Scientists Replicate Potential Step in Fin-to-Limb Transition in Zebrafish

A new study reports that by changing just a single gene in the zebrafish genetic code, researchers showed they could begin the creation of an entirely new set of bones and joints.

This image shows how mutant zebrafish transform their limbs to be close to human limbs. (Credit: M. Brent Hawkins)

(CN) — Experts can engineer zebrafish, well known for their regenerative abilities, to form an entirely new limb-like appendage — an amazing feat accomplished by tweaking just a single gene.

As early life on Earth evolved from single microscopic organisms to the wide host of creatures that walk, fly and swim on this planet today, few evolutionary leaps were as critical as the creation of the jointed limb. 

These appendages gave lifeforms the ability to thrive beyond the confines of the ocean, lending the gifts of flight to birds and gait to vertebrates and served as a crucial and quite literal stepping stone for new life to form on Earth.

Now, new research has shown that this evolutionary instinct still rests within the genetic code of at least one species of fish — and they have the limb to prove it.

In a new study published Thursday in Cell, researchers report they have found a way to genetically engineer zebrafish, a common aquarium fish widely hailed for their ability to regenerate their own cells, to create an entirely new limb made from bones and joints.

Experts say this extraordinary ability rests in two genes within the zebrafish, known as the vav2 and waslb genes. While these two genes have never been previously tied to researchers’ understanding of skeletal formation in fish, Thursday’s study reports that small changes to just one of these two genes can kickstart a process that causes a zebrafish to create an entirely new and functional limb for itself.

M. Brent Hawkins, first author of the study who recently earned a doctorate from Harvard’s Department of Organismic and Evolutionary Biology, said researchers came across these findings while screening for gene mutations among fish and they were stunned at what they uncovered.

“It was a little bit unbelievable that just one mutation was able to create completely new bones and joints,” Hawkins said in a statement. “In the 30,000 species of teleost fishes, none of them have this sort of variation, so the fact that we found a mutant like this really knocked us off our feet.”

Researchers report that after the genes have been changed, the mutation occurs within zebrafish’s pectoral fin bones known as the proximal radials, which attach to the fish’s shoulder. 

While zebrafish do not naturally come equipped with a skeletal makeup that work as joints, the mutation scientists have discovered results in zebrafish expressing a brand new set of long bones called intermediate radials. Once formed, they pair with the fish’s pre-existing proximal radials to create a new joint similar to the human elbow.

For such a complex process that results in an entirely new set of bones, researchers were shocked to discover what little effort it took to jumpstart the reaction.

“In this one mutation, you get the new bone, you make the joint, and you make the muscle attachments all in one go,” Matthew Harris, an associate professor of genetics at Harvard Medical School and Orthopedics at Boston Children’s Hospital, said. “You didn’t need to have a mutation in the muscle gene, a joint gene, and in the bone gene; the system is coordinated such that whatever our change is, it’s able to push all these things together in unison.”

Experts also report looking forward to seeing how these changes adjust fish movement patterns. With an entirely new limb to contend with, researchers say moving forward they want to study how — if at all — the mutation influences how the fish navigate and move once they are armed with a new appendage.

Researchers are optimistic that on top of being a simply fascinating discovery, this mutation could open up new pathways into our understanding of how fins evolved into limbs during Earth’s formative years. 

The results suggest that some species of fish may have never lost their latent ability to grow limbs and joints as evolutionary needs change, presenting a host of fresh questions for researchers to explore regarding how these instincts function and how they are triggered by genetic systems buried within DNA.

Harris says that with many of these questions left to be answered, there is no telling what other lessons these mutant fish can teach us in the long and often mysterious history of evolution on Earth.

“And for me, I’m left with ‘What can these mutants tell us about development and the ability to form complex structures,” Harris said. “It’s a great reminder that not all monsters are scary. If you look closely, sometimes they can actually tell you a lot about yourself.”

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