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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"What [molecules] do and how they do what they do," says Associate Professor M.G. Finn. "That's what I love to think about." Photo by Jason S. Bardi.