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John Yin

Chemical and Biological Engineering

A tenfold improvement
in measuring virus infectivity

Professor John Yin (pictured) and graduate student Ying Zhu tweaked the standard system for measuring virus infectivity, digitized it, quantified it, analyzed it, and discovered a method more than 10 times as sensitive.

Plaque tests are regarded as the gold standard for measuring virus infectivity. The technique involves introducing tens to hundreds of virus particles into a Petri dish containing millions of healthy cells. Technicians cover the cells with an agar or Jell-O-like substance that keeps the virus from flowing freely, yet allows it to infect nearby cells. As these infections spread, they produce visible spots of dead cells called plaques. Counting the plaques gives a measure of infectivity.

Path of infection in liquid growth medium and infection in an agar.

Left: Virus particles in liquid medium flow to cells well beyond their neighbors. The path of destruction creates a firework-like pattern. Right: Virus infectivity in agar. (Large image)

“It’s sort of like watching a pandemic spread in a Petri dish,” says Yin. “What we’ve found is a way to amplify the signal that a virus can give when it infects. The traditional idea is that one tries to prevent the random flow of the virus particles by using the agar, but we’ve found that fluid flows can be quite uniform and actually enhance the readouts for infection.”

Ultimately, a more sensitive detection system could help clinicians provide more individualized and finely tuned therapy to their patients, aid drug developers in testing anti-viral drugs, and assist health scientists in identifying drug-resistant viruses. The system also could give scientists the beginnings of a new way to understand how some viruses spread in people.


The right genes—in the right place at the right time

Gene therapy— the idea of using genetic instructions rather than drugs to treat disease—is not yet a viable therapeutic method. One sizeable hurdle is getting the right genes into the right place at the right time.

Assistant Professor David Lynn and his colleagues have created ultrathin nanoscale films composed of DNA and water-soluble polymers that allow controlled release of DNA from surfaces. When used to coat implantable medical devices, the films offer a novel way to route useful genes to exactly where they could do the most good.

Lynn has used his nanoscale films to coat intravascular stents, small metal-mesh cylinders inserted during medical procedures to open blocked arteries. While similar in concept to currently available drug-coated stents, Lynn’s devices could offer additional advantages. For example, Lynn hopes to deliver genes that could prevent the growth of smooth muscle tissue into the stents (a process that can re-clog arteries), or that could treat the underlying causes of cardiovascular disease.

Preliminary laboratory tests of the DNA-coated materials are promising. “The films survive basic mechanical forces associated with placement and expansion of stents,” Lynn says. He and his colleagues also have demonstrated gene delivery to cells grown in a dish.

In preliminary experiments conducted in collaboration with Matthew Wolff, Timothy Hacker and Jose Torrealba in the UW-Madison School of Medicine and Public Health, Lynn has shown that DNA film-coated stents can successfully deliver a gene encoding a fluorescent protein into a rabbit artery, demonstrating that the films also can work in the complex environment of living tissue.

When placed in or near a body tissue, the films are designed to degrade and release the DNA. Large strands of DNA cannot normally penetrate cells, so Lynn constructs his films with special polymers designed to bundle the genes into small, tight packages that cells can import. Once inside, the genes instruct the cells to make proteins.

Stem cells used to create critical brain barrier in the laboratory

The blood-brain barrier is a critically important structure, says Associate Professor Eric Shusta. Not only does it physically block the movement of substances between blood and brain, but it also possesses active properties that enable cells to pump unwanted molecules back into the bloodstream. What’s more, it has a metabolic function that can alter the chemical properties of the molecules that do get through to the brain.

Using nascent rat neural stem cells, a group led by Shusta prodded blood vessel cells to assume properties of the blood-brain barrier.

Demonstrating that developing brain cells can release factors that may coax small blood vessels to exhibit the properties of the blood-brain barrier is important for a number of reasons. First, it forms a basis for understanding the mechanism that provides critical protection for the brain. Second, it may lead to insights regarding ways to overcome a barrier that frustrates neuroscientists, drug companies and clinicians who would like to sneak drugs past it to treat disease.

“What we have shown is that these neural stem cells have the ability to stimulate adult blood-vessel endothelial cells to display enhanced blood-brain barrier properties,” Shusta says. “This may lead to new in-vitro models of the blood-brain barrier.”

That in turn may help researchers devise new therapies to treat brain disease and to form a clear understanding of how the barrier forms during the course of development.

“One of the big questions of (brain) development is how does the blood-brain barrier form and when does it form,” says Shusta. “That’s poorly understood.”

The research team included UW-Madison School of Medicine and Public Health Professor Clive Svendsen—a stem cell authority—and postdoctoral fellow Christian Weidenfeller.

The study was funded by a grant from the National Institutes of Health.

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