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Artist's drawing of the eye cross-section showing the detail of the lens'
engineering and the pigment layer that surrounds the retina.
Photoreceptors in the retina detect light and send nerve signals to the brain.
The retinal pigment epithelium keeps the photoreceptors healthy. When it
dies in age-related macular degeneration, the light detectors die as well. A
new study that implanted new RPE cells raises new hope for stem-cell
therapy.
Graphic: Edited from orginal by National Eye Institute, National Institutes of
Health
A field long on promise and short on healing was energized on Oct. 15, 2014,
when The Lancet reported on the transplant of retinal cells into 18 people
who were blind because cells had died in the center of the retina.
The study focused on safety, but the hints that the transplant worked fed a
desperate hunger for progress on stem cells the long-awaited spare
parts that may someday revolutionize medicine. Getting the story precisely
backwards, CNN headlined Stem cells help nearly blind see, then
proceeded to explain that Researchers say that human embryonic stem cells
have restored the sight of several nearly blind patients and that their latest
study shows the cells are safe to use long-term.
Macular degeneration can destroy central vision; roll over image to see how a
person afflicted with AMD might see these kids.
Images: National Eye Institute, National Institutes of Health
In fact, the experts we talked to were optimistic about the safety issue a
huge hurdle for stem cells but less sanguine about the getting the blind to
see aspect.
So, how much progress are we making in stem cells, in the clinic and the
laboratory?
The clinic part is easy: The U.S. Food and Drug Administration has not
approved any non-experimental transplant of cells derived from the most
versatile stem cells. These are the embryonic stem cells (ESC) that sparked
all the attention 16 years ago, when they were first isolated by Jamie
Thomson at the University of Wisconsin-Madison.
A pluripotent a stem cell can develop into any type of human cells, including
neurons, muscle and blood cells. Roll over image to see how the stem cell
differentiates into various developmental pathways as cells become more
specialized.
Graphic 1: Preeti Gokal Kochar. Graphic 2: National Institute of Health
Stem cells, transitional cells that can further specialize, or differentiate, into
other cell types, come in several flavors:
Embryonic stem cells are formed in the embryo shortly after conception. The
ESC, the most flexible stem cell, was the source of the retinal transplant cells
in the recent Lancet1 study.
Induced pluripotent stem cells are versatile (pluripotent) stem cells created
from adult tissue. iPSCs are similar to ESCs, but no embryo is destroyed. If
iPSCs are crafted from the patients own cells, immune problems during
transplant are negated.
The cells replaced in the Lancet study, called retinal pigment epithelium,
came from ESCs. The RPE provides essential metabolic support to
photoreceptors the cells that convert light into nerve impulses.
Patients in the Lancet study had either dry age-related macular degeneration
(AMD) or Stargardts macular dystrophy, which affects younger people. In
both diseases, the RPEs die, which kills the photoreceptors. The dying starts
at the center of vision, causing blindness exactly where detailed vision is
most needed.
The diseases chosen illustrate the type of condition most appropriate to early
human tests of pluripotent stem cells, says William Murphy, co-director of the
Stem Cell and Regenerative Medicine Center at UW-Madison. You need a
substantial, unsolved clinical problem like AMD, ALS (Lou Gehrigs disease) or
spinal cord injury.
The new study was important from the basis of safety, says David Gamm,
an associate professor of ophthalmology and visual sciences at UW-Madison,
and an expert in retinal stem cell biology and cell-based therapies, but I
think its difficult to read too much into the efficacy data.
Why?
The examiner and the patient both knew which eye was treated (you cant
fake that, Gamm says) and patients may try harder on vision tests with that
eye after the transplant;
After repeated eye-chart testing, AMD patients may learn to use surviving
retinal regions; and
The procedure replaced the RPE, not the photoreceptors. Because those
light-sensitive cells in the center of vision are dead, the treatment at best
could have awoken photoreceptors on the edge of the lesion that are not
dead but are not working because they dont have the RPE, Gamm explains.
