Vol 6. Issue 13 / April 10, 2006
Simple Tools for Complex Problems
By Eric Niiler
Valery Fokin seemed destined to be a top scientist after his seventh grade chemistry teacher kicked him out of class. He wasn't a troublemaker. He got too far ahead of the rest of the students.
"The teacher said I was not learning anything, and she let me go to the back room, where chemicals were stored and demonstrations were prepared," says the affable 34-year-old Scripps Research Institute assistant professor, who grew up in Nizhny Novgorod, formerly known as Gorky, Russia. "I played there for the rest of the year with anything I wanted. When I think about it today, 'liability' was not a big word in Russia. Nothing was too dangerous."
Classroom exile led to typical boyhood experiments—any substances he could find that would react explosively when thrown together in a test tube. But Fokin also developed a sense of wonder about the simple yet powerful chemical reactions that nature produces on its own.
Even today, Fokin prefers working with the fundamental building blocks of chemistry. He also likes to push the boundaries of experimental progress instead of making the slow, steady steps that many scientists favor.
"My personal approach is very utilitarian—if there is hope that something interesting can happen, you have to push it to extremes," Fokin says. "Don't overthink it. If you want to answer all the 'what ifs' up front, then it's probably going to remain an academic task."
Exploring Chemical Bonds
Fokin's sense of scientific risk-taking as a chemist continues at Scripps Research. He has been on the La Jolla campus since 1998, first as a postdoctoral fellow in the laboratory of Nobel laureate Professor K. Barry Sharpless, and now as an assistant professor in the Department of Chemistry.
His current work at Scripps Research involves development of chemical catalysts using metals, using them to understand biological interactions, developing new materials such as a group of large molecules called dendrimers, as well as making new high-tech adhesives and coatings for electronics and medicinal use.
What these research interests have in common is Fokin's search for chemical bonds that are strong, easy to make, and unproblematic in the human body. Pursuing those goals is possible at Scripps Research—a place where scientists can be highly focused on narrow scientific fields, but where conversations and ideas cross-pollinate.
"I often don't know to which department people officially belong because the atmosphere is so conducive for collaboration," he says. "It has been an ideal environment to learn the biology from the masters and to explore the applications of chemistry we develop. I am certain that much of what we have accomplished was only possible at Scripps."
In fact, as an assistant professor at Scripps Research Fokin made a discovery about a special kind of chemical reaction that has gained attention throughout the research community. He used chemicals that contain azides and alkynes, molecules that are not very reactive by themselves, but that produce a five-membered ring called a triazole when they do react with each other. Fokin found a powerful way to stitch molecules together with triazoles in the presence of water, oxygen, and other biological substrates by using copper-containing additives to speed up the azide-alkyne reaction. Colleagues have described this copper-catalyzed process as "a molecular USB plug" that has implications for basic science as well as more applied research.
"It answers some fundamental questions about reactivity, and it's a platform for doing many different things in chemistry, biology, materials, and electronics, " he says. "Triazoles are remarkably stable, both in biological systems and in more extreme environments, yet they interact with many organic, inorganic, and biological substances in special ways."
Although azide- and alkyne-containing molecules are easy to make, and the reaction between them has been known for over 100 years, it was not widely used because it is so slow under most conditions. "One reaction has been sitting on my office desk more than three years, and it just began to show signs of triazole formation," says Fokin. To speed it up, he filled a vial with water, alcohol, an azide, and an alkyne, added plentiful copper sulfate along with a reducing agent—ascorbic acid. He picked up a bottle of Vitamin C at Trader Joe's, and voilà, this mixture proved to be remarkably effective. The reaction only took several hours and produced the desired triazole product.
He tried the same experiment in human plasma and the reaction went even faster. Fokin ran it again filling the vial with copper wire instead of copper sulfate and ascorbate, and the pure white product appeared the next morning.
Because of their stability and interactions with biological macromolecules, such as receptors and enzymes, triazoles are good base structures to develop potential pharmaceuticals. Fokin says the copper-catalyzed azide-alkyne cycloaddition becomes "a universal stitching tool, because it brings together any building blocks we want to assemble in a stable way. [The reaction] makes it easier to do more complicated things."
Fokin's research on copper reactions is part of a new wave of "click chemistry," a field pioneered by Fokin's mentor Sharpless, former Scripps Research Professor Hartmuth Kolb, and Scripps Research Professor M.G. Finn several years ago.
Click chemistry seeks to build useful molecules by using only the simplest and best reactions, not necessarily the most sophisticated, according to Sharpless. Just as nature uses only a few types of reactions to stitch together its functional molecules (proteins and nucleic acids), chemists using click reactions canquickly discover new molecules from pre-made building blocks. Sharpless said Fokin's discovery of the copper catalysis was the kind of big picture thinking that click chemistry requires. "You can use this reaction in a sewer or in minestrone soup," Sharpless notes. "Valery knew this in a matter of weeks. Most scientists do this one step at a time and then in 50 years find out something."
Sharpless describes Fokin as a non-linear thinker who sees beyond traditional ways of going from one place to another during the experimental process. Sharpless adds, "When I talk with him, I often say to myself 'I wish I'd done that.'"
A Chain Reaction
Since Fokin and his colleagues published the report on the copper-catalyzed azide-alkyne reaction in 2002, many other researchers have built upon this work. Fokin has collaborated with Scripps Research Professor Chi-Huey Wong to use the reaction to find inhibitors of fucosyltransferase, a target for controlling inflammation and cancer metastasis. Scripps Research Professor Benjamin Cravatt III has used the reaction to profile whole proteomes.
And Fokin has collaborated with Craig J. Hawker's group at the IBM Almaden Research Center and the University of California, Santa Barbara, to build giant molecules called dendrimers that are shaped like a series of symmetrical tree branches emanating from a central core.
Dendrimers are bigger than most molecules, about the size of proteins, but have a much more regular structure. Fokin compares dendrimers to foamy, but perfectly round balls. "You can coat them with anything you want to make them sticky, shiny, glossy," he said. "They can stick to certain things but not to other, delivering a specific function selectively. This is another molecular building block."
In 2004, Hawker and Fokin used the reaction to make dendrimers more quickly and more efficiently. They've also used it to attach carbohydrates, fluorescent dyes, and other compounds to the dendrimer's outer shell.
David A. Tirrell, a professor of chemistry at the California Institute of Technology, is using the copper reaction to attach molecular "tags" to bacteria in order to visualize changes in the cell membrane, and to proteins in mammalian cells to see what happens to them during a disease. Stanford Professors James P. Collman and Christopher Chidsey are using it to modify metal surfaces to better understand electron transfer processes. Micro-engineers are using the copper reaction as a stitching tool for building nano-devices, such as molecular-sized switches.
As for his next research project, Fokin says he's looking for catalytic properties of other metals that may be more powerful than copper. That could lead to the development of new molecular structures useful in chemistry, biology, and medicine. It's likely he'll be looking for an interesting, yet uncomplicated way to make these reactions work.
"The assumption by many scientists is that complex problems require complex solutions," he says. "My goal is to demonstrate that complex problems can be addressed with simple tools if they are used properly."
Send comments to: mikaono[at]scripps.edu