An image of a cancer cell undergoing apoptosis (cell death). Image: National Cancer Institute |
Researchers
at the Massachusetts Institute of Technology (MIT) and Switzerland’s ETH Zurich have found a way to program cells to
determine whether they have become cancerous, and if they have, to order their
own suicide.
The
new technology, described in Science, offers the possibility of
designing cell-death-inducing programs specific to any type of cancer, which
could effectively kill tumors while leaving healthy tissues unharmed.
To
create their tumor-killing program, the researchers designed a logic circuit—a
system that makes a decision based on multiple inputs. In this case, the
circuit is made of genes that detect molecules specific to a type of cervical
cancer cell. If the right molecules are present, the genes initiate production
of a protein that stimulates apoptosis, or programmed cell death. If not,
nothing happens.
Because
the genes used to create the circuits can be easily swapped in and out, this
approach could also yield new treatments or diagnostics for many other
diseases, says Ron Weiss, an MIT associate professor of biological engineering
and one of the leaders of the research team. “This is a general technology for
disease-state detection,” he says.
Yaakov
Benenson of ETH Zurich (the Swiss Federal
Institute of Technology in Zurich) co-led the
research team, which also included first author and MIT postdoc Zhen Xie, MIT
postdoc Liliana Wroblewska, and Laura Prochazka of ETH Zurich.
Targeting microRNA
The researchers chose a type of genetic material called microRNA (miRNA) as
their target. These snippets of RNA, discovered only 10 years ago, help
regulate gene expression by selectively destroying messenger RNA, which relays
DNA’s instructions to the rest of the cell.
There
are about 1,000 different miRNA sequences found in humans. Cancer cells often
have too much of some miRNAs and too little of others; each distinct type of
cancer has its own miRNA profile.
In
this paper, the researchers wanted to distinguish a particular type of cervical
cancer cell, known as HeLa, from other cancer cells. To do that, they
identified six miRNAs—some found in large numbers in HeLa cells, others in low
numbers—that, taken together, differentiate HeLa from any other cancer cell.
Then,
the researchers created a synthetic gene for a protein, called hBax, that promotes
cell death. They designed the gene with two separate safeguards against the
killing of healthy, non-HeLa cells: It can be turned off by high levels of miRNAs
that are ordinarily low in HeLa, and can also be deactivated by low levels of
miRNAs that are normally plentiful in HeLa. A single discrepancy from the
target miRNA profile is enough to shut off production of the cell-death
protein.
If
all miRNA levels match up with the HeLa profile, the protein is produced and
the cell dies. In any other cell, the protein never gets made, and the synthetic
genes eventually break down.
A complex state
The researchers are now working on optimizing the circuit to eliminate any
false positives and developing new circuits that can identify additional cell
types. They also hope to test the approach in living animals and eventually
humans.
They
are also investigating possible methods to package and deliver the DNA that
comprises the circuit, in collaboration with MIT chemical engineers Robert
Langer and Daniel Anderson.
