Over the course of evolution, immense megafauna have roamed the lands or swum in the seas. The growth of these creatures early in their life is typically quite rapid. It has to be. They need to grow fast or be eaten. Extensive studies on megafauna have addressed the unique challenges of supporting and moving such massive bodies. But the greatest and largely ignored obstacle to extreme growth for both terrestrial and aquatic megafauna may involve the rapid development of their nervous system.
Unlike all other cell types, neurons do not increase tissue volume by cell division but rather by expanding the volume of the cells themselves. Early in development, neurons sprout nerve fibers, or axons, that extend from their cell body—which houses the nucleus and other structures—by using chemical and physical cues to navigate and slowly grow toward target cells, typically no more than a few millimeters away. Once the target is reached, this well-studied first phase of axon growth culminates with formation of a junction with another neuron, known as a synapse.
But the growth and elongation of axons does not stop there. It continues by relying solely on mechanical forces that can extend the fibers at seemingly impossible rates. This poorly studied second phase, called “stretch growth,” continues as the distance between the neuronal cell bodies and their targets increases.
As a creature grows, axons engage in a tug-of-war contest. Tension from pulling on the rope-like axons threatens to rupture the fibers because they only stretch so far. Tautness is relieved by stretch growth that continuously adds length to axons. Mechanical stretching of the axons as a body grows is ubiquitous throughout nature and thought to drive the formation and organization of axon tracts that make up the white matter in the brain and spinal cord and peripheral nerves outside the brain. The growth of vertebrae during development stimulates the growth of axons in the spinal cord. Axons in peripheral nerves extend alongside the growing long bones and other rigid structures. Still, many mysteries remain about this process, and just how fast and far axons stretch in both terrestrial and aquatic megafauna has yet to be settled.
A Few Centimeters a Day
One obvious example of massive growth is the blue whale, which can reach colossal lengths of up to 30 meters at maturity. Using recorded measurements of the whale’s body length at different times during development, we previously calculated the peak stretch growth rate of axons that span the spinal cord as an astonishing 3.4 centimeters per day. This rate stands in marked contrast with those described in neuroscience textbooks. Indeed, a crucial axon building block called neurofilament protein moves down these nerve fibers at only up to a few millimeters each day. This approximately matches the extension rates of axons sprouting in culture and regenerating from injury, both of which add to cell volume at the ends of extending axons.
Even at this speed, it would still take years for proteins to complete the journey down the longest axons in maturing whales. Recent computational modeling analyses, however, suggest that the new proteins for axon stretch growth are extruded, or pushed out, from the neuron cell body so that they don’t have to make the increasingly longer trip to the end of the cell to extend axon length.
Even here, the pace of axon building in the blue whale seems impossible to maintain. Indeed, every 3-cm increase in axon length is calculated to add more than double the volume of the neuronal cell body to the axon each day.
Remarkably, this increase in size rivals the peak growth rate of aggressive cancer cells that double in number each day. In the blue whale, this process reaches astonishing proportions—spinal cord axons can extend 24 meters in length from brain stem to tail. Although axons are quite thin in diameter, such a long extension ultimately results in their volume being more than 1,000-fold greater than that of their cell bodies. This bizarre geometry of neurons with very long axons potentially represents one of the largest cells by volume for any mammal. For routine cellular maintenance, it is hard to imagine how the neuronal cell body can provide sufficient proteins and other cellular supplies for such a large axon volume that extends so far away from the cell body. It has been suggested that protein synthesis might occur along axons themselves to overcome the challenges in production and distribution, but we still have much to learn about this unusual cellular process.
Enter the Dinosaurs
Despite the many mysteries of its mechanisms, extreme axon stretch growth obviously works well for the immense blue whale. Yet while 3.4-cm-a-day axon growth is impressive, the blue whale has steep competition from other megafauna. Enter a dinosaur known as a sauropod, who in particular is thought to have had high growth rates in the first several years after hatching to avoid predation. Unlike the extensive documentation for the blue whale, however, scant fossil evidence exists to help calculate how the largest dinosaurs grew. Limited fossil clues from relatively large but not the most massive dinosaurs permit a rough estimation of body growth rates, including relatively complete fossils of the duck-billed dinosaur Maiasaura at different stages of development. Measurements show that it grew from a hatchling length of 0.5 m to slightly more than half of its adult length of 7 m in its first year of life. That’s about 3.6 m in the first year, or about 1 cm per day.
During this time, we know that Maiasaura had lines of arrested growth in its bones, indicating that it reached those 3.6 m in the first seven to nine months. If so, its daily growth rate would have been approximately 1.33 to 1.71 cm each day. Assuming its spinal axons grew at the same speed as well, that falls far short of the blue whale’s peak axonal growth rate.
But wait! Perhaps the recent discovery of a juvenile sauropod, Rapetosaurus krausei, puts dinosaurs back in the competition. This new find provides the missing link between previously studied hatchlings and 15-meter-long adult specimens of this species. Comparing differences in the lengths of the femur between a hatchling and a juvenile Rapetosaurus, the extrapolated growth in body length is estimated to be up to 2.7 cm per day during the first months of life. Notably, this time span appears to be prior to the animal’s first arrested growth period. As such, the average growth rate for the spinal cord axons matching body growth at 2.7 cm per day is competitive but still less than that for the blue whale, leaving the Rapetosaurus in a close second place.
Moving from examining full body length growth to a focus on axon growth in a rapidly extending neck could bring a new mammalian player into the competition. Prenatal giraffes have a relatively short neck, which is thought to protect them from injury during birth. Yet thereafter their neck can grow up to 2.5 cm each day. This suggests a similar rate of growth for their cervical spinal cord axons, which falls short of the blue whale and Rapetosaurus peak spinal axon growth rate. Still, a potential evolutionary mishap in the trajectory of a nerve in the neck may help the giraffe surge past the blue whale in the race for the most extreme axon stretch growth.
Following a direction that makes little anatomical sense, the giraffe’s left vagus nerve exits the brain stem and travels down the neck, where it splits off into the left recurrent laryngeal nerve. That in turn loops under the aortic arch, part of the large artery carrying blood from the heart, and then travels back up the neck to the vocal cords. During development, the axons in the animal’s left vagus and recurrent laryngeal nerve must grow roughly twice as fast as its neck does. This brings the growth rate of these axons to approximately 5 cm each day. So the giraffe appears to take the lead from the blue whale.
The Winner Is …
Hold on, the Rapetosaurus also had a long neck, which is thought to have had the same odd anatomical distribution of the recurrent laryngeal nerve as the giraffe’s neck, bringing the sauropod back into the contest. But with Rapetosaurus’s neck accounting for only about half the length of its body, even if we double the growth rate for the recurrent laryngeal nerve, we are back to approximately 2.7 cm per day. So in the final stretch, the winner is the giraffe—by a neck! At least that is the case for now. Other sauropod species were much larger than Rapetosaurus, and if they developed along the same time line, much more spectacular rates of axon growth may have occurred. That enticing possibility can only be explored by future research on the growth rates of the largest dinosaurs.
Humans may also soon enter the competition for the most extreme axon stretch growth. No, not by having people rapidly grow supersized necks and bodies, but by pushing the limits of axon growth in the laboratory. Indeed, extreme axon stretch growth of 1 cm a day has already been achieved in a lab dish using bioreactors that mimic nature by mechanically elongating axon tracts spanning two populations of neurons. Much faster rates of growth are thought to be possible as mechanisms of this otherwise mysterious form of axon growth are experimentally revealed. With this promising experimental work, as well as emerging understanding of rapid nervous system development in other species, the competition is far from over.
