USF Disease Warriors Explore New Use For Research

Two USF researchers manning a metabolic assault on debilitating diseases such as ALS (often referred to as Lou Gehrig's Disease), epilepsy and even brain cancer are attracting interest from an unexpected potential partner.

The U.S. Department of Defense and Office of Naval Research (ONR) is interested in the medical research by Drs. Csilla Ari and Dominic D'Agostino for its potential to increase the physical and cognitive performance of war fighters.

For example: The Navy has a problem with deep-water divers and seizures, especially when they're using a diving apparatus known as a re-breather to eliminate bubbles. Closed-loop re-breathers require a diver to breathe highly concentrated oxygen, which then makes them more vulnerable to seizures. This oxygen-toxicity problem puts limits on Special Ops diving when the ability to go unnoticed is paramount.

An anti-seizure drug is an option, however, it may limit diver performance and produce nasty side effects. Synthetic ketone bodies, the subjects of the USF researchers, on the other hand, may enhance performance, while significantly lowering the seizure risk.

Brains of the Operation

Dr. Csilla Ari speaks with a residual Hungarian accent -- a gift from her upbringing near Budapest. In addition to her Eastern European intonations, she also brings an unflagging work ethic to her endeavors. She's embarked upon more than 400 global diving expeditions, while somehow finding the time to develop expert language competencies in English, Spanish, Hungarian and Esperanto.

Formally trained in zoology and neuroscience, Ari cut her academic teeth studying the brains of cartilaginous fishes (think: sharks and rays), while taking a particular interest in the brains of giant ocean mantas rays. That experience, coupled with an article in National Geographic where she is shown diving with mantas 3-4 times her size, helped her land at the Byrd Alzheimer’s Research Center at USF under the tutelage of a recent Harvard University transplant - the celebrated researcher, Dr. Huntington Potter. 

Her research in Potter’s lab required her to attend a confocal microscope training. Once there, she struck up a conversation with D'Agostino around diving -- an interest they both share. Soon after, a research proposal was written, and a project was underway. 

D'Agostino is an assistant professor of Molecular Pharmacology and Physiology in the Morsani College of Medicine at USF. He's anything but your typical science geek. For starters, he stands about 6'1'' and has Popeye arms, and in addition to being a fitness enthusiast, he's also an avid diver.

The project they launched together is an extension of D'Agostino's research into a relatively unknown, yet rapidly advancing area of medical science involving water-soluble energy metabolites known as "ketone bodies.'' 

Excited by the potential of the science, yet lacking statistical evidence, an ALS Foundation (Winning the Fight) funded a pre-clinical study to test a ketone-based metabolic therapy in D'Agostino's lab. Ari is currently working on testing the efficacy of this metabolic therapy, known as the "Deanna protocol'' for ALS. The goal is extension of life for those afflicted with ALS, and while the study is not yet complete, the preliminary results may be worthy of excitement.

If you've ever heard of the Atkins weight loss plan, then the concept of a ketogenic diet may be familiar. Under the conditions of a normal diet such as the standard food pyramid you grew up with in grade school, the brain is using 100 percent glucose for fuel.

If you cut out the carbs, however, your brain won't have sufficient glucose to work with, so it enlists your liver to convert fatty acids into a brain-friendly type of fuel known as a ketone.

It's like your brain's plan B for dinner. No access to carbs? No problem. Break out the ketones!

But don't worry; you don't need to starve yourself in order to get the benefits of a ketosis. To some extent, that's the real genius behind D'Agostino's work. He and his colleagues have figured out a way to make synthetic ketone bodies. Essentially, they're penning a new chapter in grandma's cookbook, and they want to swap out the starches & potatoes section, for a new chapter on nutrition for debilitating disorders, including brain cancer.

The Rub

If given a choice between dining on ketones or carbs, your brain will default to carbs every  time. To further complicate things, when it comes to sticking with a ketogenic diet, human compliance tends to be low. For a healthy individual, this might not be all that enticing. However, for those with any of the following conditions, a ketogenic treatment option may be the best option:

  • Seizure disorders (including status epilepticus)
  • Cancer (including untreatable stage 4 and metastatic cancer)
  • Alzheimer's disease (cognitive and physical enhancement)
  • Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS)
  • Metabolic syndrome (glucose control)
  • Pediatric care (enteral and parenteral nutrition)
  • Weight loss and nutritional support for therapeutic fasting
Medical Moon Shot

"When hunting for cancer, we can look for elevated rates of glucose consumption and then image the tumor with a fluorescent dye that outlines where the glucose consumption is very high,'' says D'Agostino. "Cancer cells use excessive sugar for energy and that’s why we can image them.''

