normal fidelity, or the accuracy of translating genetic code into proteins. The octopus ribosome adaptation appears to enhance the fidelity of protein synthesis, even when transplanted into very different creatures.
The researchers found the rRNA break was universal among shallow water octopuses (the suborder Incirrates) which diverged from their deep-water cousins (the Cirrates) about 100 million years ago.
The researchers obtained a sample of a deep sea octopus that had been collected many years ago. When they analyzed the tissue, they discovered the Cirrate octopus did not possess the same change in its ribosome.
Likewise, squid, which diverged from the octopus lineage about 300 million years ago, did not possess the same change.
The researchers suspect the newly-discovered adaptation may be tied to the evolution of the large octopus nervous system, including the acutely sensitive "taste by touch" sensory system of shallow water octopuses. Most of the 500 million octopus neurons are in the arms and single suction cup contains some 10,000 sensory cells.
Despite these advanced sensory capabilities, octopuses do not show much genetic novelty compared to other invertebrates. Instead, their nervous system is believed to arise from how widely-shared genes are regulated, or switched on and off.
Cephalopods (the taxonomic class of mollusks that includes octopus, squid and cuttlefish) are known to edit their RNA far more than other organisms, which allows them to use existing genes to adapt proteins to new functions. But this shift also increases the potential for errors, or "misfolding" of proteins and the formation of toxic clumps known as aggregates.
Bellono suggested that the newly-discovered feature of the ribosome might serve as a brake or filter to prevent this evolutionary innovation from running amok. "They have the ability to make many protein products from single genes, but the ribosome will only allow certain ones to be made," he said.
Similarly, Lee described the rRNA adaptation as "controlled plasticity for the genetic information."
"The major surprise is that the the ribosome, which is highly conserved across life, can actually undergo evolutionary changes that impact function," she said, "and may even contribute to new innovations—such as the more complex nervous system in the octopus."
Lee suggested that these discoveries about protein-making ribosomes might someday be pursued for potential therapies for protein-folding diseases. These diseases include neurodegenerative disorders such as Alzheimer's and Parkinson's diseases and occur when misfolded proteins lose their ability to function normally.
"What's really cool is that by looking into the natural world, we are potentially starting to identify these hot spots we could target to change function," she said.
