Capturing small molecules for
Tiny molecules can provide a completely different view of biology from
the more common sequencing methods (which focus on DNA and RNA)
and may help uncover new avenues to treat disease. Even so, many of
these small molecules are still relatively unknown.
Leveraging his chemistry background and the latest mass spectrometry
technologies, Saghatelian is taking a closer look at small molecules.
By seeing how they change between samples—for example, between
cancerous and noncancerous tissues—he can find molecules of interest
that could point to potential treatments for disease.
Identifying and synthesizing a previously unknown small molecule is
slow and difficult, but there have been payoffs. As an assistant professor
at Harvard University, Saghatelian partnered with a local medical center
to discover an entirely new class of lipids, called FAHFAs. The group found
that, when they administered FAHFAs to mice with the equivalent of type
2 diabetes, the elevated blood sugar in the mice dropped. The lipids also
show up in normal human tissue and less so in at-risk patients, hinting at
their use for a potential diabetes therapy.
In a collaboration that spins off of his research in metabolism, Saghatelian
is also partnering with Salk Professor
to look for weaknesses
in cancer. Shaw’s lab has been able to show that genes that are critical in
cancer are also key players in metabolism. Shaw and Saghatelian are trying
to use the links between cancer genes and metabolism to identify specific
small molecules that cancer cells need to grow.
Now, they will use mass spectrometry to detect and quantify thousands of
small molecules in cells where cancer genes are turned on in the hopes of
uncovering—and eventually blocking—the molecules and pathways cancer
uses to grow.
“Alan has cutting-edge techniques to discover brand new natural lipids
in our bodies that regulate metabolism and may fight diabetes,” says
Shaw. “But these same methods can be used to study what lipids and
other metabolites are different between cancers with one type of gene
mutation versus the same type of cancer, but bearing a different gene
mutation.” By decoding the metabolic changes in closely related cancers,
they may be able to discover opportunities for new precision cancer
treatments and cancer diagnostics.
In another collaboration—spurred on after informal conversations—
Saghatelian is partnering with Associate Professor
better image critical protein-protein and protein-DNA interactions within
“The idea came about right at that bleeding edge of biology and chemis-
try,” says O’Shea, holder of Salk’s William Scandling Developmental
Chair. O’Shea—who also works with Saghatelian to tag cancer-killing
viruses with small molecules—credits many factors to these and other
exciting collaborations that are commonplace at the Salk Institute. “You
don’t have 10 researchers in the same field competing against each other.
Instead, you have the best-of-the-best from their respective fields working
together. Everyone here is a singularity, experts in their particular areas,
but with converged themes,” she says.
Saghatelian is also working with other Salk labs to understand jumping
genes and genetic mosaicism; distinguish how stem cells may differ from
each other more than expected; find out how cells in the brain known as
astrocytes contribute to Alzheimer’s disease; and uncover the connection
between metabolism and the cancer gene p53, to name a few.
“The integration of mass spectrometry into the Salk will enable new
questions to be asked and answered in all fields, including cancer,
metabolism and neurodegenerative disease,” says Saghatelian. “These
exciting collaborations are just the beginning.”
From left: Reuben Shaw and Alan Saghatelian
Inside Salk 04 | 15www.salk.edu