Could mutant flies give epilepsy sufferers greater peace of mind?

Mar 21, 2011

"Exceptional, Unconventional Research Enabling Knowledge Acceleration" — is the name of a rare and competitive grant that Reenan recently won from the National Institutes of Health. Beginning April 1, Reenan will use the four-year, $1.3-million award to look for genes that can suppress seizures in fruit flies that he has cleverly engineered to mimic human epilepsy.

The epiphany, which came a few years ago, was about the surprising genetic similarity between fruit flies and people. For years Reenan has conducted basic gene expression research on a particular fruit fly gene nicknamed "para" that governs how sodium ions can trigger brain cells to electrically signal muscles to move. Ominously, the gene's name is short for paralytic.

"I'd known for years that there are sodium channel-related in humans," he said. "One day, I thought, 'I should check out what's the closest human homolog of the para gene.' So I did that."

He found a very close match between para and the human gene SCN1A. Subsequently he found that mutations on that gene underlie forms of epilepsy including the childhood forms generalized epilepsy with febrile (fever-triggered) seizures and severe myclonic epilepsy of infancy.

Reenan realized that if he could precisely and reliably create the epilepsy mutations found in the human SCN1A gene in the fruit fly para gene, he'd have a mass producible platform for genetic research into the disease. Fruit flies can be bred, engineered and observed by the thousands, and his flies would be genetically meaningful stand-ins for people.

Now that he's succeeded in making flies that mimic human epilepsy, his goal is to breed and observe the mutant flies in ways that intentionally mutate them further. Maybe one of those mutations will suppress the disease.

A unique technique

The trick, one that the NIH reviewers found to be "exceptional and unconventional" enough to support with the EUREKA grant, was making the epileptic flies in the first place. Reenan uses a technique called "homologous recombination." It's an established practice, but one that most other biologists find tricky and cumbersome. Reenan, however, has it down to a science.

When biologists have a mutation to insert, they often use a "transgenic" technique that employs a bacterium or a virus to stuff a copy of a gene, or maybe a few, into a random location on a random chromosome in a embryonic cell. It can produce interesting results once the engineered organism develops, Reenan said, but it's an inexact way to instill a genetically inherited disease.

Because the transgenic method is a way to break genetic material into an embryonic cell, Reenan uses it as the first step in a more sophisticated genetic rearrangement. For the job, Reenan's mutant snippets of DNA carry a few special tools. One is a gene on each end that allows the snippets to break free from wherever they first land and to float around the cell. Another is the gene to give the flies red eyes.

The mutant snippet very closely resembles the unmutated para gene, so when it is floating freely, it will be picked up by the cell's natural DNA repair machinery and plopped into exactly the right place on the right chromosome. In this way the fly embryos are more likely to grow up to have engineered epilepsy.

In almost every fly where the rearrangement works, the fly's eyes turn out a tell-tale red instead of their usual white. To find the flies with the epilepsy mutation, undergraduates in Reenan's lab merely need to look for the flies with the red eyes.

Cast of thousands

As Reenan and his group create and breed more and more epileptic flies, they can build a large enough population to induce mutations with chemical mutagens or radiation. Somewhere in all that genetic code that thousands of flies carry around, he's betting, some switch will flip and a mutation will turn out to interfere with epilepsy and suppress seizures in flies that were created to have them. In essence, the flies will then contain what he calls "a genetic cure."

This is clearly a methodology that cannot be employed with people, but given the genetic overlap between para and SCN1A, if there's a genetic means to combat epilepsy in people, Reenan's flies might reveal it.

"With , the treatments are generally fairly broad and with a lot of side effects and we don't really understand epileptigenesis — why do seizures happen, how are we going to treat them," Reenan said. "So the idea is pretty simple. Let's just use standard fruit fly suppressor genetics and find mutations that suppress or cure the seizures."

Explore further: Improving the productivity of tropical potato cultivation

add to favorites email to friend print save as pdf

Related Stories

Human aging gene found in flies

May 12, 2008

Scientists funded by the Biotechnology and Biological Sciences Research Council (BBSRC) have found a fast and effective way to investigate important aspects of human ageing. Working at the University of Oxford and The Open ...

Severe Epilepsy Linked to Gene Mutation

Sep 14, 2009

University of Utah medical researchers have identified a gene with mutations that cause febrile seizures and contribute to a severe form of epilepsy known as Dravet syndrome in some of the most vulnerable patients - infants ...

Searching for shut eye: Study identifies possible sleep gene

Jul 29, 2008

While scientists and physicians know what happens if you don't get six to eight hours of shut-eye a night, investigators have long been puzzled about what controls the actual need for sleep. Researchers at the University ...

Recommended for you

Building better soybeans for a hot, dry, hungry world

2 hours ago

(Phys.org) —A new study shows that soybean plants can be redesigned to increase crop yields while requiring less water and helping to offset greenhouse gas warming. The study is the first to demonstrate ...

Gene removal could have implications beyond plant science

2 hours ago

(Phys.org) —For thousands of years humans have been tinkering with plant genetics, even when they didn't realize that is what they were doing, in an effort to make stronger, healthier crops that endured climates better, ...

Chrono, the last piece of the circadian clock puzzle?

16 hours ago

All organisms, from mammals to fungi, have daily cycles controlled by a tightly regulated internal clock, called the circadian clock. The whole-body circadian clock, influenced by the exposure to light, dictates the wake-sleep ...

User comments : 0

More news stories

Ranchers benefit from long-term grazing data

Scientists studying changes in the Earth's surface rely on 40 years of Landsat satellite imaging, but South Dakota ranchers making decisions about grazing their livestock can benefit from 70 years of data ...

Floating nuclear plants could ride out tsunamis

When an earthquake and tsunami struck the Fukushima Daiichi nuclear plant complex in 2011, neither the quake nor the inundation caused the ensuing contamination. Rather, it was the aftereffects—specifically, ...

Unlocking secrets of new solar material

(Phys.org) —A new solar material that has the same crystal structure as a mineral first found in the Ural Mountains in 1839 is shooting up the efficiency charts faster than almost anything researchers have ...