We've seen few medical
breakthroughs since the human genome was completed
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Picking up where the Human Genome
left off, a new project aims to describe drugs and diseases
in the same language — the genetic code. In three
papers published last month in Science and Cancer
Cell, researchers from the Dana-Farber Cancer Institute,
Children's Hospital Boston, and the Broad Institute
of Harvard and MIT argue that by defining both diseases
and drugs by their gene expression signature, a new
world of interconnections emerges. Put it all in a database,
and you have the Connectivity Map, an open-access research
tool that allows anybody to match drugs to diseases
by looking at the most basic of all biological processes.
"The notion is that we could build a large database
of genetic profiles of drugs that scientists and researchers
around the world could mine to find connections between
drugs and disease," says Dr Todd Golub of the Broad
Institute and one of the leading collaborators in the
project.
FAILURE
TO COMMUNICATE
It's been three years since the atlas of the human genome
was completed, but we've seen very few medical breakthroughs
as a result. The problem is, the genome is speaking
a different language from mainstream medicine. Diseases
are still mostly characterized in terms of symptoms,
risk factors and large-scale biological mechanisms like
inflammation. Drugs are commonly described in the language
of molecular biology: proteins, neurotransmitters, surface
receptors. The two simply don't meet. Advances rely
on leaps of intuition, and lengthy trial and error testing.
Dr Golub likens the Connectivity
Map to a Google search. Like the search engine, it will
be widely, and freely, available. "One can use this
information to figure out, given a drug, what other
drugs are nearest to it genetically? Or one could think
about a particular disease and ask what other diseases
or molecular processes are nearby?"
The first use of this would be
to find new uses for existing drugs. "It takes a very
long time for a drug to pass safety testing," says Dr
Golub. "But drugs that we've been giving for many years
often have more than one effect in a cell." There's
even a possibility, not yet fully explored, of identifying
potential common side effects in new drugs.
But one of the big bonuses of the
Connectivity Map, Dr Golub says, is to make more sense
of the Human Genome itself. We still don't know what
many of these genes do. "We could use the Map to connect
the actions of genes to the diseases they might be involved
in. If we see a match, that might suggest a gene no
one was thinking about is involved in the disease."
SIGNS
OF SUCCESS
Already the Connectivity Map has scored some early successes.
Pediatric oncologist Scott Armstrong
of Boston Children's Hospital and colleagues identified
an existing drug that could be effective in children
with acute lymphoblastic leukemia who are resistant
to treatment with glucocorticoids. The researchers entered
signatures of cells from patients who responded well
to glucocorticoids, and from those who didn't, into
the database and looked for drugs that would make the
latter group more like the former. The Map suggested
rapamycin, originally created as an antifungal agent
and nowadays used to prevent organ transplant rejection.
Sure enough, in some cell lines rapamycin did appear
to increase susceptibility to glucocorticoids. A trial
of the drug is now planned in children who have seen
cancer recurrence after glucocorticoid treatment.
In the same journal, Dana-Farber
researcher Haley Hieronymus and colleagues describe
how gedunin, a poorly-understood plant derivative with
a long history of medicinal use, was found to block
androgen receptor signalling in prostate tumours.
The Connectivity Map is online
now at http://www.broad.mit.edu/cma/and will be added
to over the next few years.
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