SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1433IMAGES: (TOP TO BOTTOM ELLA MARU STUDIO/SCIENCE SOURCE; WEIZMANN INSTITUTE OF SCIENCE
CRISPR fixes genes inside the body
The gene-editing tool CRISPR had its first
clinical victory in 2020, when it appeared
to cure people with two inherited blood
disorders, sickle cell disease and beta-
thalassemia. Those treatments took place
in a lab dish: Scientists removed defective
blood stem cells from patients, edited them,
and reinfused the cells into patients. This
year, scientists took things one step further,
deploying CRISPR directly in the body. In
small studies, the strategy reduced a toxic
liver protein and modestly improved vision
in people with inherited blindness.
Gene editing could tackle many more
diseases if the therapy could be injected into
an organ or the bloodstream. But getting
CRISPR to work inside a person, or in vivo,
poses significant challenges. Before CRISPR’s
molecular components can correctly modify
a specific gene, they must be ferried safely to
the right cells in the right quantities.
To fight hereditary transthyretin (TTR)
amyloidosis, a disease in which a mis-
folded TTR protein builds up and damages
nerves and the heart, researchers at IntelliaTherapeutics and Regeneron Pharmaceuti-
cals gave six patients an infusion of tiny fat
balls encasing a guide RNA and the RNA
instructions for CRISPR’s genome-snipping
enzyme. The team hoped the patients’ own
liver cells would take up the particles and
make the CRISPR components, which would
snip both strands of DNA at the TTR gene.
The cell’s repair system would mend the cutsimperfectly, leaving the gene disabled. It
worked: After 4 weeks, average blood levels
of TTR dropped 52% or 87% depending on
the dose, researchers reported in June in The
New England Journal of Medicine.
It will take many months to learn whether
the drop in TTR eases symptoms. The hope
is that the one-time treatment will work as
well as, if not better than, an RNA-based
drug that must be injected every 3 weeks.
In another study, researchers at Editas
Medicine injected a harmless virus carrying
CRISPR DNA into the eyes of six adults with
an inherited vision disorder called Leber
congenital amaurosis 10. The scientists
hoped to snip out extra DNA that disrupted
a mutated eye gene so cells would then make
its missing protein. After 3 to 6 months, two
patients—who had been almost completely
blind—could sense more light, and one could
navigate an obstacle course in dim light, the
researchers reported at a September meet-
ing. They hope for greater vision gains in
adults receiving a higher CRISPR dose, and
in young patients. —Jocelyn KaiserGuide RNA (blue) from a CRISPR injection leads a
DNA-cutting enzyme (white) to its target (orange).Embryo ‘husbandry’ opens windows into early development
Insights into early embryonic development can help scientists under-
stand miscarriages and birth defects—and hone in vitro fertilization
(IVF) protocols. But legal, practical, and ethical limitations constrain
studies with human embryos. This year, scientists unveiled potential
stand-ins: mouse embryos reared far longer than before, and embryo
replicas made from human stem cells or reprogrammed adult cells.
Scientists have struggled to grow mouse embryos outside a mother
mouse’s body for much longer than 3 or 4 days. But in March, one
team reported a recipe for stretching that to 11 days. A key step, they
found, was rotating the jars containing the embryos on a device that
resembles a miniature Ferris wheel. It continually mixes the nutrient
broth that bathes the embryos and ensures that oxygen levels and
atmospheric pressure are congenial. The embryos underwent a key
stage of cellular reorganization, grew organs, and sprouted hind legs.
Other scientists devised substitutes for a crucial embryonic stage
known as the blastocyst. A hollow ball harboring only a few hundred
cells, the blastocyst implants into the uterus and is the first embry-
onic stage to feature specialized cells. It’s also inserted by many IVF
clinics into prospective mothers.
One team made blastocyst replicas from human embryonic stem
cells and induced pluripotent stem (iPS) cells, stem cells repro-
grammed from specialized adult cells. Another discovered that skin
cells undergoing the transition to iPS cells produce blastocystlike
structures. These ersatz blastocysts aren’t real embryos, but some of
them could offer an instructive—and less controversial—alternative.
The field received another boost in May. The international
organization that sets stem cell research guidelines relaxed its long-
standing prohibition on growing human embryos in the lab for more
than 14 days, allowing scientists to probe embryonic events that occur
after that time. —Mitch LeslieA mouse embryo grows in a rotating jar. Such embryos can help researchers
better understand the early stages of human development.