Transplanting retinal cells may sound like a magic bullet, But its not like
putting a new carburetor into a car, says Gamm. Eyes in advanced cases of
both diseases are like a beat-up engine. A lot of those not-so-subtle details
were not discussed in the article.
The study was more convincing on the safety issue, Gamm says, but
unfortunately that often does not get the attention it should get. The patients
were followed for a median of 22 months, and nothing like the formation of
tumors was seen, or cells getting to the wrong place. These are all important
aspects of the study and were done well. I would flip the order of priority on
the study to the safety aspect. Thats the part that will advance the field.
Graph of stem cell publications from 1996 to 2012. The growth was
exponential in the early 2000s followed by an apparent leveling after 2010,
though more publications on iPSCs may drive higher growth.
Stem cell researchers are cranking out publications. Between 2008 and 2012,
stem cell publication output grew at a 7 percent compound rate, while the
total of all subjects grew at a 3 percent compound rate. The bulk of literature
in the past two decades focused on non-human embryonic stem cells, but
recent advances in reprogramming human adult cells have spawned a
cascade of iPSC publications.
Graphic (with slight modification) from Research Trends
But if the retinal cell transplant was the most impressive clinical trial to date,
how much longer must we wait?
How long?
For people with untreatable disease, the 16 years since the discovery of
human embryonic stem cells amounts to forever. But its fair to say that when
ESCs were first isolated, they resembled a gang of trouble-prone youths more
than a disciplined cadre of bio-workers.
Their unlimited capacity to form any cell type gave embryonic stem cells
plenty of potential for mischief, so the first step in putting them to work was
to decipher the biochemical cues that guide stem cells into useful
occupations.
Even though biomedical technology has advanced rapidly since the 1980s,
stem cells are significantly more complex than monoclonals, Hei says.
Cells can differentiate, integrate and replace dead cells, can secrete factors
to help other cells survive, and it would not surprise me if it takes 30 years
from the initial discovery, to where we have pluripotent stem cells becoming
mainstream therapy.
Nonetheless, Hei was pleased with the latest results. You dont really
understand all the potential risks and technical issues until you start
developing therapy. You will learn things in the first clinical trials that you
cant learn in animal studies. Its safe to assume that unanticipated
problems will need to be solved, he adds.
of pilot studies to try understand how to screen drugs against diseased stem
cells.
The dream of one day being able to grow in the laboratory an unlimited
amount of human tissues for transplantation is one step closer to reality.
The achievement has profound implications for transplant medicine, drug
discovery and basic developmental biology. It opens the door to growing from
scratch everything from heart muscle to bone marrow and brain tissue.
But he says researchers could benefit from a more sophisticated model-in-adish. Since the nerves do not operate in isolation, an ideal model would
include nerve cells joined to muscle cells. That is currently not available, due
to complexity, Zhang says. For one thing, when a nerve cell in a dish signals
contract! to a muscle cell, the contraction can cause them to jump right out
of the dish. We are still trying to figure out a way to build such a system,
Zhang says, but we are not there yet.
Making life easy for the robots, he adds, is a pure technology issue.
Challenge remain
All of which is to say that pluripotent stem cells are a work in progress,
especially in in terms of the ultimate pay-off: treating disease by replacing
broken parts. Here are some critical areas for improvement:
Cell maturity: How much is enough? Some situations require that mature
cells be transplanted, says Murphy, who explains that partly developed
pancreatic cells would not release insulin. But to replace cartilage in
osteoarthritis, a slightly immature cartilage-forming cell is better, since very
mature cells dont make that essential friction reducer. Immaturity is also
valuable for neural-cell transplants, says Zhang. If you move a mature cell, it
will die. A young neuron in a hospitable location will connect to the right
place. If it projects to the wrong place, that creates problems.
Getting realistic. Cells dont live in isolation and flat dishes of a single cell
type are gross simplifications of a real organ. Therefore, researchers are
developing organoids that fuse multiple cell types to screen drugs and
If you provide them with the right surrounding conditions, stem-cell selfassembly can build complex structures, tissues, even organs, says Murphy.
