Collaborations Are Everything
By Jason Socrates Bardi
"All
things are connected..."
Quote
attributed to Chief Seattle, 1854
Of all the collaborations in which Associate Professor M.G.
Finn has participated since coming to The Scripps Research
Institute (TSRI), few have been more rewarding than a day
he spent in his laboratory making molecules last summer.
That day, he was entertaining and being entertained by his
eight-year-old son, Marc, to whom he was giving a hands-on
demonstration of the magic of organic synthesis and discovery.
Earlier in the week, Finn had set up a synthetic reaction
so that it was all but complete. The last step—simply
mixing two solutions together—he had saved for his son.
"When I handed [the beakers] to him," says Finn, "I said,
'You are making something that has never existed on earth
before.'"
Finn's son then mixed the ingredients and the solution changed
color (no stranger to the education process, Finn had set
up the reaction this way). This brought a smile to the child's
face, who realized the color change meant he had created something
new. And Finn smiled as well, pleased to see his son as excited
as he was about making molecules.
The more advanced lesson, what these molecules do, would
wait for another day. For the moment, both father and son
shared the joy of basic discovery, and were satisfied with
their collaboration.
The Mechanism is the Message
Indeed, collaboration has been a satisfying way of life
for Finn, who trained originally as an inorganic chemist and
spent the bulk of his career in organometallic chemistry before
pursuing an interest in biology after he heard a lecture by
TSRI President Richard Lerner in the mid-1990s. Hoping to
learn more molecular biology, Finn asked Lerner after the
lecture about the possibility of doing a sabbatical at TSRI.
"I knew no molecular biology, and I wanted to learn," says
Finn.
Finn arrived at TSRI in 1996 to do a year-long sabbatical
while he was still a professor at the University of Virginia.
He worked with Professor Carlos Barbas and Lerner on catalytic
antibodies—looking at metal additives to the aldolase
antibody system, a class of antibodies that are capable of
catalyzing aldol reactions.
After he returned to Virginia, he was offered a position
at TSRI, including an invitation to join The Skaggs Institute
for Chemical Biology. He accepted, returning the next year
with a small number from his group and working temporarily
out of a few fume hoods in the laboratory of TSRI Professor
and 2001 Nobel laureate K. Barry Sharpless. By 1999, Finn
had transitioned his entire laboratory to TSRI and occupied
space in the CVN building, where part of his group remains
today.
Another part of his group occupies some of the brand-new
laboratory space devoted to the Center for Integrative Molecular
Biosciences (CIMBio) at TSRI, of which Finn is a founding
member. CIMBio is a new collaborative effort whose mission
is to foster multidisciplinary studies of molecular "machines,"
with the aim of determining their structure, their mechanism
of action, and their dynamic behavior in the context of living
cells.
CIMBio suits Finn well, because as a chemist, he loves to
synthesize molecules, especially those that might be useful
catalytic engines, and to study their mechanisms and how they
behave. "What they do and how they do what they do," says
Finn. "That's what I love to think about."
And his broad research goals are to use the reactivity of
these molecules—especially metal-containing ones—to
drive reactions in chemistry and biology. CIMBio provides
him with lots of opportunities to collaborate with biologists
and conduct research that asks what his molecules do in living
cells and organisms.
Mass Spectrometry as an Analytical Tool
Finn has many other collaborations as well, including some
that he started shortly after he first arrived at TSRI. One
of his first collaborations was with Gary Siuzdak, who directs
the Center for Mass Spectrometry at TSRI. Finn and Siuzdak
have been using mass spectrometry as an analytical tool for
the high-throughput screening of catalytic compounds and for
measuring the efficiency of enantioselective chemical catalysis—reactions
that produce either right- or left-handed enantiomers.
"We're interested in profiling the activities of new and
known catalysts, screening them against a variety of potential
substrates all at once, and getting a rough idea of what is
good and what is not good," says Finn.
For instance, the scientists can react different chiral
catalysts with different "mass-tagged" chiral substrates,
making products that can be read according to their masses.
