Leila Eter ’18 and Lauren Smith ’18


When we visit the doctor with a medical concern we typically expect to leave with a prescription. One pill in the morning, one at night, and some water and nourishing foods to fuel the body for healing. But when Hollywood producer Jim Abrahams took his one year old son, Charlie, to Johns Hopkins in 1993 for treatment of epilepsy, he was prescribed… high fat diet? Doctors prescribing fat? It seems a little bit counterintuitive, but to Jim’s surprise, this once-controversial treatment stopped his son’s crippling seizures altogether in only three days, a feat that several medications and surgical attempts had failed to accomplish1! Charlie is one of about 2.5 million people in the U.S. living with epilepsy, one-third of whom also do not respond to anti-seizure medications2. Charlie remained on the diet for five years, and has since been seizure free. The high-fat diet that miraculously stopped Charlie’s seizures is now a standard treatment for epilepsy patients. But this diet and its unexpected success raises a flustering question for scientists: How on earth can fat rewire a brain to prevent seizures?

To begin to answer this question, let’s zoom in to a single cell in Charlie’s brain. In the nucleus of this cell you’ll find DNA. This DNA contains the instructions for Charlie’s body in the form of “genes.” Each cell contains his entire copy of genes, including the brain genes. But if you look a little bit closer, you’ll notice that there are other molecules interacting with and modifying these genes. These molecules act like signals to the cell’s machinery, telling it when to turn a gene “on” or “off”. These modifications are added to the DNA, but they never actually change the DNA sequence. The Greek prefix “epi” means on, above, or nearby, so these modifications are called “epigenetic,” and they allow the cell to turn genes on or off in response to its environment. As the bridge between genes and environment, epigenetics is a promising explanation in solving the mystery of how the high fat diet can prevent seizures. This opened up a door into a new world of epilepsy research, one that would now focusheavily on better understanding the role of the environment and not just genes in epilepsy and its treatment.

Scientists have found that one way in which epigenetics is involved in epilepsy is DNA methylation. We can think of our genes as street traffic. When genes are “on”, they have a green light. DNA methylation is a tag that is added to DNA that acts like a red light at a stoplight, turning the gene “off” (Figure 1). Interestingly, studies show that the DNA methylation tags are different in the brains of epileptic rats. In a recent study, scientists found too many red lights in the brains of epileptic rats when they should have been green lights, so genes that should have been “on” were now “off”3. So now that there are known epigenetic differences in patients with epilepsy, how can this information be used to help treat real people like Charlie and the other 2.5 million people suffering from epilepsy?

The scientists’ solution? High fat diet! One recent study looked into the possibility that DNA methylation might play a role in the high fat diet’s effect of preventing epilepsy. Scientists wanted to know how they could turn red lights back into green lights to help these patients. They haven’t found a connection between high fat and the methylation tags of specific genes, but they are working towards answers.

Figure 1: DNA Methylation, (modified from https://atlasofscience.org/dna-methylation-markers-in-colorectal-cancer-state-of-the-art/)

The same diet that stopped Charlie’s seizures was able to fix the methylation tags in epileptic rats and turn their red lights back into green lights3. At the present time, it is thought that the high-fat diet causes an increase in a molecule called adenosine. We can think of adenosine molecules as people in a parade through the streets. Even though the traffic lights had been red previously, turning the genes “off” via methylation tags, this parade effectively turns the traffic light green again, allowing traffic to move regardless of the light’s instructions. Therefore, genes that were “off” are now back “on” again. This can help return high levels of methylation tags back to healthy levels in epileptic patients. In another recent study, researchers fed epileptic mice a high-fat diet and then reversed their diet back to normal to observe the long term effects on their brains. They saw that 2 months later, there were still less methylation tags in the part of the brain affected by epilepsy, and the animals had fewer seizures even up to six months after4. This shows that not only can the high-fat diet improve epilepsy treatment, but also that these effects can be long-lasting. These findings are consistent with Charlie’s experience, as he no longer eats a high-fat diet and has not had a seizure in over two decades. Eventually, this work could translate into patients not having to consistently maintain this high fat diet that comes with many other health consequences.

Like DNA methylation, microRNAs (miRNA) are another likely epigenetic culprit in epilepsy. miRNAs are molecules that are like construction, so even if the light is green, you still can’t get where you need to go, causing the gene to be effectively “off”. Scientists have found that there are more miRNAs in the epileptic rat brain than there should be, so more genes are blocked by this construction, turning more genes “off”5. One of the miRNAs that scientists found to be upregulated in epilepsy is miR-134 . These scientists’ findings suggest that miR-134 is partially responsible for causing seizures to recur.

Other potential avenues of treatment taking advantage of these different epigenetic features are also being investigated. The same group that found miR-134 to be increased in epilepsy found that a synthetic molecule called an “antagomir” acts like a detour through the construction, building a different path for the gene so that it can be turned “on” again. This antagomir can block miR-134 and reverse the effects of miR-134. Cells typically show more wear and tear in the brain of a patient with epilepsy, with more cells dying and becoming disorganized. However, upon providing a detour for the DNA by treating with the antagomir, they found the brains were healthier, with less neuronal damage and cell death. Treating with this antagomir also caused a decrease in the number of seizures within a two week period, and there was even an increase in the number of seizure-free days still at two months after treatment6.

Let’s return to Charlie now, and we can see that the distinction between “nature” and “nurture” has become quite fuzzy. Conditions like Charlie’s epilepsy are ones in which your environment, for example what you eat, can directly affect your DNA and how it relays messages throughout the cells in your body. Patients like Charlie have different methylation tags on their DNA turning traffic lights red as well as more miR-134 causing construction, which both work to turn genes “off”. In acknowledging the intertwining factors that impact diseases like epilepsy, we can begin to target the “nurture” using what “nature” we do know.

References

  1. Baruchin, A. (2008, May 06). Evidence a High-Fat Diet Works to Treat Epilepsy. Retrieved March 20, 2018, from http://www.nytimes.com/2008/05/06/health/research/06epil.html
  2. Holland, K. (2014, October). Epilepsy: Statistics, Facts and You. Retrieved March 20, 2018,from https://www.healthline.com/health/epilepsy/facts-statistics-infographic
  3. Kobow, K., Kaspi, A., Harikrishnan, K. N., Kiese, K., Ziemann, M., Khurana, I., Fritzsche, I., Hauke, J., Hahnen, E., Coras, R., Muhlebner, A., El-Osta, A., Blumcke, I. (2013). Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathologica, 126(5), 741-756.
  4. Lusardi, T. A., Akula, K. K., Coffman, S. Q., Ruskin, D. N., Masino, S. A., & Boison, D. (2015). Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats. Neuropharmacology, 99, 500–509.
  5. Gorter, J.A., Iyer, A., White, I., Colzi, A., Van Vliet, E.A., Sisodiya, S., Aronica, E. (2013). Hippocampal subregion-specific microRNA expression during epileptogenesis in experimental temporal lobe epilepsy. Neurobiology of Disease, 62, 508-520.
  6. Jimenez-Mateos, E. M., Engel, T., Merino-Serrais, P., McKiernan, R. C., Tanaka, K., Mouri, G., Henshall, D. C. (2012). Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nature Medicine, 18(7), 1087–1094.