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A Collaboration Built Upon Structures

Some time in late 1999, Finn wandered down to the laboratory of TSRI Professor John Johnson, whom he had recently met. As Finn describes it, the two of them then spent a "golden afternoon" in Johnson's laboratory looking at the viral structures that Johnson had been working on. Among these structures was the one of cowpea mosaic virus, an icosahedral RNA virus that infects the plant that produces black-eyed peas.

"I learned from Jack that you could make these [viruses] in gram quantities," says Finn. The structures of the virus particles were known from Johnson's work, and Finn realized as he was fiddling with some of the three-dimensional models that afternoon that they could be just the building blocks he was looking for. Finn saw these virions as "supramolecular" chemical reagents that can be manipulated to display a number of interesting molecules by attaching other chemicals to the side chains of the viral component proteins.

"At that moment, I proposed to Jack that we collaborate," says Finn.

And collaborate they did. As a member of The Skaggs Institute for Chemical Biology, Finn used funding that was provided to him by The Skaggs Institute for Research to get the project started. Johnson and TSRI Assistant Professor Tianwei Lin helped Finn's group get a handle on the molecular biology of the viruses, showing him how to manipulate their protein sequences and to express and purify them, and Finn contributed his organic synthetic experience to Johnson's virions, designing ways to attach new molecules to their surfaces.

The molecular biology of the virions can be tweaked so as to provide different kinds of "hooks" onto which different chemicals can be attached. The attachments are made after the particles are harvested, intact, from infected plants, and these particles are so sturdy that the chemistry can be done over a wide range of pH levels, temperatures, and organic solvent concentrations.

These attachments are made via lysine or cysteine side chains on the subunits of the proteins that come together to make the viral shell. Since there are multiple protein subunits and potentially multiple exposed lysine or cysteine side chains, multiple copies of the added chemical can be attached.

In so doing, it is possible to produce materials with a number of different properties and a variety of potential uses. The fertile ground created by this intersection of chemistry and biology was recognized in 2001 by the David and Lucile Packard Foundation, which made Finn and Johnson the recipients of its Interdisciplinary Science Program award in a national competition.

Finn's collaboration with Sharpless also allowed him to pioneer click chemistry as a method for making attachments to biological molecules, using viruses as the test case. This has been picked up by a number of laboratories, including that of Cell Biology and Chemistry Associate Professor Ben Cravatt, for making bonds in and around cells.

Drug Delivery and Materials Design

One of the most obvious uses of virus particles is biomedical—the delivery of a drug to a particular tissue or cell type in the body, for instance. "Can you take this big particle, steer it to a particular cell type, and deliver a payload?" Finn asks.

The first step in this process, he says, is chemical sensing, or targeting a particle to a certain part of the body. For this targeting, Finn collaborates with Cell Biology Assistant Professor Marianne Manchester, who has an adjacent office and shares laboratory space in the CIMBio building. Manchester has specialized in following dye-decorated virus particles through whole animals and tailoring them genetically to find particular tissues. The goal of their collaboration is to turn the viruses into molecules that could report on disease states and perform drug delivery.

"I think we are getting pretty close," Finn says, adding that the next step is extending the technology to deliver a payload.

For the delivery, Finn works with Department of Cell Biology Chair Sandra Schmid to characterize the receptor-mediated endocytosis of virus particles with carbohydrates displayed on their surfaces. The hope is to be able to induce the cells to take up the virus particle selectively. One key to this is the fact that the virions are polyvalent, and multiple copies of some endocytosis "effector" molecule can be displayed on their surface in well-defined patterns and distances.

Finn is also working with Associate Professor Glen Nemerow in the Department of Immunology to try to design plant virus particles that mimic adenovirus, the virus that causes the common cold, which Nemerow studies. Adenovirus is already adept at getting into cells through a complicated binding and entry mechanism.

In a different twist, Finn and his laboratory are trying to use Johnson's virions to make new materials, and they have made progress in getting the virions to assemble themselves into supermolecular assemblies, aggregates, and other nanostructures by putting different molecules on the outside of the virions.

"This is the first step for us," says Finn, who adds that his goal is to be able to program the virions to make the emergent assemblies he desires.

To test this, graduate student Erica Strable, a Ph.D. candidate in TSRI's Kellogg School of Science and Technology who is a joint member of the Finn and Johnson laboratories and is funded by the La Jolla Interfaces in Science Program directed by TSRI Professor Libby Getzoff and UCSD Professor Jose Onuchic, chemically attached DNA oligonucleotides to the outside of the virus and created different pools of such oligo–virus particles with complimentary bases. Depending on where the oligos were placed on the virus, Strable found that she could assemble the pieces into two-dimensional arrays or three-dimensional aggregates in a temperature-sensitive fashion (since high temperature melts DNA).

He also has been experimenting with assembling these particles by attaching antibodies to some and antigen to others, by using metal interactions and attaching sugars to some virions and carbohydrate binding proteins to others. All of these have potential uses in biology and nanotechnology, applications that Finn is currently exploring with his many collaborators

"The best part about being here," he says. "is all the fabulous people who are in my group and around the institute. I delight in being a mentor to the wonderful students and postdocs that I find here at Scripps, both in my group and in the graduate program."

"And," says Finn, "I'm having the time of my life."


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An array of cowpea mosaic virus particles bearing complementary oligonucleotides attached to the outside surface of the virus coat protein (top panel). On the bottom panel is a cartoon of the packing of such particles; red and blue shapes indicate virions with complementary sequences.