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Endless Possibilities

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At Nashville's Vanderbilt Institute for Integrative Biosystems Research and Education, the motto might well be, 'Anything's possible.' As a center for technology development that's building microfabricated devices, cellular biosensors, and everything in between, the institute, which is affiliated with Vanderbilt University, is forging full steam ahead into collaborative biology.

Some of the technologies that VIIBRE is helping to pioneer include cellular biosensors for cancer research, single- and multi-cellular instrumentation and control devices, biomedical imaging, biological applications of nanosystems, cellular and tissue bioengineering, as well as advancing an internationally regarded undergraduate research program. A specialty at VIIBRE is microfluidic devices with thin-film and optical sensors, and the center, which is located on the first and eighth floors of the Stevenson Center for the Natural Sciences and Engineering, has 500 square feet dedicated to the process.

All this would not be possible without the focus on interdisciplinary science. John Wikswo, a professor of physics and bioengineering and director of VIIBRE, says he has focused from day one on encouraging a broad range of disciplines working under one roof. "VIIBRE works like a scientific research cooperative. We have a group of like-minded faculty from all over the university — physics, chemistry, mathematics, biomedical engineering, mechanical engineering, chemical engineering, environmental engineering, cancer biology, cardiology, pathology — that basically are trying to solve problems in biology that are difficult to solve with existing technologies."

Wikswo says a lot of engineering development is in response to biologists' needs, and stems from dreaming up novel ways to study single cells or small populations of cells. "Primarily we're trying to do experiments that are very difficult in conventional cell culture where cells are in such large volumes of fluid" that the signaling factors they're trying to measure are diluted, he notes. "We build microfluidic devices where the cells are trapped in a very small volume. When they excrete something, they excrete it in[to] such a small volume that the concentration stays high, which allows you, one, to measure it and, two, to have an effect on the cell," he adds. The devices are useful for watching how cells move during metastasis, for instance.

They tend to build simple devices since biologists are used to straightforward, low-cost assays rather than high-tech gadgets. In terms of collaboration, the engineers and biologists exchange a lot of cross-talk to get things done. "It's engineers who are teaming with biologists [and saying], 'What do you need to measure that you currently can't measure?'" Wikswo says.

Single cells

Lisa McCawley has been collaborating with VIIBRE for some time, actively helping to develop microfluidic tissue bioreactors to model and observe, on a single-cell level, the tumor microenvironment and how immune and tumor cells migrate out of the endothelium. With pilot funding from VIIBRE, she and her team developed prototypes and got initial data, and now she's nailed down instrumentation grants to further develop her devices.

McCawley is a professor of cancer biology at the Vanderbilt University School of Medicine, but her background is in pharmacology and toxicology. At VIIBRE, she is able to advance her focus on wound healing and modeling tumorigenesis by working with engineers to design a way "to actually look at all the processes of immune cells infiltrating out of blood vasculature," she says. She was matched with a postdoc and "it's been an interesting journey because I'm not an engineer and he is."

In their reactor systems, they've built channels that are lined with receptors or endothelium; these will eventually become model vessels over which they'll flow immune or tumor cells to see how they migrate out of endothelium. The main advantage of this system is that it's a much smaller scale than using tissue culture, and "you can have much ... finer control over what you're introducing and also how you're introducing it," McCawley says. "Can we actually start to measure forces of interactions by looking at these cells rolling on endothelium or on receptors … and actually start to challenge the system in different ways?"

One of the draws of the institute was the ease of interaction and the ability to create things that biologists might not be able to come up with, McCawley says. "To be honest, I think our biggest challenge was developing enough of a common vocabulary to communicate with each other," she says. "I think it took a good year of Dmitry and I meeting and also showing each other what we meant, before we had a good working vocabulary and could use just a few words to get our points across to each other." She says being part of VIIBRE has changed the way she thinks about doing research. "If I want to measure something and the correct technologies are not available, I figure that we can just build it," she says.

Modeling cancer

Playing with single cells can be just as fun in silico, too. Vito Quaranta, a professor of cancer biology at the Vanderbilt-Ingram Cancer Center, came from Scripps in 2003 and got a grant for cancer research. "It's been an interesting journey," he says. Over the past five years, he says, "I think the biggest achievement is that we've started to look at some old problems that have dogged cancer research for a long time with completely new eyes — with the eyes of mathematics."

To study trends in growth and metastasis, Quaranta's team builds computer simulations, forms new hypotheses, and then tests them by populating their models with real data. In true systems biology fashion, they'll often then attempt to validate their predictions experimentally. The group is made up of many different scientists, from cell and molecular biologists to mathematicians, engineers, bioengineers, bioinformaticians, and computational biologists.

"We're looking at defining certain properties of cancer cells, [meaning] properties at the cellular level," Quaranta says. "Today the big challenge is to really define in quantitative terms what does it mean for a cancer cell to be more proliferative, what does it mean for a cancer cell to be less susceptible to natural death, and what does it mean for a cancer cell to be more motile?"

Here, single-cell analysis and microfluidic devices have come in handy. "The key technological development is the ability to actually track down — at least in the laboratory — single cells," he says. Not only can Quaranta watch how single cells function, but he can also begin to tackle the problem of tumor heterogeneity, finding those few cells in a tumor that don't react like the rest and therefore make getting rid of the whole tumor so difficult. "That's why we follow single cells," Quaranta says. "Because if we can actually put numbers on what every single cell does — in terms of proliferation, metabolism, whatever — then we can put those numbers into the simulation and have simulations that are more realistic."

Because they're located so close to one another at VIIBRE, the different disciplines are actually forced to interact. Additionally, they have mixed offices so that people can form friendships and become "unafraid of each other's jargon," Quaranta says.


Vanderbilt Institute for Integrative Biosystems Research and Education

Nashville, Tenn.
Director: John Wikswo
Established: 2001
Facility: VIIBRE is located on the first and eighth floors at the Stevenson Center for the Natural Sciences and Engineering, Vanderbilt University
Faculty: More than 40 fellows and external associates
Funding: A $5 million, five-year grant from the Vanderbilt Academic Venture Capital Fund
Focus: Bridging biology, physics, medicine, engineering, and education, VIIBRE's research focuses on cellular biosensors for cancer research, chemical and biological warfare defense and infectious disease detection, single- and multi-cellular instrumentation and control, biomedical imaging, biological applications of nanosystems, cellular/tissue bioengineering and biotechnology, and bioengineering education technologies.
Core labs: Cardiac imaging, Superconducting Quantum Interference Device (SQUID) imaging, microfabrication, cellular instrumentation and control, and more

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