YSM Issue 96.3

FOCUS
Ophthalmology
happen when melanocytes were UVirradiated.
Cells that are UV-irradiated
develop a specific type of DNA damage
called cyclobutane dimers.
Brash eventually showed that, when
exposed to UV radiation, melanin was
oxidized by free radicals—meaning that
its chemical structure lost electrons—to
produce dioxetane, a chemical compound
on melanin that then splits to give a
molecule with a similar high-energy state
to ultraviolet light in sunlight. The radicals
and dioxetanes continued long after the UV
light was turned off. Dioxetane’s high-energy
state was a specific kind called a triplet state,
which is capable of initiating reactions that
ordinary chemistry cannot. He also knew
that melanin was found in many places
in the body, such as the eye and the ear,
and the two radicals behind its oxidation,
superoxide and nitric oxide, were found in
many conditions such as inflammation.
“These [are] events that can’t not happen.
Why aren’t we dead?” Brash recalled thinking.
Could the high-energy reaction cause
deafness and blindness? A surprising clue
to the exact opposite conclusion came from
Ulrich Schraermeyer, an ophthalmologist at
the University of Tubingen in Germany, who
had heard about Brash’s work with melanin
chemistry. Schraermeyer had an idea that
completely opposed the norm
ten years ago. He suggested that
perhaps melanin actually had a
protective role in the retina.
For years, he had been
working on studies to show
that when melanin was
associated with another
molecule called
lipofuscin, the retina
was less susceptible
to macular
degeneration.
Lipofuscin, a
pigment that
accumulates in the
retina with age, is associated
with neurodegeneration in AMD,
but its exact composition is unclear.
While Schraermeyer was convinced of the
critical involvement of melanin in AMD
prevention, he could not figure out the
chemistry. And while Brash was intrigued
by melanin having a protective role, the
mechanism would need to be proven.
In Schraermeyer’s initial experiments, he
proved many drugs could actually slow or
prevent macular degeneration in mice and
monkeys. Brash noticed that these drugs were
all chemicals that could create triplet states,
the unique high-energy chemical state that
Brash had previously created in melanin after
it was treated with radicals. This led to their
theory that the dioxetane in melanin that led
to the triplet state was the step responsible for
melanin’s protective role in the retina.
In his initial experiments, Schraermeyer
showed that under electron microscopy, a
type of imaging technique used to visualize
subcellular structures, melanin was often
seen together with lipofuscin in the retina
in what is called melanin-lipofuscin (MLF)
granules. He observed that MLF granules
accumulated in the eyes of humans above
the age of sixty. Building on this observation,
the group showed that the toxic lipofuscin
component of MLF granules could be
degraded by treating mice with a nonmelanin
molecule that was in a triplet state.
The degradation was blocked if mice also
received a molecule that siphons the triplet
energy away. Thus, it seemed like melanin
chemiexcitation, using chemicals to create
a high-energy state, and melanin-lipofuscin
association could be studied as a pathway for
lipofuscin degradation.
Schraermeyer believes that upregulating
melanin in the retina could be a therapeutic
target. Having already shown that people
lose melanin in the retina with age, he
theorizes that the melanin is being
used up in its protective
role throughout one’s
life. Brash, on the other
hand, is convinced about
the importance of dioxetane
chemistry, but not so much
about melanin itself. “I’m willing
ABOUT THE
AUTHORS
to bet
that as you
get older, the
melanin may well
contribute to AMD,
so it’s like a double-edged
sword,” Brash said. Brash’s
therapeutic goal is to get tripletstate
precursors into the eye so that
dioxetane chemistry can be harnessed
for AMD prevention.
Seeing Eye-to-Eye
While Hafler and Brash took two very
different approaches to characterizing
some of the underlying mechanisms of
AMD, their findings both pave a new
way forward for the development of
potential treatments. With scores of
scientists studying AMD from various
specialties and backgrounds, the pursuit
of an effective treatment that accounts for
multiple mechanisms grows increasingly
hopeful—while potentially also addressing
diseases beyond the retina as well. ■
RISHA CHAKRABORTY
JOHNNY YUE
RISHA CHAKRABORTY is a third-year Neuroscience and Chemistry major in Saybrook
College. In addition to writing for YSM, Risha plays trumpet for the Yale Precision Marching
Band and La Orquesta Tertulia, volunteers at YNHH, and researches Parkinson’s Disease at
the Chandra Lab.
JOHNNY YUE is a second-year student majoring in Molecular, Cellular, and Developmental
Biology in Trumbull College. Outside of YSM, Johnny volunteers at HAVEN Free Clinic and
researches alcohol use disorder in the Cosgrove Lab at the Yale School of Medicine.
THE AUTHOR WOULD LIKE TO THANK Dr. Brian Hafler and Dr. Douglas Brash for their time
and enthusiasm about their research.
18 Yale Scientific Magazine September 2023 www.yalescientific.org