says Nogales, who visualizes CRISPR molecules using cryo-EM.

For example, Synthego, which Church is affiliated with, has introduced kits designed to address different gene editing tasks. Its $1,495 Gene Knockout Kit (GKO) drops powerful capabilities into the hands of researchers. It taps predictive software and automation tools that help a researcher select a human gene to modify. It then applies a synthetic RNA gene to direct a protein to the specific location required for a DNA cut. The firm claims this toolkit has boosted the accuracy of CRISPR editing methods from around 50% to as much as 80%, or even more. The net result is an ability to cycle through variations of edited genes faster, speeding research and development for new procedures and drugs.

Paul Dabrowski, co-founder and CEO of Redwood City, CA-based Synthego, has said the firm’s gene editing system reduces the time it takes for a scientist to perform gene edits from several months to approximately one month. This, he has noted, helps researchers focus on results and outcomes, rather than the mechanics of an experiment.

Nogales says that while CRISPR
tools fundamentally change the na-
ture of research, they also present
challenges. For one thing, because
of uncertainty about errors caused
by systems, CRISPR is not yet been
approved for medical use by the U.S.
Food and Drug Administration. For
another, there is a learning curve as-
sociated with the technology. “Mak-
ing a cut in the wrong place could be
very deleterious. This is one of the
reasons why CRISPR is used for agri-
culture more than human treatment,
and Cell Biology at the University of
California, Berkeley, and senior fac-
ulty scientist at Lawrence Berkeley
National Laboratory. “CRISPR and
Cryo-EM allow researchers to perform
an array of tasks faster and better.”

Adds Richard Henderson, research scientist at the Medical Research Counsel Laboratory of Molecular Biology in Cambridge, U.K., and a recipient of the 2017 Nobel Prize in Chemistry for his pioneering work on Cryo-EM, “We are at the cusp of remarkable advances in agriculture, medicine, and many other fields. These technologies will reshape science and the world.”

Cracking the Code on CRISPR

In only a few short years, the ability to reengineer the genetic structure of living things has moved from obscure research labs to the mainstream of science. CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, beckons with the promise of producing better tomatoes, insect-resistant grains, malaria-resis-tant mosquitos, and new types of pharmaceutical drugs to combat conditions ranging from sickle cell anemia and Alzheimer’s disease to cancer. Users can perform direct operations on genes by modifying and recombining molecular structures. “As the technology has advanced, the need to build everything from scratch in a lab has been replaced with commercially available products that produce effective results,” Church says.

Indeed, commercial firms with
names like Synthego, Inscripta, and
Twist Biosciences have developed kits
that advance gene editing in much
the way same way visual program-
ming replaced the need to manually
write endless lines of code for some
software application. Although these
firms take aim at the task through ap-
proaches that range from providing
molecular resources to computation-
al tools in software packages, the
common denominator for the end-
user is an ability to conduct research
faster, more effectively, and at a lower
cost. In fact, gene-editing tools that
once had a price tag extending into
the billions of dollars are now avail-
able for less than $1,000. Essentially,
“Any cell biology lab can use CRISPR,”
Further advances in software and
algorithms will drive smarter and
better gene editing tools, Nogales
adds. For instance, Inscripta, head-
quartered in Boulder, CO, has focused
on developing a biological genetic en-
gineering framework that resembles
the all-in-one capabilities of a personal
computer, while San Francisco-based
Twist Biosciences is developing a sys-
tem that places custom strands of syn-
thetic DNA—the As, Ts, Cs, and Gs that
serve as building blocks for biology—
on semiconductor chips. This allows
researchers to make up to a million
CRISPR edits with a single chip, rather
than using multiple systems and soft-
ware to accomplish the task. The com-
pany’s self-described “smart algo-
rithm” informs users within seconds
whether the sequence they are testing
can be synthesized.

Cryo-EM Enters the Picture
Although gene editing has introduced
powerful capabilities into the research
lab, scientists continue to struggle with
understanding the mechanical func-
tions of basic biological structures.
From the invention of the microscope
in the 13th century to more advanced
forms of electron microscopy, improv-
ing resolution and reducing noise—
particularly at extremely high levels of
magnification—has proved vexing.
“Obtaining clearer images is an ongo-
ing challenge,” states Craig Yoshioka,
research assistant professor and co-di-
rector of the Pacific Northwest Cryo-
EM Center at Oregon Health Sciences
University (OHSU) in Portland, OR.
For instance, one issue with cryo-
electron microscopy is that bombard-
ing a frozen sample with electrons can
vaporize the specimen. As a result, Yo-
shioka says, scientists must essential-
ly collect their images in “low light,”
thereby reducing specimen damage,
but also resulting in noisy data. The
resulting noise makes it more difficult
to view the behavior of the molecules
and understand how they react to dif-
ferent conditions.
Meanwhile, another technique,
called X-ray Crystallography, can pro-
duce a three-dimensional (3D) image of
a molecular structure at high resolu-
tion by measuring how diffracted X-ray
“We are at the cusp of
remarkable advances
in agriculture,
medicine, and many
other fields. These
technologies will
reshape ... the world.”