Hammarlund had a hunch about how they did it, and how those changes might have incidentally unlocked animals’ morphological freedom. To prove it, she needed Påhlman’s help. In particular, she needed his knowledge of stem cells and cancer.

Their hypothesis is that the evolution of the capacity to maintain undifferentiated cells — even when those cells were exposed to higher levels of oxygen — allowed animals to keep stocks of stem cells for tissue growth and repair. That capacity, in turn, made it possible for animals to become more complex and diversify.

Stem cells have a “pluripotent” ability to give rise to the other cell types that make up healthy tissues. Throughout life, they play a crucial part in the regeneration and repair of tissues. Scientists are still trying to find out what enables stem cells to maintain their pluripotent, undifferentiated state when other cells cannot.

One factor researchers have identified is oxygen: The cells require low oxygen levels to remain in their stem states. Experiments have illustrated that exposing stem cells to greater amounts of oxygen usually causes them to differentiate abruptly. This observation explains why stem cells are so often sequestered in regions of the body like the bone marrow, where oxygen levels are relatively low (hypoxic).

But there are exceptions to this rule: Stem cells also reside in more oxygen-rich niches, such as the retina and the skin. Cancers have stem cells, too, which help drive a tumor’s formation and growth, and those cells are resilient in the face of oxygen. Påhlman and Hammarlund figured that if they could determine how our bodies and malignancies preserve those stem cells despite the oxygen, they might be able to explain how early animals solved their own oxygen problems millions of years ago.

So they focused on a family of proteins called hypoxia-inducible factors (HIFs), chief among them the protein HIF-2α. Its activity is heavily implicated in cancers of the kidneys and the sympathetic nervous system (including the neuroblastomas that Påhlman studies).

The HIFs help modulate how cells react to different oxygen conditions. When oxygen is low, cells activate HIFs to shift their metabolisms from aerobic to anaerobic and to start other processes that keep the cells alive; when oxygen is high, the HIFs are no longer needed and get degraded. But HIF-2α remains active in some tumors even during oxygenation, according to Påhlman, and it helps the cells act as if they’re experiencing hypoxic conditions when they aren’t. Take neuroblastoma cells, he said: Suppressing HIF-2α in the stemlike cells causes them to differentiate, suggesting that the protein is part of what keeps cancer stem cells in an immature state in the presence of oxygen.

Hammarlund and Påhlman then took a leap: They posited that HIF-2α functions similarly in normal animal tissues. They’ve seen some preliminary evidence of this in the skin and the sympathetic nervous system (knocking out the protein in the latter interferes with its development), but further experiments are needed to confirm the idea.

A New Freedom of Form

Next Hammarlund set out to unpack how HIFs might have factored into the evolutionary story of the Cambrian explosion. Picture a blob of ancient animal cells in which HIFs hadn’t yet evolved. The distribution of oxygen within the blob would have dictated that stem cells could hide only at the blob’s center, safely away from oxygen, while differentiated cells filled the more oxygenated periphery. All would be well, so long as the oxygen in the organism’s environment remained stable. But any shift in the oxygen level around the multicellular blob would change the oxygen gradient within it as well.

Hammarlund then considered HIF-1α, the molecule in vertebrates that she and Påhlman describe as resembling “the ancestral HIF form” that would have evolved first. It behaves as a metabolic switch that allows cells to “enter or exit a low-oxygen consumption mode,” she said, so it would have allowed emerging animals to be less sensitive to oxygen fluctuations in their environments.

“Organisms could start to manage stem cells better,” Hammarlund explained. Their tissues could grow with fewer oxygen-imposed constraints, so they could be made of more diverse cells growing in more varied structures. Moreover, the animals could begin to populate more habitats with varying oxygen levels. Hammarlund wonders whether the Ediacaran creatures, which disappeared at the start of the Cambrian, lacked this ability and therefore lived in the deep parts of the ocean because oxygen concentrations were more stable there.