The exciting news is that cancer cells are unable to use ketones for energy, and therefore, they are subject to starvation. D'Agostino believes that there is great potential for patients combining a ketogenic diet with additional intake of synthetic ketones.

Remember their shared diving background? Ari and D'Agostino have also included hyperbaric oxygen treatment into the mix in an attempt to reverse the conditions that allow cancer cells to grow so aggressively in the first place.

This hybrid strategy of metabolic therapy (the ketogenic diet) and hyperbaric oxygen treatments has great potential because cancer cells receiving too much oxygen can be tricked into killing themselves, while preserving the healthy cells around them.

This might seem pie-in-the-sky at first, however, it hits home for Ari. In 2012, her father was diagnosed with colon cancer, and, after consulting with physicians (including his daughter and D'Agostino) he chose a post-surgery ketogenic diet strategy instead of chemotherapy.

With a glowing smile, Ari says that he's experienced a full recovery. His blood results are improving and he says that he feels 15 years younger, mentally and physically. He's running and swimming and leading a life that no doctors considered possible after his diagnosis.

D'Agostino also describes his consultations with patients who've been diagnosed with stage 4 glioblastoma brain tumors (the worst kind); some are using the ketone strategy as a standalone treatment, while others are using it as a complement to chemotherapy because it sensitizes the tumor to chemo, and reduces side effects.

Then there's the story of Dr. Fred Hatfield. Diagnosed by three oncologists, and given three months to live, he embraced the calorie-restricted ketogenic diet and starved his cancer. He's been cancer free for over a year.

Alzheimer's, Too

Maybe you saw the Tampa Bay Times article about Dr. Mary Newport lessening the impact of her husband's Alzheimer's disease by giving him a regimen of coconut oil? D'Agostino works with Newport, and mentions that the closest thing Mother Nature produces to synthetic ketones is, you guessed it: extra virgin coconut oil. The theory is the same: energizing brain cells with ketones. D'Agostino cautions that not everyone responds so dramatically, however, the approach really does seem to slow the growth of cancer cells under many conditions.

"The field is rapidly developing,'' says D'Agostino. "When I got into this in '08, the only person I could find online was Dr. Thomas Seyfried, the pioneer of metabolic therapy for cancer. Since then, the research has exploded and there are teams of scientists and clinicians working on it all over the world.''

Science, Meet Entrepreneurship

D'Agostino is one of two people in the United States developing and testing ketone esters. Ketone esters are very difficult to make because the pre-cursors are expensive and the organic chemistry takes some serious brainpower to navigate. Think of it as a delivery vehicle, but a really cleverly designed vehicle that breaks down and turns into ketone itself. As a result, you get maximum bang for the buck, and the process happens in a very controlled and predictable way. For their efforts, D'Agostino and his colleagues have been awarded provisional patents for the "composition of matter'' (what it is and how it's made) and also a "use patent'' (for their intended application of the technology).

Here's where it gets even more interesting. Their ketone ester is less like a drug, and more like a synthetic food; it's a source of calories, and it's really difficult to classify it as a drug for that reason. When compared to a standard pill, people will have to take relatively large volumes of the Ketone Ester for it to work. For example, the average user may have to drink at least shot glass of it, and high-performance athletes will end up drinking half a liter of it.

In a way, this may be a saving grace for the Ari/D’Agostino vision. If it's regulated as a drug, they'll have to compete with the cancer treatment industry -- an industry with entrenched players, and billions of dollars at stake. If it's classified as food or "GRS'' (generally recognized as safe), it will be categorically different from a pharmacological drug, production and development costs will be drastically lower, and it will eligible for sale over the counter.

The Magnet

There is no such thing as an innovation hot bed without a local academic research institution. The University of South Florida system plays a key role in this equation for the Tampa Bay region.

"Research and innovation have become very inherent in our culture as we've transitioned into a major research institution over the past decade,'' says Dr. Paul Sanberg, USF senior VP for Research and Innovation. "We have focused on creating a collaborative, interdisciplinary environment where faculty members like Dr. D'Agostino can do their best work.'' Sanberg also cites technology transfer as a key goal of the institution and believes that patenting and bringing scientific discoveries of USF researchers to market is a priority.

"You can see the results in our rankings,'' says Sanberg. "Last year, USF was ranked for the second year in a row in the top 10 among universities worldwide for U.S. patents. We are more and more being seen as a place that is creating real world solutions to real world problems.''

Nathan Schwagler is a freelance journalist, creativity researcher and visiting instructor of entrepreneurship at USF St. Petersburg who will buy you a cup of coffee or a delicious pint if you promise to tell him something interesting and on the record. Comments? Contact 83 Degrees.
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