by Carol Flaherty
MSU News Service

1/19/2000 - BOZEMAN – Under Mark Young's tutelage, parts of a plant virus may help us as faithfully as a friendly pet by fetching and delivering medicines.

Young, a Montana State University plant scientist, has learned how to open and empty the protein "cage" that is part of a cowpea virus. He can then tell the empty cage to manufacture medicine or other material, and after that, tell it to open and release the medicine. Now he is adding a way to target exactly where the virus cage delivers its contents.

The first target will be cancer cells.

Jack Johnson, a molecular biologist at Scripps Research Institute in La Jolla, Calif., says Young's research "occupies a totally unique niche in the world of material sciences. No one has used these particles as a container to do chemistry and crystalization before . . . It is an interesting and important new direction in both chemistry and material sciences."

Historically, we have used everything from animal intestines to purses to carry things. Young's work simply makes a tote-bag out of something we can't see without an extremely high-powered microscope. He plans to have the virus cage find cancer cells by latching onto their unique chemistry. If the protein cage accurately finds its way to targeted cancer cells, it could mean the difference between spreading chemotherapy throughout a body compared to sending it only where needed, says Young.

Several parts of the puzzle have already been reported in the scientific literature, including the prestigious journal Nature and the popular magazine Discovery in 1998, and in chemical journals, including Advanced Materials in 1999. Young says he plans to complete the targeting process and report on it in the year 2000.

There are two conceptual ingredients to what he is doing, says Young: understanding how a virus puts itself together and knowing what a virus does well.

"A virus is good at transporting itself and at delivering what is inside of its protein cage," says Young. "Normally it delivers its own genetic information, which then reproduces to create more virus. But if we get rid of that genetic information, we have empty protein cages that we can use as cooking pots. . . . We selectively entrap materials or even get the protein cage to make a material."

Synthesizing medicines inside a cage too small to see is done by changing the electrical charge of the cage. Opening and closing the cage is done by changing its degree of acidity. At more acidity, the empty cage of a cow pea virus is sealed off from its environment. At less acidity, the cage swells up and little triangular holes open to create an exit for the substance inside.

Young has repeatedly been able to empty, open and close the cage and synthesize materials inside, but at first lacked a way to target the product to a useful site. Jean Starkey, an MSU microbiologist, provided that. After hearing Young describe his work, Starkey told him that her lab and others are working with an amino acid sequence that binds to the protein of cancerous tumors.

That sequence will be the key to targeting cancer cells. Knowing a protein's amino acid sequence is like knowing the shape of the interior of a lock. Once you know it, you can determine a complementary sequence to fit it like a key. These keys are so tiny that you can coat the outside of the empty virus cage with them. Then the human system circulates the key until it fits into a lock.

"The more malignant the tumor, the more of this protein is made," said Starkey.

To add to the system, Young says he will coat the outside of his empty protein cage with molecules of metal. Once the cage has attached to a cancer cell, doctors can use the metal molecules to target radiation therapy or to accurately see the cancerous area by x-ray or magnetic resonance imaging.

"The problem has always been getting a good enough signal to target," says Starkey. "This will be a very hot signal. Medical imaging people will be able to see very small numbers of cancerous cells."

Now that Young has the basic tool of the protein cage, he says adding functions is "just like adding parts to Legos."

Mark Young in his lab in MSU's Agricultural Bioscience Building.

A 300 dpi color image is available at: http://www.montana.edu/wwwpb/ag/markyoung.jpg 

ABOUT THE FOLLOWING IMAGES: Mark Young explains that the shape seen in the computer images is identical to the true shape of the virus, though the color is not. Two different techniques (high resolution transmission electron microscopy and X-ray crystallography) are designed to determine the 3-D shape of small biological molecules such as viruses. The resolution of these techniques allows us to see individual molecules (i e amino acids) that make up the protein cage of the virus particle.

Colorful image shows the shape of the cowpea virus with its protein "cage" accented in red. A web resolution color preview of this is available at:

http://www.montana.edu/wwwpb/ag/viruscageLR.jpg

A 300 dpi color image of this is available at:

Black and white drawing, originally 72dpi modified to 300 dpi, demonstrating the opening and closing of the cowpea virus and releasing of its content.

Higher resolution at: http://www.montana.edu/wwwpb/ag/openshuthands.jpg

Web resolution at: http://www.montana.edu/wwwpb/ag/openshuthandsLR.jpg

The "betahexamers" that make up the protein cage look like intricate groups of dancers. Originally 72 dpi, a 300 dpi version of this red and green image are at:

http://www.montana.edu/wwwpb/ag/betahexamer.jpg