I dont think anyone would have anticipated that, but its tremendously
useful.
Bringing stem cells to the clinic has been a long struggle, but Murphy admits
to cautious enthusiasm. There remains a great deal of potential for
treatment, but there are real technical and regulatory hurdles that have to be
passed.
Stem cell products transplanted into the retina may or may not have restored
vision in the recent study, says ophthalmologist Gamm, but the study was
still a watershed. You have taken cells derived from embryonic stem cells
and put them into the retina, and did not hurt anybody; thats good. Its
possible there may have been a limited positive effect on vision, and there
was no negative. This was major, very positive.
David J. Tenenbaum
23456
Kevin Barrett, project assistant; Terry Devitt, editor; S.V. Medaris,
designer/illustrator; David J. Tenenbaum, feature writer
dibujo del artista de la seccin transversal del ojo que muestra el detalle de
la ingeniera de la lente 'y la capa de pigmento que rodea la retina.
Fotorreceptores en la retina detectan la luz y envan seales nerviosas al
cerebro. El epitelio pigmentario de la retina mantiene los fotorreceptores
saludable. Cuando se muere en la degeneracin macular relacionada con la
edad, los detectores de luz mueren tambin. Un nuevo estudio que implanta
nuevas clulas del EPR plantea una nueva esperanza para la terapia de
clulas madre.
Grfico: Editado de orginal por el Instituto Nacional del Ojo, Institutos
Nacionales de Salud
Un campo de largo en la promesa y corto en la curacin fue activado el 15 de
octubre de 2014, cuando The Lancet inform sobre el trasplante de clulas
de la retina en 18 personas que eran ciegos, porque las clulas haban
muerto en el centro de la retina.
"El nuevo estudio fue importante desde la base de la seguridad", dice David
Gamm, profesor asociado de Oftalmologa y Ciencias Visuales en la
Universidad de Wisconsin-Madison, y un experto en biologa de clulas madre
de la retina y las terapias basadas en clulas, "pero creo que es difcil a leer
demasiado en los datos de eficacia ".
Por qu?
Despus de la prueba del ojo-carta repetida, los pacientes con AMD pueden
aprender a utilizar sobrevivir a las regiones de la retina; y
El trasplante de clulas de la retina pueden sonar como una bala mgica ",
pero no es como poner un carburador nuevo en un coche", dice Gamm. Ojos
en casos avanzados de ambas enfermedades son como "un motor
destartalado. Muchos de esos detalles no tan sutiles que no se discutieron
"en el artculo.
Cunto tiempo?
William Murphy, un ingeniero biomdico de la Universidad de WisconsinMadison, dice "La industria ha estado aumentando de cribado",
especialmente ahora que se pueden comprar cras ya preparado de clulas
iPS. "No creo que iPSCs o los CES han sustituido el sistema de descubrimiento
de frmacos actual, en trminos generales, pero en determinadas zonas, hay
un buen montn de estudios piloto para tratar de entender" cmo analizar
frmacos contra las clulas madre enfermas.
desafo permanecen
Todo lo cual quiere decir que las clulas madre pluripotentes son un trabajo
en progreso, especialmente en en cuanto a lo ltimo pago de compensacin:
el tratamiento de la enfermedad mediante la sustitucin de piezas rotas.
Estas son algunas de las reas crticas de mejora:
"Si usted les proporciona las condiciones que rodean a la derecha, con clulas
madre de auto-ensamblaje puede construir estructuras complejas, tejidos,
incluso rganos", dice Murphy. "No creo que nadie hubiera esperado que,
pero es tremendamente til."
Con lo que las clulas madre a la clnica ha sido una larga lucha, pero Murphy
admite que "el entusiasmo cauteloso. Sigue habiendo una gran cantidad de
posibilidades de tratamiento, pero hay obstculos tcnicos y reglamentarios
reales que tienen que pasar ".
- David J. Tenenbaum
23456
Kevin Barrett, asistente de proyecto; Terry Devitt, editor; S.V. Medaris,
diseador / ilustrador; David J. Tenenbaum, articulista