FINALIST
Arun Sharma
Arun Sharma received his
undergraduate degree from
Duke University and a Ph.D.
from Stanford University.
Having completed a postdoc-
toral fellowship at the Harvard Medical School,
Sharma is now a senior research fellow jointly
appointed at the Smidt Heart Institute and
Board of Governors Regenerative Medicine
Institute at the Cedars-Sinai Medical Center
in Los Angeles. His research seeks to develop
in vitro platforms for cardiovascular disease
modeling and drug cardiotoxicity assessment.
http://www.sciencemag.org/content/367/6483/1206.1SCIENCE sciencemag.org 13 MARCH 2020 • VOL 367 ISSUE 6483 1205PHOTOS: (LEFT TO RIGHT) COURTESY OF J. NEVES; COURTESY OF A. SHARMA; JOYDEEP BHADURY
By Joana NevesA
central promise of regenerative medi-
cine is the ability to repair aged or
diseased organs using stem cells (SCs).
This approach will likely become an
effective strategy for organ rejuvena-
tion, holding the potential to increase
human health by delaying age-related dis-
eases ( 1 ). The successful translation of this
scientific knowledge into clinical practice will
require a better understanding of the basic
mechanisms of aging, along with an inte-
grated view of the process of tissue repair ( 1 ).
The advent of SC therapies, now progress-
ing into clinical trials, has made clear the
many challenges limiting the application of
SCs to treat disease. Our duty, as scientists,
is to anticipate such limitations and propose
solutions to effectively deliver on the promise
of regenerative medicine.ROADBLOCKS LIMITING THE PROGRESS
OF REGENERATIVE THERAPIES
Degenerating tissues have difficulty engaging
a regulated repair response that can support
efficient cell engraftment and restoration of
tissue function ( 2 ). This problem, which I
encountered when trying to apply SC-based
interventions to treat retinal disease, will
likely be an important roadblock to the clini-cal application of regenerative medicine ap-
proaches in elderly patients, those most likely
to benefit from such interventions. I therefore
hypothesized that the inflammatory environ-
ment present in aged and diseased tissues
would be a major roadblock for efficient re-
pair and that finding immune modulators
with the ability to resolve chronic inflamma-
tion and promote a prorepair environment
would be an efficient approach to improve
the success of SC-based therapies ( 2 , 3 ).
Immune cells, as sources and targets of
inflammatory signals, emerged naturally as
an ideal target for intervention. I chose to
focus on macrophages, which are immune
cells of myeloid origin that exist in virtually
every tissue of the human body and which
are able to reversibly polarize into specific
phenotypes, a property that is essential to
coordinate tissue repair ( 3 , 4 ).EVOLUTIONARILY CONSERVED PROCESSES
DRIVING NEW THERAPEUTIC APPROACHES
If there is an integral immune modulatory
component to the process of tissue repair
that has evolved to support the healing of
damaged tissues, then it should be possible
to find strategies to harness this endogenousmechanism and improve regenerative thera-
pies. Anchored in the idea that tissue damage
responses are evolutionarily conserved ( 5 ), I
started my research on this topic using the
fruit fly Drosophila as a discovery system.
The fruit fly is equipped with an innate im-
mune system, which is an important player
in the process of tissue repair. Using a well-
established model of tissue damage, I sought
to determine which genes in immune cells
are responsible for their prorepair activity.
MANF (mesencephalic astrocyte-derived
neurotrophic factor), a poorly characterized
protein initially identified as a neurotrophic
factor, emerged as a potential candidate ( 6 ).
A series of genetic manipulations involving
the silencing and overexpression of MANF
and known interacting partners led me to
the surprising discovery that, instead of be-
having as a neurotrophic factor, MANF was
operating as an autocrine immune modula-
tor and that this activity was essential for its
prorepair effects ( 2 ). Using a model of acute
retinal damage in mice and in vitro models, I
went on to show that this was an evolution-
arily conserved mechanism and that MANF
function could be harnessed to limit retinal
damage elicited by multiple triggers, high-
lighting its potential for clinical application
in the treatment of retinal disease ( 2 ).
Having discovered a new immune modu-
lator that sustained endogenous tissue re-
pair, I set out to test my initial hypothesis
that this factor might be used to improve
the success of SC-based therapies applied toInstituto de Medicina Molecular (iMM), Faculdade de
Medicina, Universidade de Lisboa, Lisboa, Portugal.
Email: [email protected]GRAND PRIZE WINNER
Joana Neves
Joana Neves received under-
graduate degrees from NOVA
University in Lisbon and a
Ph.D. from the Pompeu Fabra
University in Barcelona. After
completing her postdoctoral fellowship at the
Buck Institute for Research on Aging in Cali-
fornia, Neves started her lab in the Instituto
de Medicina Molecular (iMM) at the Faculty
of Medicine, University of Lisbon in 2019. Her
research uses fly and mouse models to un-
derstand the immune modulatory component
of tissue repair and develop stem cell–based
therapies for age-related disease.REGENERATIVE MEDICINEAging eyes and the immune system
PRIZE ESSAY
Reining in age-related inflammation may enhance stem cell therapies for retinal disease
FINALIST
Adam C. Wilkinson
Adam C. Wilkinson received
his undergraduate degree
from the University of Oxford
and a Ph.D. from the Uni-
versity of Cambridge. He is
currently completing his postdoctoral fellow-
ship at the Institute for Stem Cell Biology and
Regenerative Medicine at Stanford University,
where he is studying normal and malignant
hematopoietic stem cell biology with the aim
of identifying new biological mechanisms un-
derlying hematological diseases and improving
the diagnosis and treatment of these disorders.
http://www.sciencemag.org/content/367/6483/1206.2Published by AAAS