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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

Reuben Shaw

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

Clodagh O’Shea

to

better image critical protein-protein and protein-DNA interactions within

living cells.

“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.”

»

View video:

www.salk.edu/saghatelian

From left: Reuben Shaw and Alan Saghatelian

6

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Inside Salk 04 | 15

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