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\begin{document}

\title{Cancer research encourages explorations of hypoxic conditions as a
necessity for multicellularity and how animals solved the challenge of
life in the oxic setting}



\author[1]{Emma Hammarlund}%
\author[2]{Kristoffer von Stedingk}%
\author[3]{Sven Påhlman}%
\affil[1]{Nordic Center for Earth Evolution (NordCEE)}%
\affil[2]{Clinical Sciences}%
\affil[3]{Translational Cancer Research}%


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  \date{May 07, 2024}


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\begin{abstract}
Large life, as currently present on Earth, diversified during a late and
seemingly non-trivial historic event. Although other biological
revolutions -- such as the advent of photosynthesis or the eukaryotic
cell -- are attributed to innovations within life itself, the dramatic
diversification of animals tends to associated with a change in the
environment. The environmental change that remains most thoroughly
explored and debated is that of a synchronous increase of free oxygen.
Paradoxically, studies of multicellularity from the perspective of
tissue and of successful tumor growth highlight how oxic settings are
incompatible with the core mechanism of tissue renewal (Ivanovic, 2009).
Tumor biology also demonstrates biological mechanisms that, through the
hypoxia inducible transcription factors (HIFs), overcome this paradox
(Pietras et al., 2008) and, thus, allow tissue renewal despite oxic
settings. We have explored how HIFs may serve as an adaption within
multicellularity that allow viable large life forms in the oxic setting,
by offering improved control of the cellular hypoxia-response machinery
that sustain oxygen-insensitive growth of complex tissue. We found that
this control is animal-specific and is at its highest refinement within
vertebrate animals; in which the innovation of high-oxygen carrying
capacity through red blood cells followed first subsequently (Hammarlund
et al., 2018). We hypothesize that such a refinement within biology
itself, during the Neoproterozoic, allowed metazoans to fully access and
exploit the primordial oxic niche on Earth. Testable predictions of this
perspective, such as that invertebrate animals and other large
multicellular organisms still require phases or settings of truly
hypoxic conditions to manage tissue renewal, have implications that
reach from geology and medicine to astrobiology. Indeed, a perspective
based in the prerequisites of tissue maintenance suggests that being
large is a biological achievement of cosmic proportions.%
\end{abstract}%



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