Working to Fix the Genetic Cause of Disease
From Bench to Bedside
Doctors at Seattle Children’s have developed groundbreaking
tools that promise to fix the genetic causes of disease. Now
they seek funding to turn the tools into cures.
In the clinic office and in the lab, Dr. Dave Rawlings is driven to advance the field of gene repair because of its potential to bypass the side effects of
current treatments for life-threatening illnesses like AIDS, cancer and autoimmune deficiencies.
Imagine a prowler casing a neighborhood, looking for a
way into a home. That’s essentially what HIV, the human
immunodeficiency virus that causes AIDS, does: It moves
through the bloodstream trying to gain entry to T-cells – the primary warrior cells of the immune system. The open
door HIV seeks is a protein called CCR5, a special receptor
on the T-cell’s surface. Once the virus gains entry, it hampers
a T-cell’s ability to do its job, leaving people vulnerable to
infection and disease – and enabling HIV to spread.
Now imagine you can lock that door forever. The virus
can’t enter the T-cells and interfere with the immune system
and the body can fight off the infection.
That vision is getting closer to reality thanks to
Drs. Dave Rawlings and Andy Scharenberg at Seattle
Children’s. Working with colleagues at the University of
Washington and Fred Hutchinson Cancer Research Center,
they have figured out how to modify genes and knock the
CCR5 receptor off T-cells. They can make it work in the lab – now they want to turn it into an effective therapy for people
who have AIDS.
It’s just one application for a promising biological “toolkit”
they developed to modify genes – an important advance for
the emerging field of gene editing that promises to cure
chronic, debilitating diseases like AIDS.
Creating new ways to modify genes
Easing life for patients facing
life-threatening illnesses spurs
develop less intrusive treatments.
Genes are the basic building blocks of DNA. They tell a cell
how to behave and what to do. Advances in understanding
the human genome have sped up researchers’ ability to
identify the genes responsible for a growing number of
diseases and birth defects.
“Being able to identify the genetic cause is like finding
the bottleneck in the system,” says Rawlings, a pediatric
immunology specialist. “It got us thinking ‘how can we clear
the jam and eliminate the problem rather than just treat the
About a decade ago, he and Scharenberg began
assembling several teams of experts from different
disciplines with a common vision: to create cutting-edge
biological tools that treat illnesses of the blood. Their work
kicked into high gear in 2007 with a five-year, $24-million
boost from the National Institutes of Health (NIH) to fund
the Northwest Genome Engineering Consortium (NGEC)
and develop the tools needed to modify genes. One of
NGEC’s great successes was creating homing endonucleases
that can find exact locations along the DNA and precisely
cut within specific genes.
Several other organizations around the world are also
working to develop new methods of gene repair, but
Rawlings thinks the tools created here are more efficient
“We started with nature’s scissor to build our homing
endonucleases – it’s a naturally occurring enzyme that
evolved in fungus over millions of years with the sole
purpose of cutting a DNA sequence and inserting its own
DNA,” he says. “Our process also includes a second enzyme
that chews away just a bit of the DNA so it can’t repair itself
exactly as it was. This allows levels of gene editing that are
AIDS and what else?
The tools developed by the NGEC have potential to improve
the immune system’s ability to fight many diseases, including
leukemia and brain cancer. For example, Dr. Mike Jensen
and his team are genetically modifying T-cells so they can
recognize cancer cells as dangerous and eliminate them.
But cancer cells are smart and they send a signal to the T-cells, telling them to stop working. Scharenberg and
Rawlings figured out how to prevent the cancer cells from
sending the “stop” message to the engineered T-cells, thus
enabling them to do their work better.
What’s the holdup?
Like many researchers whose laboratory work has made
promising discoveries, Rawlings and Scharenberg are at a
precarious financial juncture in their journey: if they can’t
secure ample funding they will be unable to translate their
exciting scientific achievement into viable new therapies.
“We’re on the cusp of changing what’s possible... Now it’s time to take these tools and make
something that helps people.”
With funding to move into human clinical trials, a cure for
HIV could come to fruition within three to five years. Yet the
organizations that typically fund biomedical research offer
limited support for the work needed to move basic science
from the laboratory to the bedside of real patients.
“We’re on the cusp of changing what’s possible. We’ve
shown in the lab that we can now edit whatever gene we
want to,” says Scharenberg. “Now it’s time to take these
tools and make something that helps people.”