Device to mimic brain to test drug therapies

NASHVILLE – A mechanical device as small as a grain of rice is about to replace the mice.

“It eventually will save time,” Wikswo said. “It will clearly save money. More importantly, it has significant implications for all of biology and medicine because you get to see how organs interact in a much more controlled way than you can in a whole animal.”

Mice are most often used in research because their genes are very similar to those of humans and can be genetically engineered to mimic diseases like diabetes and cancer. But drugs that work in mice often turn out to not have the same effect in humans. In fact, more than 30% of the medicines that show promise in animal studies prove to be toxic when human trials begin, according to the National Institutes of Health.

Advancements in microfabrication over the past 10 years have made tiny devices — organ-on-a-chip technology — seem like a promising alternative.

That doesn’t mean mice will be completely free from laboratory cages.

“I don’t think it would get rid of the mouse model entirely,” Wikswo said. “Mice are probably going to be easier to use than this. The idea is you use the mouse when it is appropriate, but there are a lot of times when it is not the best thing. It is the only thing in town right now.”

A group of professors large enough to field a baseball team is working on the microbrain project, but the most valuable player so far has been a post-doctoral researcher at Vanderbilt. Shannon Faley, a biomedical engineer, built a chip back in 2007 to track lymph node interactions. She convinced Wikswo to start writing proposals to design a brain on a chip.

The team will initially focus on how three naturally occurring blood-brain barriers react to substances. These barriers act as traffic cops for the brain, letting some substances through, blocking others and sometimes altering the chemistry of potential drug therapies.

Donald J. Alcendor, a professor of microbiology at Meharry, has expertise with one type of blood-brain barriers, which are called pericytes. His research has revealed how cytomegalovirus spreads into the brains of fetal babies by infecting the pericytes. This virus causes deaths in babies and birth defects, including hearing loss, blindness and mental retardation.

Alcendor said the microbrain could also help with the discovery of treatment for AIDS-related dementia and non-viral brain diseases if it can identify pathways for drugs to get around the bottleneck caused by the blood-brain barrier.

“This blood-brain barrier in itself is very protective,” Alcendor said. “At that same time, it is a problem for drugs to be delivered into the brain. When you look at those abnormalities, we are talking about Alzheimer’s disease, epilepsy, stroke and so forth. These are serious conditions.”

Instead of using laboratory mice to test new drug therapies, scientists will put human cells into microfabricated bioreactors that mimic how organs respond to experimental medicines. This new technology could speed up drug development, cut costs and curb false hopes.

Vanderbilt University has a $2.1 million grant to develop a “microbrain” as part of a $70 million initiative by the National Institutes of Health. The over-arching goal is to solve brain function mysteries related to obesity, Alzheimer’s, epilepsy and viral infections.

Vanderbilt, working in partnership with scientists from the Cleveland Clinic and Meharry Medical College, was among 17 research institutions that received funding. All 17 are on a quest to create tiny devices that will reveal how human cells in the brain, heart, lung and other organs react to medicines.

John P. Wikswo, a professor of biomedical engineering and molecular physiology at Vanderbilt, is heading the microbrain project. The device will contain human brain cells donated by patients and be connected to tubes as thin as spiderweb threads that supply cerebral spinal fluid and other substances. Sensors will gauge how the cells respond to drug molecules.

The team has high hopes. BethAnn McLaughlin, a professor of neurology at Vanderbilt, sees the microbrain as a valuable tool for even more potential discoveries.

“Not a single drug has passed FDA approval to protect the brain from stroke, and we only have one that breaks up clots,” McLaughlin said. “We need to do better.”

Other members of the microbrain team include Vanderbilt professors Donna Webb, who works in biological sciences; Deyu Li, whose expertise is mechanical engineering; John McLean, a bioanalytical chemist with expertise in mass spectrometry, and David Cliffel, a chemist who works in microfluidic technologies and electrochemical detection.

Once the device is fully developed and tested, Scott Daniels, a Vanderbilt professor of pharmacology, will coordinate drug testing with the Cleveland Clinic.

Other Vanderbilt professors, Kevin Niswender and Kate Ellacot, plan to use the device to study obesity triggers in the brain.

Besides potential drug therapies, the microbrain also may be used to better understand how the brain processes and reacts to environmental toxins or other chemical agents. That is one of the reasons Defense Advanced Research Projects Agency is collaborating with the NIH on the 17 funded projects. DARPA is part of the Department of Defense. Wikswo said he is confident that federal funding will continue for the initiative.

Source: USA Today

Category: Technology & Devices