By tweaking the cellular properties of the organoids, the research
team found that a molecule called retinoic acid determines whether a
cone will specialize in sensing red or green light. Only humans with
normal vision and closely related primates develop the red sensor.
Scientists
have thought for decades that red cones formed through a coin-toss
mechanism in which the cells haphazardly commit to sensing green or red
wavelengths. Research from Johnston’s team recently hinted that the
process could be controlled by thyroid levels. Instead, the new research
suggests red cones materialize through a specific sequence of events
orchestrated by retinoic acid within the eye.
The
team found that high levels of retinoic acid in early development of
the organoids correlated with higher ratios of green cones. Similarly,
low levels of the acid changed the retina’s genetic instructions and
generated red cones later in development.
“There
still might be some randomness to it, but our big finding is that you
make retinoic acid early in development,” Johnston said. “This timing
really matters for learning and understanding how these cone cells are
made.”
Green
and red cone cells are remarkably similar except for a protein called
opsin that detects light and tells the brain what colors people see.
Different opsins determine whether a cone will become a green or a red
sensor, though the genes of each sensor remain 96% identical. With a
breakthrough technique that spotted those subtle genetic differences in
the organoids, the team tracked cone ratio changes over 200 days.
“Because
we can control in organoids the population of green and red cells, we
can kind of push the pool to be more green or more red,” said author
Sarah Hadyniak, who conducted the research as a doctoral student in
Johnston’s lab and is now at Duke University in North Carolina. “That
has implications for figuring out exactly how retinoic acid is acting on
genes.”
The
researchers also mapped the widely varying ratios of these cells in the
retinas of 700 adults. Seeing how the green and red cone proportions
changed in humans was one of the most surprising findings of the new
research, Hadyniak said.
Scientists
still don’t fully understand how the ratio of green and red cones can
vary so greatly without affecting someone’s vision. If these types of
cells determined the length of a human arm, the different ratios would
produce “amazingly different” arm lengths, Johnston said. “The future
hope is to help people with these vision problems,” Johnston said. “It's
going to be a little while before that happens, but just knowing that
we can make these different cell types is very, very promising.”
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