The mass spectrometry then enables the scientists to determine
the most efficient catalysts, and Finn and his colleagues
are applying this technique to many different catalytic reactions
and many broad classes of substrates, including alcohols,
epoxides, ketones, aldehydes, and olefins.
The technique is quick, sensitive enough to detect very
small amounts of material, and does not require the substrate
to be altered (by adding a fluorophor, for instance).
Finn and Siuzdak are also working to couple this technique
with another, which Siuzdak has pioneered, that uses laser
desorption/ionization of small molecules on porous silicon.
Small amounts of substrate can be chemically attached to the
porous silicon, and Finn and his coworkers have discovered
a unique set of cleavable linkers that allows selective detachment
of these molecules during the ionizing laser pulse—the
first step in analyzing their mass molecules.
Another Research Project is Born
Finn's work with Professor Sharpless dates back long before
Sharpless loaned him laboratory space when Finn first arrived
from Virginia. Finn received his Ph.D. degree from Sharpless's
group in the mid-1980s, and he and Sharpless had stayed in
touch since. When Finn arrived at TSRI in the late 1990s,
their longstanding collaboration was reborn.
Sharpless was working on a new idea called "click chemistry."
Click chemistry, a modular protocol for organic synthesis
that Sharpless developed, is a powerful and original approach
to drug design. In its "in situ" variant, the target itself
is recruited to play a decisive role in the synthesis of its
own inhibitor in the last step.
The first target molecule that Sharpless and his colleagues
worked on was acetylcholinesterase, a brain enzyme that breaks
down acetylcholine, the neurotransmitter that propagates nerve
signals. Inhibitors of acetylcholinesterase are used to treat
the dementia associated with Alzheimer's disease, increasing
the amount of acetylcholine in the brain, in turn enhancing
brain activity.
Finn's student Warren Lewis, a Ph.D. candidate in TSRI's
Kellogg School of Science and Technology, sorted out the kinetics
of the system with the help of Sharpless and Finn's collaborator
Palmer Taylor at the University of California, San Diego.
Finn notes that the mass spectrometry technique developed
by his and Siuzdak's laboratories was instrumental in identifying
the "hit" in the project. It enabled them to pick out the
tiny amount of inhibitor that was synthesized with the help
of the acetylcholinesterase enzyme. This success was reported
last year by Lewis, Finn, Taylor, Sharpless, and several others
in an article in the journal Angewandte Chemie.
The success of the acetylcholinesterase work also gave Sharpless
and Finn the opportunity to join a program project grant directed
by TSRI Professor Arthur Olson. The project seeks to establish
a drug design cycle aimed at developing, testing, and refining
novel approaches to making specific inhibitors that will hit
resistant mutants of HIV protease.
"That enzyme," says Finn, "should, in principle, be amenable
to the same kind of [click chemistry] strategy as acetylcholinesterase."
The strategy, he explains, is best applied where protein-protein
interfaces exist. Such regions often have multiple potential
binding sites for small molecules—as in the case of the
HIV protease, a dimer formed by two identical protease monomers.
Acetylcholinesterase itself is not a dimer but has two known
binding regions adjacent to each other.
TSRI Assistant Professor Valery Fokin of the Sharpless lab
is directing the synthesis of component molecules that will
be used as building blocks for designing inhibitors. Other
collaborators in the program project will provide mutant and
wild-type protease, and the Sharpless, Fokin and Finn laboratories
will attempt to hit them with these diverse blocks, as they
did before with acetylcholinesterase, and fish out those combined
molecules that the protease enzyme itself assembles.
"We want to let the enzyme teach us what inhibitors [it
prefers]," says Finn. "Those, in general, should be the better
inhibitors."
The Finn and Sharpless laboratories are also using click
chemistry to develop new materials, and they have chosen to
make adhesives first. They quickly found a metal adhesive
that is far stronger than the glues currently sold for the
purpose.
And Finn, chemist at heart that he is, has also continued
to develop new synthetic methods and apply them to the biological
targets of his collaborators. Finn's group recently published
a new method to make a new class of pharmacophores by bringing
together urea compounds with guanidine-like compounds. This
has allowed them to create "tunable" electrophiles that react
with a wide range of nucleophiles.
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